WO2021032088A1 - L-赤型生物蝶呤类化合物的制备方法 - Google Patents

L-赤型生物蝶呤类化合物的制备方法 Download PDF

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WO2021032088A1
WO2021032088A1 PCT/CN2020/109818 CN2020109818W WO2021032088A1 WO 2021032088 A1 WO2021032088 A1 WO 2021032088A1 CN 2020109818 W CN2020109818 W CN 2020109818W WO 2021032088 A1 WO2021032088 A1 WO 2021032088A1
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formula
compound represented
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compound
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French (fr)
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荣彬
赵立志
李巍
任毅
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Shanghai Forefront Pharma Co Ltd
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Shanghai Forefront Pharma Co Ltd
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Priority claimed from CN201910764541.4A external-priority patent/CN112390800B/zh
Priority claimed from CN202010806347.0A external-priority patent/CN114075234B/zh
Application filed by Shanghai Forefront Pharma Co Ltd filed Critical Shanghai Forefront Pharma Co Ltd
Priority to US17/636,193 priority Critical patent/US11878989B2/en
Priority to EP20855543.3A priority patent/EP4019523A4/en
Priority to CA3147838A priority patent/CA3147838C/en
Priority to KR1020227008537A priority patent/KR102673606B1/ko
Priority to JP2022511260A priority patent/JP7587862B2/ja
Publication of WO2021032088A1 publication Critical patent/WO2021032088A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of medicine preparation, in particular to a preparation method of L-erythro-type biopterin compounds.
  • Formula (I) indicates that L-erythrobiopterin compounds are important intermediates of most drugs, especially sapropterin drugs.
  • NOS nitric oxide synthase
  • hydrochloride ie sapropterin dihydrochloride
  • the main method for synthesizing sapropterin dihydrochloride is obtained by hydrogenation reduction of the compound represented by formula (Ia).
  • the thioacetal produced by the reaction of L-rhamnose as a raw material with ethyl mercaptan is oxidized to sulfone, and one carbon is removed by alkali treatment to obtain 5-deoxy-L-arabinose (D).
  • 5-deoxy-L-arabinose is then reacted with 2,4,5-triamino-6-hydroxypyrimidine (TAP) to produce L-erythrobiopterin.
  • TAP 2,4,5-triamino-6-hydroxypyrimidine
  • the method is to first treat 5-deoxy-L-arabinose (D) with phenylhydrazine and then with acetic anhydride to convert it into the corresponding acetophenhydrazone (G). It is then cyclized with TAP, which does not undergo separation but immediately undergoes oxidation to obtain acetylated L-erythro-type biopterin. Further deprotection to obtain L-erythro-type biopterin.
  • the present invention provides a method for preparing L-erythro-biopterin compounds, which has high production efficiency, low cost, and environmental protection, and is suitable for industrial production.
  • the first reagent is boric acid ester or boric acid
  • the second reagent is a chiral amino alcohol
  • W is NH x , X is 0, 1 or 2;
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 and R 3 are each independently a hydrogen atom or an amino protecting group; and R 2 and R 3 can form a cyclic lactimide group together with the nitrogen atom connected to R 2 and R 3;
  • R 4 is -COOR 5 , -CONR 6 or -CN;
  • R 5 and R 6 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Substituted heteroaryl;
  • Z is a hydrogen atom or a leaving group
  • Y is O or does not exist.
  • the preparation method of the above intermediate includes the following steps:
  • the compound to be resolved, the first reagent, the second reagent, and an aprotic solvent are mixed, heated to reflux, and after the reaction is completed, an intermediate of the structure represented by formula (IVa-1) or formula (IVa-2) is obtained by crystallization; wherein ,
  • the compound to be resolved is a mixture of formula (IVa) and formula (IVa');
  • a preparation method of L-erythro-type biopterin compound said L-erythro-type biopterin compound has a structure represented by formula (I), and the L-erythrotype represented by formula (I) Biopterin compounds are prepared by the compound represented by formula (II) or the compound represented by formula (III) through dihydroxylation reaction;
  • Y is O or does not exist
  • Z is a hydrogen atom or a leaving group
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 and R 3 are each independently a hydrogen atom or an amino protecting group; and the R 2 , R 3 may form a cyclic imide group together with the nitrogen atom connected to the R 2 , R 3;
  • R 4 is -COOR 5 , -CONH 6 or -CN;
  • R 5 and R 6 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Substituted heteroaryl;
  • R 7 is -OH or -NH 2 .
  • the L-erythro-type biopterin compound prepared by the above-mentioned L-erythro-type biopterin compound preparation method prepared by the above-mentioned L-erythro-type biopterin compound preparation method.
  • a preparation method of sapropterin medicine includes the following steps:
  • the L-erythro-biopterin compound represented by formula (I) is prepared by using the above-mentioned preparation method of L-erythro-biopterin compound;
  • the L-erythrobiopterin compound represented by formula (I) is hydrogenated and reduced.
  • L-erythro-type biopterin compound in the preparation of a medicine for treating phenylketonuria and hyperphenylalanine.
  • Figure 1 is a single crystal image of compound 3a.
  • a leaving group should be understood as a common meaning in the art, and refers to an atom or a functional group that can be separated from a larger molecule in a chemical reaction. It is understandable that, unless otherwise specified, the compound containing a leaving group participates in the reaction steps, including the introduction step and removal step of the leaving group. The introduction and removal of the leaving group can be based on the used leaving group. The specific type of the group adopts common methods in this field and is not particularly limited here.
  • an amino protecting group should be understood as a common meaning in the art, and refers to an amino protecting group. It is understandable that, unless otherwise specified, the protective group-containing compound participates in the steps of the reaction, including the step of introducing the protective group and the step of removing the protective group. The introduction of the protective group and the removal of the protective group can be based on the protection adopted. The type of the base adopts common methods in this field, and is not specifically limited here.
  • substituted or unsubstituted means that the defined group may be substituted or unsubstituted.
  • the defined group when the defined group is substituted, it should be understood to be optionally substituted by a group acceptable in the art, including but not limited to: an alkyl group having 1 to 20 C atoms, a ring having 3-20 ring atoms Alkyl groups, heterocyclic groups with 3-20 ring atoms, aryl groups with 5-20 ring atoms, heteroaryl groups with 5-20 ring atoms, silyl groups, carbonyl groups, alkoxycarbonyl groups, aryloxy groups Carbonyl, carbamoyl, haloformyl, formyl, -NRR', cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, hydroxyl, trifluoromethyl, nitro Or halogen, and the above-mentioned groups can also be further substituted with substituents acceptable in the
  • a site without a stereo configuration should be understood to include a variety of stereo configurations that can exist stably.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups.
  • the C 1 -C 6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylp
  • the C 1 -C 4 alkyl group refers to an alkyl group containing 1 to 4 carbon atoms.
  • the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.
  • Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbyl substituent.
  • a 3-8 membered cycloalkyl group is meant to include 3 to 8 carbon atoms.
  • the 3-8 membered monocyclic cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , Cycloheptatrienyl, cyclooctyl, etc.
  • Polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls. Cycloalkyl groups may be optionally substituted with one or more substituents.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2)
  • the heteroatom is preferably a nitrogen or oxygen heteroatom; but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • a 4-10 membered heterocyclic group means that the ring contains 4 to 10 ring atoms, of which 1-3 are heteroatoms; preferably, the heterocyclyl ring contains 5 to 6 ring atoms, of which 1-2 are heteroatoms.
  • the monocyclic heterocyclic group is dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or homopiperazinyl, and the like.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably phenyl and naphthyl , Phenyl is most preferred.
  • the aryl ring can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, and the aryl can be substituted or unsubstituted.
  • Heteroaryl refers to aryl groups containing heteroatoms, where heteroatoms include oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted.
  • the substituent "amino” includes primary, secondary and tertiary amino groups.
  • the amino group includes -NR 16 R 17 , wherein R 16 and R 17 are hydrogen atoms or any optional groups, such as H, substituted or unsubstituted Linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic group, or substituted or unsubstituted heteroaromatic Groups etc.
  • sil group refers to -Si(alkyl) 3 , and the three alkyl groups connected to silicon may be the same or different from each other.
  • Cyclic lactimide finger The number of ring atoms contained in ring A is not particularly limited, and may be a 5-membered ring, a 6-membered ring, etc., such as glutarimide, succinimide, and the like.
  • One embodiment of the present invention provides a formula (IVa-1), formula (IVa-2), formula (IVa-3), formula (IVa-4), formula (IVa) or formula (IVa') Intermediate:
  • the first reagent is boric acid ester or boric acid
  • the second reagent is a chiral amino alcohol, a chiral amino acid, a chiral amino acid ester or a chiral diol;
  • W is O or NH x , and X is 0, 1 or 2;
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 and R 3 are each independently a hydrogen atom or an amino protecting group; and R 2 and R 3 can form a cyclic lactimide group together with the nitrogen atom connected to R 2 and R 3; wherein, the amino protecting group Including but not limited to: -Boc, -Cbz, -Ac, -Ts, -Ms, -Bz, -Bn, -PMB, or schiff base.
  • R 4 is -COOR 5 , -CONR 6 (ie CONHR 6 ) or -CN;
  • Z is a hydrogen atom or a leaving group; wherein, the leaving group includes but is not limited to: halogen (for example: Cl, Br, I), OSO n R 9 , OCOR 10 or OPO 2 R 11 ; R 9 , R 10 Or R 11 is each independently selected from: -CF 3 , alkyl, phenyl, or alkyl-substituted phenyl (for example, tolyl), n is 0, 1 or 2, and the silyl group may be a silyl group or the like.
  • the leaving group includes but is not limited to: halogen (for example: Cl, Br, I), OSO n R 9 , OCOR 10 or OPO 2 R 11 ;
  • R 9 , R 10 Or R 11 is each independently selected from: -CF 3 , alkyl, phenyl, or alkyl-substituted phenyl (for example, tolyl), n is 0, 1 or 2, and the silyl group may be a sily
  • Y is O or does not exist.
  • R 1 is selected from C 1-6 alkyl, 3-8 membered cycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, TMS, TBS, or -CH 2 X; X is a leaving group. In one embodiment, R 1 is selected from C 1-6 alkyl, cyclopropyl, phenyl, pyridyl, TMS, TBS, or -CH 2 X; X is a leaving group. In one embodiment, R 1 is methyl.
  • R 5 and R 6 are each independently a hydrogen atom, or a substituted or unsubstituted C 1-20 alkyl group. Wherein, when C 1-20 alkyl is further substituted, the substituent may be C 1-6 alkyl, 3-8 membered cycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, hydroxyl, halogen , Amino, cyano or C 1-4 alkoxy.
  • R 5 and R 6 are each independently a hydrogen atom, or a substituted or unsubstituted C 1-6 alkyl group.
  • the substituent may be C 1-4 alkyl, 3-8 membered cycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, hydroxyl, halogen, amino , Cyano or C 1-4 alkoxy.
  • R 4 is -CN.
  • Y is absent, Z is a hydrogen atom, R 4 is a cyano group, and R 1 is a methyl group.
  • the R 8 group is determined according to the selected borate; further, R 8 is a substituted or unsubstituted alkyl group; further, R 8 is a substituted or unsubstituted C 1-10 alkyl group, or substituted or unsubstituted C 3-10 cycloalkyl group; further, R 8 is a substituted or unsubstituted C 1-8 alkyl group or a substituted or unsubstituted C 3-8 cycloalkyl group; further, R 8 is a substituted or Unsubstituted C 1-6 alkyl or C 3-6 cycloalkyl;
  • the borate in the present invention can be any acceptable borate reagent in the art; in one embodiment, the borate is selected from: trimethyl borate, triethyl borate, triiso borate Propyl ester or isopropanol borate pinacol ester; in addition, the chiral amino alcohol in the present invention can be any acceptable chiral amino alcohol in the art; in one embodiment, the chiral amino alcohol is selected from: L- Phenylglycol, L-prolinol, L-amphetamine, (S)-(-)- ⁇ , ⁇ -diphenylprolinol, quinine or cinchoni to obtain a higher ee value and Yield of the desired configuration product.
  • the chiral amino acid in the present invention can be any acceptable chiral amino acid in the art; in one embodiment, the chiral amino acid is selected from: L-phenylalanine, L-alanine, L-proline, Chiral amino acids such as L-leucine, L-valine and L-phenylglycine.
  • the chiral amino acid ester in the present invention can be any acceptable chiral amino acid ester in the art; in one embodiment, the chiral amino acid ester is selected from: L-phenylalanine ester, L-alanine ester, L -Proline ester, L-leucine ester, L-valine ester, L-phenylglycinate and other chiral amino acid esters, the selected esters can be alkyl esters or aryl esters; the hand in the present invention
  • the chiral diol can be any acceptable chiral diol in the art; in one embodiment, the chiral diol is a diol containing 1,2-diol or 1,4-diol chiral structure; further, The chiral diol is selected from: chiral BINOL, chiral hydrogenated benzoin, (trans)-9,10-dihydroxy-9,10-dihydrophenanthrene, or (cis)-9,10-dihydroxy- 9,
  • the second reagent is a chiral amino alcohol to obtain a better resolution effect.
  • At least one of the carbon atoms connected to R 20 and R 21 and the carbon atoms connected to R 22 and R 23 is a chiral carbon
  • R 20 , R 21 , R 22 and R 23 are each independently selected from: H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted quinyl Linyl
  • R 24 and R 25 are each independently selected from: H, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted phenyl;
  • R 23 and R 24 may be connected to each other to form a ring structure
  • R 23 , R 24 and R 25 may be connected to each other to form a bridged ring structure.
  • cyclic structure in the present invention includes monocyclic rings (such as aromatic rings, heterocyclic rings), spiro rings, bridged rings and the like.
  • R 20 , R 21 , R 22 and R 23 are each independently selected from: H, phenyl, C 1-6 alkyl or alkoxy substituted quinolinyl;
  • R 24 and R 25 are each independently selected from: H, C 1-6 alkyl or phenyl;
  • R 23 and R 24 may be connected to each other to form a five-membered nitrogen-containing heterocyclic ring
  • R 23 , R 24 and R 25 may be connected to each other to form structure.
  • the present invention also provides a preparation method of the above-mentioned intermediate, including the following steps:
  • the compound to be resolved, the first reagent, the second reagent, and an aprotic solvent are mixed, heated to reflux, and after the reaction is completed, an intermediate of the structure represented by formula (IVa-1) or formula (IVa-2) is obtained by crystallization; wherein ,
  • the compound to be resolved is a mixture of formula (IVa) and formula (IVa');
  • reaction process of the above reaction should not be understood as a limitation of the present invention.
  • the above reaction can firstly cause the compound to be resolved and the first reagent to react to form the structure represented by formula (IVa-3) and formula (IVa-4) The mixture, and then the mixture of the structure represented by the formula (IVa-3) and the formula (IVa-4) is reacted with the second reagent to prepare the intermediate of the structure represented by the formula (IVa-1) or the formula (IVa-2).
  • the mixture of the structures represented by the formula (IVa-3) and the formula (IVa-4) can be separated or not separated, and it should be understood that both are within the protection scope of the present invention.
  • the aprotic solvent in step S001 is selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (ACN), toluene, benzene, 1,4-dioxide One or more of hexacyclic (1,4-diox) and acetone (Acetone) to increase the solubility difference of intermediates with different configurations, and to make the intermediates with the desired configuration (Formula (IVa-1)) Precipitating in the form of precipitation further reduces the difficulty of separation, and at the same time increases the yield and ee value of the product; furthermore, the aprotic solvent is selected from acetonitrile.
  • aprotic solvent per 1g of the compound to be resolved; furthermore, add 20-80mL aprotic solvent per 1g of the compound to be resolved; furthermore, add 30- to each 1g compound to be resolved. 60mL aprotic solvent.
  • the diastereomer is introduced into a new chiral center to obtain a pair of diastereomers, and finally the resolution can be achieved by crystallization; and the formula (IVa-1 ) Is a key intermediate for the preparation of L-erythro-type biopterin compounds, which are precipitated in solid form in most conventional aprotic solvents, which can significantly reduce the difficulty of separation and increase the ee value of the product; for example:
  • the specific reaction mechanism is as follows:
  • the first reagent is boric acid ester or boric acid
  • the second reagent is a chiral amino alcohol, a chiral amino acid, a chiral amino acid ester, or a chiral diol; further, the second reagent is a chiral amino alcohol;
  • the first reagent and the second reagent are as described above and will not be repeated here.
  • the borate is triisopropyl borate
  • the chiral amino alcohol is L-prolinol
  • the solvent is acetonitrile
  • the molar ratio of the compound to be resolved to the borate is less than or equal to 1;
  • the molar ratio of the first reagent to the second reagent is 1:(1.0-1.3); further, the molar ratio of the first reagent to the second reagent is 1:1;
  • step S002 the order of reagent addition in step S002 is not particularly limited and should not be construed as a limitation of the present invention.
  • the first reagent can be added first and then the second reagent can be added, or the first reagent and the second reagent can be added simultaneously
  • the reaction time of step S002 is not particularly limited, and it is adjusted according to the type of reagents used, which should not be understood as a limitation of the present invention;
  • step S002 the first reagent is added to react for 25 minutes to 50 minutes, and then the second reagent is added to react for 8 hours to 24 hours;
  • Crystallization After the reaction is completed, the temperature of the reaction liquid is lowered, and solids are precipitated for solid-liquid separation, and the desired configuration product is a solid phase product or a liquid phase product.
  • the above-mentioned resolution reagent group composed of the first reagent and the second reagent has mild conditions and a wide range of requirements for the quality and purity of the substrate.
  • the ee value dr value and purity of the product after the resolution are extremely high, even if the purity of the compound to be resolved is 70 % Can still be split, and the purity of the obtained product can be increased to 99%, effectively achieving the effect of one-pot split and purification;
  • the obtained intermediates of the structure represented by the formula (IVa-1) or the formula (IVa-2) are all solid, the structure is stable, the quality control, the production, and the storage and transportation are easy.
  • the present invention also relates to a chiral resolution reagent set, comprising a first reagent and a second reagent, the first reagent is boric acid ester or boric acid; the second reagent is chiral amino alcohol, chiral amino acid, chiral amino acid ester or Chiral diols; wherein, the above reagents are as described above and will not be repeated here.
  • the invention also relates to a chiral resolution reagent set, which is composed of chiral amino alcohol and boric acid ester.
  • the above-mentioned chiral resolution reagent group is composed of boric acid ester and L-proline. Further, the aforementioned chiral resolution reagent group is composed of boric acid ester and L-phenylglycinol. Further, the aforementioned chiral resolution reagent group is composed of boric acid ester and (S)-(-)- ⁇ , ⁇ -diphenylprolinol. Further, the aforementioned chiral resolution reagent group consists of boric acid ester and quinine. Further, the aforementioned chiral resolution reagent group consists of boric acid ester and cinchoni.
  • the invention also relates to the application of the aforementioned chiral resolution reagent set in the preparation of L-erythro-type biopterin compounds.
  • L-erythrobiopterin compound in one embodiment of the present invention is mainly prepared by the compound represented by formula (II) or the compound represented by formula (III) through dihydroxylation reaction.
  • L-erythro-type biopterin compounds have the structure shown in formula (I):
  • Y is O or does not exist; in one embodiment, Y does not exist.
  • Z is a hydrogen atom or a leaving group; wherein, the leaving group includes but is not limited to: halogen (for example: Cl, Br, I), OSO n R 9 , OCOR 10 or OPO 2 R 11 ; R 9 , R 10 Or R 11 is each independently selected from: -CF 3 , alkyl, phenyl, or alkyl-substituted phenyl (for example, tolyl), n is 0, 1 or 2, and the silyl group may be a silyl group or the like.
  • the leaving group includes but is not limited to: halogen (for example: Cl, Br, I), OSO n R 9 , OCOR 10 or OPO 2 R 11 ;
  • R 9 , R 10 Or R 11 is each independently selected from: -CF 3 , alkyl, phenyl, or alkyl-substituted phenyl (for example, tolyl), n is 0, 1 or 2, and the silyl group may be a sily
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2 and R 3 are each independently a hydrogen atom or an amino protecting group, wherein the amino protecting group includes but not limited to: -Boc, -Cbz, -Ac, -Ts, -Ms, -Bz, -Bn, -PMB , Or schiff base.
  • R 2 and R 3 can form a cyclic lactimide group together with the nitrogen atom connected to R 2 and R 3, such as glutarimide and succinimide. It is understandable that R 2 and R 3 do not necessarily form a cyclic lactimide group together with the nitrogen atom to which they are connected, and they are selected as required.
  • R 4 is -COOR 5 , -CONR 6 or -CN; in one embodiment, R 4 is -CN.
  • R 5 and R 6 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Substituted heteroaryl.
  • the preparation method of the above-mentioned L-erythro-biopterin compound innovatively uses the olefin compound represented by formula (II) or formula (III) as the raw material, and uses the dihydroxylation reaction to construct the dihydroxy group of the required configuration, which is effective It avoids the use of intermediates such as 5-deoxy-L-arabinose (D), and further avoids the use of ethyl mercaptan with a strong odor, effectively reducing environmental pollution and being green.
  • the olefin dihydroxylation reaction conditions are relatively mild, easy to operate, and the yield is high, and the raw materials of the structure shown in formula (II) or formula (III) are easily available, which can greatly shorten the reaction route, further improve efficiency, and reduce production Cost, suitable for industrial production applications.
  • R 4 is -CHO
  • R 1 is selected from C 1-6 alkyl, 3-8 membered cycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, TMS, TBS, or -CH 2 X; X is a leaving group. In one embodiment, C 1-6 alkyl, cyclopropyl, phenyl, pyridyl, TMS, TBS, or -CH 2 X; X is a leaving group. In one embodiment, R 1 is methyl.
  • R 5 and R 6 are each independently a hydrogen atom, or a substituted or unsubstituted C 1-20 alkyl group. Wherein, when C 1-20 alkyl is further substituted, the substituent may be C 1-6 alkyl, 3-8 membered cycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, hydroxyl, halogen , Amino, cyano or C 1-4 alkoxy.
  • R 7 is -OH or -NH 2 .
  • hydrolysis can be carried out under alkaline conditions to obtain a compound in which R 7 is -OH.
  • dihydroxylation reaction should be conventionally understood in the art, and refers to making the double bond site of the olefin (for example, in formula (II) or formula (III) ) To react to produce ortho-dihydroxy compounds.
  • the methods of dihydroxylation include but are not limited to: Sharpless asymmetric dihydroxylation, basic KMnO 4 dihydroxylation, Fe-catalyzed dihydroxylation or asymmetric epoxidation After hydrolysis and ring opening.
  • Sharpless asymmetric dihydroxylation reaction is used.
  • alkene group in formula (II) or formula (III) can be either a cis structure or a trans structure.
  • the compound represented by formula (II) or formula (III) can be a pure substance, that is, a compound represented by formula (II) or formula (III) containing only cis structure, or only containing trans
  • the compound represented by formula (II) or formula (III) of the structure can also be a mixture, that is, a mixture of a cis structure and a trans structure, and is not particularly limited here (preferably adopting the formula (II) of the cis structure) (Showing compound), chiral separation can be performed after the reaction, and the chiral separation method is not particularly limited, and can be an existing separation method.
  • the cyclization method can use the existing methods, such as: Journal of Organic Chemistry 1987, 52(18), 3997-4000 and Journal of Organic Chemistry 1988, 53(1), 35-38, etc.
  • the step of preparing the L-erythrobiopterin compound represented by formula (I) from the compound represented by formula (II) includes the following steps:
  • the dihydroxylation reaction in step S111 includes, but is not limited to: Sharpless asymmetric dihydroxylation reaction, basic KMnO 4 dihydroxylation reaction, Fe-catalyzed dihydroxylation reaction or asymmetric epoxidation followed by hydrolysis and ring opening, preferably Sharpless asymmetric dihydroxylation reaction.
  • step S111 may include the following steps: the compound represented by formula (IIa), the oxidant, the dihydroxylation reagent, the base and the ligand are mixed for reaction, and the reaction is quenched after the reaction is completed , Separate, get.
  • the reaction is preferably carried out at 0-25°C. After the reaction is completed, the reaction can be quenched with sodium sulfite. After quenching, the insoluble matter is filtered, the organic phase is collected, and the organic phase is chiral separated to obtain a single chiral formula (IVa ) The shown compound (R, S).
  • the dihydroxylation reagent is selected from one or more of OsO 4 , K 2 OsO 4 , OsO 4 hydrate and K 2 OsO 4 hydrate;
  • the oxidizing agent is selected from: K 3 [Fe(CN) 6 ] or NMO And one or more of them; alkali selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, NaOH, KOH, LiOH, NH 4 OH, t-BuONa, t-BuOK, t-BuOLi , Cesium carbonate, triethylamine, diisopropylethylamine, DBU, pyridine and one or more of p-dimethylaminopyridine;
  • the ligand is selected from: (DHQ) 2 PHAL, (DHQD) 2 PHAL, One or more of DHQ-IND and DHQD-IND;
  • the solvent can be one or more of acetone, methanol, ethanol, 1,4-
  • step S111 may also add an osmate ester hydrolyzing agent, and the osmate ester hydrolyzing agent includes but is not limited to methanesulfonamide.
  • the amount ratio of the compound represented by formula (IIa) to the solvent is 1g: (10-100 mL); the molar ratio of the compound represented by formula (IIa) to the oxidant is 1: (0.1%-20%); formula (IIa) )
  • the molar ratio of the compound to the base is 1: (1-10); the molar ratio of the compound of formula (IIa) to the methanesulfonamide is 1: (1-10).
  • step S111 may include the following steps: mixing the compound represented by formula (IIa), the dihydroxylation reagent, the base and the solvent to perform the reaction, and the chiral separation after the reaction is completed, Immediately.
  • the dihydroxylation reagent is KMnO 4 ;
  • the base can be potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, NaOH, KOH, LiOH, NH 4 OH, t-BuONa, t-BuOK, t- One or more of BuOLi, cesium carbonate, triethylamine, diisopropylethylamine, DBU, pyridine and p-dimethylaminopyridine;
  • the solvent is acetone, methanol, ethanol, 1,4-dioxane One or more of, tert-butanol and THF.
  • step S111 may include the following steps: mixing the compound represented by formula (IIa), the dihydroxylation reagent, the catalyst and the solvent to perform the reaction, and the chiral separation is obtained after the reaction is completed. .
  • the dihydroxylation reagent is hydrogen peroxide
  • the catalyst is one or more of Fe(ClO 4 ) 2 , Fe(OTf) 2 , FeCl 2 and FeBr 2
  • the solvent can be acetone, methanol, ethanol, 1,4-bis One or more of oxane, tert-butanol and THF.
  • step S111 may include the following steps: the compound represented by formula (II) is reacted with an epoxidation reagent to obtain an epoxidized intermediate, followed by acid or base ring opening and chiral separation , To obtain the desired dihydroxylated product.
  • the epoxidizing reagent is one or more of m-CPBA, DMDO, salen-Mn(III)/NaOCl;
  • the solvent can be methylene chloride, tetrahydrofuran, 1,4-dioxane, and tert-butanol One or more of them.
  • the acid used for ring opening can be dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, etc., and the base used can be KHCO 3 , K 2 CO 3 , KOH, etc.
  • the "chiral separation" after the above-mentioned dihydroxylation reaction can be separated by a chiral column, or a chemical resolution method can be used for chiral separation.
  • a chiral resolution reagent set is used to separate the compound to be resolved.
  • the chiral resolution reagent group includes a first reagent and a second reagent
  • the first reagent is boric acid ester or boric acid
  • the second reagent is chiral amino alcohol, chiral amino acid, chiral amino acid ester or chiral diol ;
  • the reagents are as described above, and will not be repeated here;
  • step S111 includes the following steps:
  • the chiral resolution reagent set in step S1112 includes a first reagent and a second reagent.
  • the first reagent is boric acid ester or boric acid;
  • the second reagent is chiral amino alcohol, chiral amino acid, chiral amino acid ester or chiral amino acid. Diol; specifically, the resolution method in step S1112 is the preparation method of the intermediate structure represented by the above formula (IVa-1) or formula (IVa-2), which will not be repeated here.
  • L-erythrobiopterin compound represented by formula (I) can be prepared according to the following S112a and S112b;
  • S112a Combine the compound represented by formula (IVa) with The salt undergoes a cyclization reaction to prepare an L-erythro-type biopterin compound represented by formula (I);
  • S112b Combine the compound represented by formula (IVa-1) with The salt undergoes a cyclization reaction to prepare an L-erythro-type biopterin compound represented by formula (I);
  • E is halogen, C 1-4 alkoxy, C 1-4 alkylthio or -NH 2 ; further, E is methoxy, chlorine, methylthio, or -NH 2 ;
  • the compound represented by formula (IVa-1) can quickly release the compound represented by formula (IVa) in a protic solvent, and the The solvent used in the cyclization reaction of the salt is a protic solvent, so the compound represented by formula (IVa-1) can be directly put into the subsequent reaction without dissociation, which can effectively reduce the difficulty of operation, save cost, and pass the ring
  • the chemical reaction can further increase the ee value of the desired configuration product, which has a great application prospect.
  • step S112b the compound represented by formula (IVa-1) is directly used in the subsequent reaction, but it should not be understood as a limitation of the present invention. It is also possible to first use a protic solvent to convert the compound represented by formula (IVa-1) After the compound is processed to obtain the compound represented by the formula (IVa), the compound represented by the formula (IVa) is subjected to a subsequent reaction, at this time, the same step S112a is performed.
  • Salt means to contain
  • the salt may be a salt acceptable in the art, such as hydrochloride and the like. Understandably, the The salt may contain a protecting group acceptable in the art, and it should be understood that all are within the protection scope of the present invention.
  • Step S112a is basically the same as S112b, except that the compound represented by formula (IVa) is used instead of the compound represented by formula (IVa-1) in step S112b.
  • step S112b is taken as an example for further description;
  • step S112b includes the following steps:
  • R 7 is -OH or -NH 2 .
  • the above-mentioned cyclization step includes the following steps: adding Na to MeOH, stirring until the reaction is complete, and adding Salt, protected under N 2 and stirred at room temperature for a predetermined time (preferably 3-10 min). Then, filter the insoluble matter in the system, add the compound represented by formula (IVa-1), heat to reflux, after the reaction is completed, cool to room temperature and stir for 40 min-80 min, and filter the precipitated solid matter.
  • the solvent is a protic solvent, preferably an alcohol solvent, including but not limited to one or more of methanol, ethanol and isopropanol.
  • the base may be one or more of sodium ethoxide, sodium methoxide, t-BuONa, t-BuOK, and t-BuOLi; it is preferably a strong base, such as sodium methoxide and the like.
  • the compound represented by formula (IVa-1) and The molar ratio of the salt is 1:(1 ⁇ 3); the molar ratio of the compound represented by formula (IVa-1) to the base is 1:(2 ⁇ 5); the ratio of the compound represented by formula (IVa-1) to the solvent is 1g: (5-100mL).
  • R 7 is -OH or -NH 2 .
  • the above-mentioned hydrolysis step includes the following steps: suspend the compound represented by formula (I-1) in an alkaline solution, heat to 50°C-100°C, stir for 2h-5h; cool to room temperature, then add acid to adjust the pH To 5-6, crystals are precipitated, filtered and dried to obtain the L-erythro-type biopterin compound represented by formula (I).
  • the alkaline solution may be an inorganic alkaline solution, such as sodium hydroxide solution, potassium hydroxide solution, etc., preferably a sodium hydroxide solution with a mass percentage of 5%-40%.
  • the molar ratio of the compound represented by the formula (I-1) to the base is 1:(5-20), more preferably 1:(5-10).
  • the acid may be an organic acid or an inorganic acid, such as formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, etc., preferably formic acid.
  • the step of preparing the compound represented by formula (I) from the compound represented by formula (II) includes the following steps:
  • step S121 The dihydroxylation reaction in step S121 is the same as step S111, and will not be repeated here.
  • step S122 may include the following steps:
  • the acetylation reagent includes but is not limited to: one or more of acetic anhydride, trimethyl orthoacetate and acetyl chloride; the solvent can be one or more of acetonitrile, THF, dioxane, DCM and MTBEkind and so on.
  • the compound represented by formula (VIIb-1) and/or formula (VIIb-2), nucleophile PPh 3 or Bu 3 P, diisopropyl azodicarboxylate (DIAD) or diacetate azodicarboxylate (DEAD) are dissolved in a solvent for reaction, and after the reaction is completed, the desired product is obtained by separation.
  • Specific reagent combinations include but are not limited to: DEAD/PPh 3 , DIAD/PPh 3 , DEAD/n-Bu 3 P, or DIAD/n-Bu 3 P, etc.
  • R 10 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably R 10 is a substituted or unsubstituted aryl group.
  • the substituent is selected from a C 1-6 alkyl group or a C 1-6 alkoxy group. More preferably R 10 is Indicates the connection site.
  • R 11 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably R 11 is H or C 1-6 alkyl.
  • Step S124 is the same as step S112, and will not be repeated here.
  • the definitions of Y, Z, R 1, R 2 , R 3 , R 4 and R 10 are as described above and will not be repeated here.
  • E is halogen, C 1-4 alkoxy, C 1-4 alkylthio or -NH 2 ; further, E is methoxy, chlorine, methylthio, or -NH 2 ;
  • the olefin in the compound represented by formula (II) has a cis structure
  • the dihydroxylation reaction is used to construct a dihydroxy group to form two chiral centers, and then the highly selective mono-acetylation reaction of adjacent diols is used innovatively.
  • the compound represented by formula (III) can be commercially available raw materials, or can be prepared from the compound represented by formula (II) through a cyclization reaction.
  • the compound represented by formula (II) and The salt undergoes cyclization.
  • the step of preparing the L-erythrobiopterin compound represented by formula (I) from the compound represented by formula (III) includes the following steps:
  • reaction reagents and reaction conditions of the dihydroxylation reaction in step S211 are as described in step S111, and will not be repeated here.
  • the above-mentioned chiral resolution reagent set can also be used for resolution in step S211.
  • the resolution method and chiral resolution reagent set are as described above, and only the compound to be resolved in step S111 needs to be replaced by the formula ( III)
  • the compound to be resolved produced after the dihydroxylation reaction of the indicated substrate ( The mixture of) is sufficient, and will not be repeated here, and it should be understood that all are within the protection scope of the present invention.
  • S212 The compound represented by formula (I-1) is hydrolyzed under alkaline conditions (such as sodium hydroxide and the like) to obtain L-erythrobiopterin compounds represented by formula (I).
  • alkaline conditions such as sodium hydroxide and the like
  • Step S212 is the same as step S1122, and will not be repeated here.
  • the compound represented by formula (III) can first undergo dihydroxylation reaction to form a dihydroxy group, then undergo acetylation reaction, and then carry out Mitsunobu reaction to obtain the The product to be configured.
  • the specific methods and steps are the same as S121 to S124, and will not be repeated here.
  • the olefin in the compound represented by formula (III) has a cis structure
  • the dihydroxylation reaction is used to construct the dihydroxy group to form two chiral centers, and then the highly selective diol monoacetylation reaction is used innovatively to achieve One of the hydroxy groups is acetylated, and the other hydroxy group is reversed by the Mitsunobu reaction, and the desired product can be obtained by hydrolysis, which greatly increases the selection range of raw materials and can choose relatively cheap raw materials.
  • the acetylation reaction and Mitsunobu reaction and other steps have high yields, and the by-products of mono-acetylation and the by-products that did not turn over in the Mitsunobu reaction can also be recovered as raw materials by simple hydrolysis and reused, ensuring that The economy of the entire route meets the requirements of industrial production.
  • the compound represented by the formula (V), the catalyst and the solvent are mixed and reacted under a hydrogen atmosphere. After the reaction is completed, it is filtered and concentrated to obtain the compound represented by the formula (IIa) with a cis structure.
  • the catalyst can be selected from one or more of Lindlar catalyst, palladium/carbon, Raney nickel, platinum black and platinum dioxide.
  • the solvent may be selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, methylcyclopentyl ether, methanol, ethanol, isopropanol, acetonitrile and toluene.
  • the dosage ratio of the compound represented by formula (V) to the solvent is 1 g: (1-100 mL), more preferably 1 g: (5-60 mL).
  • the weight ratio of the compound represented by formula (V) to the catalyst is 1:0.005 to 0.2, more preferably 0.01% to 0.1.
  • the pressure of the introduced hydrogen is 0.1-10 MPa, more preferably 0.1-5 MPa; the reaction temperature is preferably 0-50°C.
  • the compound represented by formula (V) can be a commercially available raw material, or it can be synthesized by an existing method, preferably the following method:
  • M is H or a leaving group, preferably M is a halogen, sulfonate, carboxylate, or phosphate.
  • the leaving group includes but is not limited to: halogen (for example: Cl, Br, I), OSO n R 9. OCOR 10 or OPO 2 R 11 ; R 9 , R 10 or R 11 are each independently selected from: -CF 3 , alkyl, phenyl, or alkyl substituted phenyl (such as tolyl), n is 0, 1 or 2, the silyl group may be a silyl group or the like.
  • the sulfonate may be: toluene sulfonate, methanesulfonate, trifluoromethanesulfonate, and the like. More preferably, M is bromine.
  • the compound represented by formula (VI) which is widely available in the market can be used as a raw material, which significantly reduces the production cost, and the reaction yield is high (>95%), and the reaction conditions at room temperature It is mild and can be obtained by conventional recrystallization.
  • the catalyst is preferably a combination of a copper catalyst and a palladium catalyst, and the ligand is a phosphorus ligand.
  • the copper catalyst may be one or more of cuprous chloride, cuprous bromide and cuprous iodide, and cuprous iodide is preferred.
  • the palladium catalyst may be one or more of palladium chloride, acetic acid, PdCl 2 (dppf), Pd 2 (dba) 3 and Pd(PPh 3 ) 4.
  • the solvent in the above step S3111 may be one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, methylcyclopentyl ether, and acetonitrile, preferably 2-methyltetrahydrofuran.
  • the base may be one or more of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU, pyridine and p-dimethylaminopyridine.
  • the amount ratio of the compound represented by the formula (VI) to the solvent is 1 g: (1-20 mL), preferably 1 g: (5-15 mL).
  • the molar ratio of the compound represented by the formula (VI) to the catalyst is 1: (1% to 15%), preferably 1: (1% to 10%).
  • the molar ratio of the compound represented by formula (VI) to the ligand is 1:(2%-30%), preferably 1:(2-20%); the molar ratio of the compound represented by formula (VI) to the base is 1:( 5 ⁇ 15).
  • the olefin in the compound represented by the formula (II) is a compound represented by the formula (IIb) with a trans structure
  • the compound represented by the formula (IIb) is obtained from the compound represented by the formula (VI) through a coupling reaction (such as: Suzuki coupling reaction) )be made of;
  • M is H or a leaving group, preferably M is halogen, sulfonate, carboxylate or phosphate.
  • the leaving group includes but not limited to: halogen (for example: Cl, Br, I), OSO n R 9 , OCOR 10 or OPO 2 R 11 ; R 9 , R 10 or R 11 are each independently selected from: -CF 3 , alkyl, phenyl, or alkyl substituted phenyl (such as tolyl), n is 0, 1 Or 2, the silyl group may be a silyl group or the like.
  • the sulfonate may be: toluene sulfonate, methanesulfonate, trifluoromethanesulfonate, and the like. More preferably, M is bromine.
  • trans-1-propenyl boronic acid reagents refer to boronic acid reagents containing trans-1-propenyl groups, including but not limited to: trans-1-propenyl boronic acid boronic acid pinacol ester , Trans-1-propenylboronic acid, or trans-1-propenylfluoroborate.
  • the preferred catalyst is selected from: 5% Pd/C, 10% Pd/C, Pd(OAc) 2 , PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , PdCl 2 (dppf), PdCl 2 (MeCN ) 2 and Pd 2 (dba) 3 one or more.
  • the solvent is selected from: methanol, ethanol, isopropanol, butanol, water, tetrahydrofuran, 2-methyltetrahydrofuran, 1.4-dioxane, DME, DMF, DMSO, NMP, acetonitrile, dichloromethane, 1,2- Dichloroethane, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethyl ether, methyl tert-butyl ether, toluene, xylene, acetone, methyl ethyl ketone and methyl cyclopentane
  • the ligand is selected from: one or more of PPh 3 , BINAP, dppf, Xantphos, Xphos monophosphorus and diphosphorus ligands.
  • the compound represented by formula (VI) can be a commercially available raw material, or can be prepared by an existing method.
  • the compound represented by formula (VI) is a pyrazine compound, which is currently widely sold in the market, for example: CAS: 6966-01-4, 612835-51-5, 17890-77-6, 17231-51-5, etc. , The cost is lower, and the preparation cost of the entire process route can be further reduced.
  • the compound represented by formula (III) can be prepared from commercially available raw materials or can be prepared by existing methods.
  • the compound represented by formula (III) is prepared by the compound represented by formula (II) through a cyclization reaction, that is, it can be cyclized first The reaction is followed by the dihydroxylation reaction, or the dihydroxylation reaction and the cyclization reaction.
  • the compound represented by the formula (VIII), the catalyst and the solvent are mixed and reacted under a hydrogen atmosphere. After the reaction is completed, the compound is filtered and concentrated to obtain the compound represented by the formula (IIIa) of the cis structure.
  • the preferred catalyst can be selected from one or more of Lindlar catalyst, palladium/carbon, Raney nickel, platinum black and platinum dioxide;
  • the solvent can be selected from: tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tertiary One or more of butyl ether, methylcyclopentyl ether, methanol, ethanol, isopropanol, acetonitrile and toluene.
  • the dosage ratio of the compound represented by formula (VIII) to the solvent is 1g: (1-100 mL), more preferably 1g: (5-60 mL); the weight ratio of the compound represented by formula (VIII) to the catalyst is 1: 0.005-0.2 , More preferably 0.01% to 0.1; the pressure of the introduced hydrogen is 0.1-10 MPa, more preferably 0.1-5 MPa; the reaction temperature is preferably 0-50°C.
  • the compound represented by formula (VIII) can be commercially available raw materials, or can be prepared by an existing method, and is preferably prepared by the following method:
  • step S3212 may include the following steps: the compound represented by formula (V), The salt, base and solvent are mixed, heated to 50-100°C, and filtered after the reaction is completed, to obtain the compound represented by formula (VIII).
  • the solvent is an alcohol solvent, preferably one or more of methanol, ethanol and isopropanol
  • the base can be one of sodium ethoxide, sodium methoxide, t-BuONa, t-BuOK and t-BuOLi or A variety of; preferably a strong base, such as sodium methoxide and the like.
  • step S3212 may include the following steps: adding Na to MeOH and stirring until the reaction is complete, then adding Salt, protected under N 2 and stirred at room temperature for 3-10 min. Then, filter the insoluble matter in the system, add the compound represented by formula (V), and heat to reflux. After the reaction is completed, cool to room temperature and stir for 40 min-80 min. Filter the precipitated solid matter to obtain formula (VIII) Compound.
  • the compound represented by formula (III) can be prepared by the following method:
  • M is H or a leaving group; preferably M is halogen, sulfonate, carboxylate or phosphate, wherein the sulfonate can be: toluenesulfonate, mesylate, trifluoromethanesulfonic acid Ester etc.;
  • step S3221 The coupling reaction of step S3221 is the same as above, and will not be repeated here.
  • step S3222 The steps of the cyclization reaction in step S3222 are the same as above, and will not be repeated here.
  • the preparation method of the L-erythrobiopterin compound represented by formula (I) includes the following steps:
  • the compound shown in (VI) is used as a starting material to undergo a cross-coupling reaction with an alkyne to catalytically hydrogenate to obtain a cis-olefin. Then innovatively use systematic dihydroxylation reaction to construct two chiral centers, and then obtain a single enantiomer (R,S)-pyrazine propylene glycol compound by chiral separation and purification. After cyclization, L-erythro-biopterin pterin compounds are obtained.
  • reaction route is greatly shortened, and the yield of each step is high, and the atom utilization rate is high, avoiding the traditional 5-deoxy-L-arabinose and 2,4,5-triamino-6-hydroxypyrimidine (TAP) condensation preparation
  • TAP 2,4,5-triamino-6-hydroxypyrimidine
  • the compound shown in (VI) is used as the starting material to undergo a cross-coupling reaction with an alkyne, followed by sequential cyclization and catalytic hydrogenation to obtain the desired cis-olefin.
  • Two chiral centers are constructed after dihydroxylation, and then through chiral separation and purification, the required L-erythro-biopterin pterin compounds can be obtained, which greatly shortens the reaction route and has high yields in each step.
  • the compound shown in (VI) is used as the starting material, the olefin is constructed by the coupling reaction, and the olefin is innovatively subjected to the dihydroxylation reaction, the acetylation reaction and the Mitsunobu reaction to obtain the product of the desired configuration.
  • the olefin is innovatively subjected to the dihydroxylation reaction, the acetylation reaction and the Mitsunobu reaction to obtain the product of the desired configuration.
  • make full use of the nature of each reaction improve stereoselectivity, expand the range of raw material selection, and the by-products of monoacetylation and the by-products that did not turn over in the Mitsunobu reaction can also be recycled into raw materials by simple hydrolysis, ensuring that The economy of the entire route.
  • TAP 2-deoxy-L-arabinose and 2,4,5-triamino-6-hydroxypyrimidine
  • the dihydroxylation reaction of compound 4 includes the following methods:
  • the dihydroxylation reaction of compound 3 includes the following methods:
  • the dihydroxylation reaction of compound 5a includes the following methods:
  • the dihydroxylation reaction of compound 5b includes the following methods:
  • the dihydroxylation reaction of compound 5b includes the following methods:
  • the testing instrument is D8 Venture, and the instrument parameters are as follows:
  • the SADABS program is used to perform empirical absorption correction on the data
  • SHELXT2014 is used to analyze the single crystal structure through the direct method
  • the least square method is used to refine the structure.
  • the hydrogen atom refinement process takes all directions Obtained by homogeneous calculation processing, the hydrogen atom on CH is obtained by calculation hydrogenation, and the riding model is used to refine it.
  • the Flack constant is -0.03(7), the chiral center is shown in Figure 1; the crystal data is shown in Table 2, the data collection is shown in Table 3, the refined parameters are shown in Table 4, and the results of other specific parameters are shown in Tables 5 to 7.

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Abstract

本发明涉及一种L-赤型生物蝶呤类化合物的制备方法。其中，L-赤型生物蝶呤类化合物具有式(I)所示的结构，且式(I)所示的L-赤型生物蝶呤类化合物主要由式(II)或式(III)所示结构的化合物通过双羟化反应制备而成；该L-赤型生物蝶呤类化合物制备方法生产效率高、成本低、且绿色环保，适宜工业生产。

Description

L-赤型生物蝶呤类化合物的制备方法
本申请要求于2019年08月19日提交中国专利局、申请号为2019107645414、发明名称为“L-赤型生物蝶呤类化合物的制备方法”和于2020年08月12日提交中国专利局、申请号为2020108063470、发明名称为“用于制备L-赤型生物蝶呤类化合物的中间体及其制备方法”中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物制备技术领域，特别是涉及L-赤型生物蝶呤类化合物的制备方法。
背景技术
式(I)表示L-赤型生物蝶呤类化合物是目前大多数药物的重要中间体，特别是沙丙蝶呤类药物。例如：式(Ib)表示的(R)-2-氨基-6-[(1R,2S)-1,2-二羟基丙基]-5，6，7，8-四氢-4(3H)-喋啶酮(BH4)，其是生物体内羟基化反应和加氧酶中必须的辅酶，是一氧化氮合成酶(NOS)最重要的辅酶，其盐酸盐(即二盐酸沙丙蝶呤，结构式为式(Ic)已被很多国家批准用于治疗苯丙酮尿症。
Figure PCTCN2020109818-appb-000001
而目前合成二盐酸沙丙蝶呤的主要方法是通过式(Ia)所示的化合物氢化还原获得。
Figure PCTCN2020109818-appb-000002
故如何安全、高效获得式(Ia)表示L-赤型生物蝶呤类化合物成了目前研发热点。
目前，存在较多关于L-赤型生物蝶呤类化合物的合成报道。例如：Andrews等人(J.Chem.Soc.1969,928)报道了5-脱氧-L-阿拉伯糖与2-氨基-4-氯-3-硝基-6-羟基嘧啶的缩合制备生物蝶呤；但其光学纯度和化学纯度均不足，无法放大。
Welustock J.(US3505329)，Taylor E.C.(J.Am.Chem.Soc.1979,98,2301)报道了光学选择性更高的方法，如下路线所示：
Figure PCTCN2020109818-appb-000003
以L-鼠李糖为原料与乙硫醇反应生成的缩硫醛，被氧化成砜后，碱处理脱除一个碳得到5-脱氧-L- 阿拉伯糖(D)。5-脱氧-L-阿拉伯糖再与2，4，5-三氨基-6-羟基嘧啶(TAP)反应生成L-赤型生物蝶呤。经后续的改进(Helv chim acta 1985:1639)，成为目前工业化的路线。方法是将5-脱氧-L-阿拉伯糖(D)先用苯肼处理然后用乙酸酐处理转化成相应的乙酰苯腙(G)。然后与TAP环合，其不进行分离而是立即进行氧化得到乙酰化的L-赤型生物碟呤。进一步脱保护得到L-赤型生物碟呤。
然而该工业路线存在重大的缺陷：1)关键中间体5-脱氧-L-阿拉伯糖的合成，需采用L-鼠李糖与具有浓重臭味的乙硫醇缩合成缩醛，操作复杂，污染严重，目前已不在工业上使用；2)中间体5-脱氧-L-阿拉伯糖本身不稳定，不能长时间储存，需现制备现用；3)5-脱氧-L-阿拉伯糖制备的各步中间体都是油状物，且均不稳定，因此需要使用粗品从C一路推到L-赤型生物蝶呤，使得该工艺难于控制质量和进行GMP生产；4)采用5-脱氧-L-阿拉伯糖衍生物与2，4，5-三氨基-6-羟基嘧啶(TAP)缩合制备L-赤式生物蝶呤，选择性差，杂质多，收率低；5)生成的L-赤式生物蝶呤，因其在常用溶剂中溶解度极差，纯化极其困难，不佳质量直接负面影响后续氢化制备盐酸沙丙蝶呤的质量。
综合目前的技术来看，目前世界范围内L-赤型生物蝶呤类化合物的工艺改进还大都停留在5-脱氧-L-阿拉伯糖制备上，特别是采用其他试剂替代硫醇，以减少气味和污染；对5-脱氧-L-阿拉伯糖衍生物与TAP缩合上没有显著进展，且原料昂贵、路线长、产率较低，导致生产成本高，安全性能低，无法满足现代药物工业生产的需求。因此，迫切需要开发出一条高效、低成本、绿色环保的适宜工业生产的L-赤型生物蝶呤类化合物制备方法。
发明内容
基于此，本发明提供了一种L-赤型生物蝶呤类化合物制备方法，该L-赤型生物蝶呤类化合物制备方法生产效率高、成本低、且绿色环保，适宜工业生产。
具有式(IVa-1)、式(IVa-2)、式(IVa-3)、式(IVa-4)、式(IVa)或式(IVa')所示结构的中间体：
Figure PCTCN2020109818-appb-000004
其中，
Figure PCTCN2020109818-appb-000005
表示双羟基、第一试剂和第二试剂反应生成的结构；
Figure PCTCN2020109818-appb-000006
表述双羟基与第一试剂反应生成的结构；
所述第一试剂为硼酸酯或硼酸；
所述第二试剂为手性氨基醇；
W为NH x，X为0、1或2；
R 1为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
R 2和R 3各自独立的为氢原子或氨基保护基；且R 2和R 3可和与所述R 2、R 3相连的氮原子一起形成环状内酰亚胺基；
R 4为-COOR 5、-CONR 6或-CN；
R 5和R 6各自独立地为氢原子、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
Z为氢原子或离去基团；
Y为O或不存在。
上述中间体的制备方法，包括以下步骤：
将待拆分化合物、第一试剂、第二试剂和非质子性溶剂混合，加热回流，反应完成后，结晶获得式(IVa-1)或式(IVa-2)所示结构的中间体；其中，所述待拆分化合物为式(IVa)和式(IVa')组成的混合物；
Figure PCTCN2020109818-appb-000007
上述中间体的在制备L-赤型生物蝶呤类化合物中的应用。
一种L-赤型生物蝶呤类化合物的制备方法，所述L-赤型生物蝶呤类化合物具有式(I)所示的结构，且所述式(I)所示的L-赤型生物蝶呤类化合物由式(II)所示化合物或式(III)所示化合物通过双羟化反应制备而成；
Figure PCTCN2020109818-appb-000008
其中，
Y为O或不存在；
Z为氢原子或离去基团；
R 1为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
R 2和R 3各自独立地为氢原子或氨基保护基；且所述R 2、R 3可和与所述R 2、R 3相连的氮原子一起形成环酰亚胺基；
R 4为-COOR 5、-CONH 6或-CN；
R 5和R 6各自独立地为氢原子、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
R 7为-OH或-NH 2。
上述L-赤型生物蝶呤类化合物制备方法而成的L-赤型生物蝶呤类化合物。
一种沙丙蝶呤类药物的制备方法，包括以下步骤：
采用上述的L-赤型生物蝶呤类化合物的制备方法制备式(I)所示的L-赤型生物蝶呤类化合物；
将式(I)所示的L-赤型生物蝶呤类化合物进行氢化还原。
上述L-赤型生物蝶呤类化合物在制备用于治疗苯丙酮尿症和高苯丙氨酸症的药物中的应用。
上述L-赤型生物蝶呤类化合物的制备方法在制备用于治疗苯丙酮尿症和高苯丙氨酸症的药物中的应用。
附图说明
图1为化合物3a的单晶图。
具体实施方式
为了便于理解本发明，下面将对本发明进行更全面的描述，并给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反的，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
术语解释
本发明中，除非本发明具有特别说明，相同符号所表示的含义应理解为具有相同的含义。另外，若未特别声明，本发明中的各术语(包括取代基简写、试剂名称缩写等)应理解为本领域通常的含义。
本发明中，离去基团应理解为本领域的通常含义，指在化学反应中能够从一较大分子中脱离的原子或官能基。可理解的，若无特别说明时，含有离去基团的化合物参加反应的步骤，包括离去基团的引入步骤和去除步骤，离去基团的引入和去除可以根据所采用的离去基团的具体种类，采用本领域的常用方法，在此不做特别限定。
本发明中，氨基保护基应理解为本领域的通常含义，指氨基的保护基团。可理解的，若无特别说明时，含有保护基的化合物参加反应的步骤，包括保护基的引入步骤和保护基的脱除步骤，保护基的引入和保护基的脱除可以根据所采用的保护基的种类，采用本领域的常用方法，在此不做特别限定。
本发明中，“取代或未取代”表示所定义的基团可以被取代，也可以不被取代。当所定义的基团被取代时，应理解为任选被本领域可接受的基团所取代，包括但不限于：具有1至20个C原子的烷基、具有3-20个环原子的环烷基、具有3-20个环原子的杂环基、具有5-20个环原子的芳基、具有5-20个环原子的杂芳基、硅烷基、羰基、烷氧基羰基、芳氧基羰基、氨基甲酰基、卤甲酰基、甲酰基、-NRR′、氰基、异氰基、异氰酸酯基、硫氰酸酯基、异硫氰酸酯基、羟基、三氟甲基、硝基或卤素，且上述基团也可以进一步被本领域可接受取代基取代；可理解的，-NRR′中的R和R′各自独立地为本领域可接受的基团所取代，包括但不限于H、具有1至6个C原子的烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-10个环原子的杂芳基；所述具有1至6个C原子的烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、具有5-20个环原子的芳基或具有5-10个环原子的杂芳基任选进一步被一个或多个以下基团取代：C 1-6烷基、具有3-8个环原子的环烷基、具有3-8个环原子的杂环基、卤素、羟基、硝基或氨基。
本发明中，未标注立体构型的位点应理解为包括多种可稳定存在的立体构型。
“烷基”是指饱和脂肪族烃基，包括直链和支链基团。C 1-C 6烷基是指含有1至6个碳原子的烷基。非限定性实施例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基。C 1-C 4烷基是指含有1至4个碳原子的烷基。在一实施例中，C 1-C 4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃基取代基。3-8元环烷基是指包括3至8个碳原子。在一实施例中，3-8元单环环烷基为环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是 任选被一个或一个以上的取代基取代。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，优选氮或氧杂原子；但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。4-10元杂环基是指环包含4至10个环原子，其中1-3个是杂原子；优选杂环基环包含5至6个环原子，其中1-2个是杂原子。在一实施例中，单环杂环基为二氢呋喃基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基或高哌嗪基等。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选苯基和萘基，最优选苯基。芳基环可以稠合于杂芳基、杂环基或环烷基环上，芳基可以是取代的或未取代的。
“杂芳基”指含有杂原子的芳基，其中，杂原子包括氧、硫和氮。杂芳基优选为是5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。杂芳基环可以稠合于芳基、杂环基或环烷基环上，其与母体结构连接在一起的环为杂芳基环。杂芳基可以任选取代或未取代。
本发明中取代基“氨基”包括伯仲叔氨基，具体地，氨基包括-NR 16R 17，其中，R 16和R 17为氢原子或任意可选基团，例如：H、取代或未取代的直链烷基、取代或未取代的支链烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳香基团、或取代或未取代的杂芳香基团等。
“硅烷基”指-Si(烷基) 3，且与硅相连的三个烷基可以彼此相同或不相同。
环状内酰亚胺基指
Figure PCTCN2020109818-appb-000009
环A中所含环原子数目无特别限定，可以为5元环、6元环等，例如：戊二酰亚胺、琥珀酰亚胺等。
本发明缩写简称如下表：
Figure PCTCN2020109818-appb-000010
Figure PCTCN2020109818-appb-000011
本发明一实施方式提供了具有式(IVa-1)、式(IVa-2)、式(IVa-3)、式(IVa-4)、式(IVa)或式(IVa')所示结构的中间体：
Figure PCTCN2020109818-appb-000012
其中，
Figure PCTCN2020109818-appb-000013
表示双羟基、第一试剂和第二试剂反应生成的结构；
Figure PCTCN2020109818-appb-000014
表述双羟基与第一试剂反应生成的结构；
第一试剂为硼酸酯或硼酸；
第二试剂为手性氨基醇、手性氨基酸、手性氨基酸酯或手性二醇；
W为O或NH x，X为0、1或2；
R 1为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
R 2和R 3各自独立地为氢原子或氨基保护基；且R 2和R 3可和与R 2、R 3相连的氮原子一起形成环状内酰亚胺基；其中，氨基保护基团包括但不限于：-Boc、-Cbz、-Ac、-Ts、-Ms、-Bz、-Bn、-PMB、或schiff碱。
R 4为-COOR 5、-CONR 6(即CONHR 6)或-CN；
Z为氢原子或离去基团；其中，离去基团包括但不限于：卤素(例如：Cl、Br、I)、OSO nR 9、OCOR 10或OPO 2R 11；R 9、R 10或R 11各自独立地选自：-CF 3、烷基、苯基、或烷基取代苯基(例如甲苯基)，n为0、1或2，硅烷基可以为甲硅烷基等。
Y为O或不存在。
在一实施例中，R 1选自C 1-6烷基、3-8元环烷基、3-10元芳基、3-10元杂芳基、TMS、TBS、或-CH 2X；X为离去基团。在一实施例中，R 1选自C 1-6烷基、环丙基、苯基、吡啶基、TMS、TBS、或-CH 2X；X为离去基团。在一实施例中，R 1为甲基。
R 5和R 6各自独立地为氢原子、或取代或未取代的C 1-20烷基。其中，C 1-20烷基被进一步取代时，取代基可以为C 1-6烷基、3-8元环烷基、3-10元芳基、3-10元杂芳基、羟基、卤素、氨基、氰基或C 1-4烷氧基。
进一步地，R 5和R 6各自独立地为氢原子、或取代或未取代的C 1-6烷基。C 1-6烷基被进一步取代时，取代基可以为C 1-4烷基、3-8元环烷基、3-10元芳基、3-10元杂芳基、羟基、卤素、氨基、氰基或C 1-4 烷氧基。
在一实施例中，R 4为-CN。
在一实施例中，Y不存在，Z为氢原子，R 4为氰基，R 1为甲基。
可理解的，
Figure PCTCN2020109818-appb-000015
中R 8基团根据所选择的硼酸酯确定；进一步地，R 8为取代或未取代烷基；更进一步，R 8为取代或未取代的C 1-10烷基、或取代或未取代的C 3-10环烷基；更进一步地，R 8为取代或未取代的C 1-8烷基或取代或未取代的C 3-8环烷基；更进一步地,R 8为取代或未取代的C 1-6烷基或C 3-6环烷基；
可理解的，本发明中的硼酸酯可以为本领域内任意可接受的硼酸酯试剂；在一实施例中，硼酸酯选自：硼酸三甲酯、硼酸三乙酯、硼酸三异丙酯或硼酸异丙醇频那醇酯；另外，本发明中的手性氨基醇可以为本领域内任意可接受手性氨基醇；在一实施例中，手性氨基醇选自：L-苯甘氨醇、L-脯氨醇、L-苯丙胺醇、(S)-(-)-α,α-二苯基脯氨醇、奎宁或辛可尼，以获得具有更高ee值和产率的所需构型产物。本发明中的手性氨基酸可以为本领域内任意可接受手性氨基酸；在一实施例中，手性氨基酸选自：L-苯丙氨酸、L-丙氨酸、L-脯氨酸、L-亮氨酸、L-缬氨酸、L-苯甘氨酸等手性氨基酸。本发明中的手性氨基酸酯可以为本领域内任意可接受手性氨基酸酯；在一实施例中，手性氨基酸酯选自：L-苯丙氨酸酯、L-丙氨酸酯、L-脯氨酸酯、L-亮氨酸酯、L-缬氨酸酯、L-苯甘氨酸酯等手性氨基酸酯，所选酯类可为烷基酯或者芳基酯；本发明中的手性二醇可以为本领域内任意可接受手性二醇；在一实施例中，手性二醇为含有1，2-二醇或1，4-二醇手性结构二醇；进一步地，手性二醇选自：手性的BINOL、手性氢化安息香、(反式)-9,10-二羟基-9,10-二氢菲、或(顺式)-9,10-二羟基-9,10-二氢菲等。
进一步地，优选第二试剂为手性氨基醇，以获得更好地拆分效果。
在一实施例中，
Figure PCTCN2020109818-appb-000016
具有
Figure PCTCN2020109818-appb-000017
的结构；进一步地，
Figure PCTCN2020109818-appb-000018
具有以下结构：
Figure PCTCN2020109818-appb-000019
其中，与R 20和R 21相连的碳原子、与R 22和R 23相连的碳原子中至少有一个碳原子为手性碳；
R 20、R 21、R 22和R 23各自独立地选自：H、取代或未取代C 1-6烷基、取代或未取代苯基、取代或未取代萘基、或取代或未取代喹啉基；
R 24和R 25各自独立地选自：H、取代或未取代C 1-6烷基、或取代或未取代苯基；
R 23和R 24可相互连接形成环状结构；
R 23、R 24和R 25可相互连接形成桥环结构。
可理解的，本发明中的“环状结构”包括单环(如芳环、杂环)、螺环、桥环等。
在一实施例中，R 20、R 21、R 22和R 23各自独立地选自：H、苯基、C 1-6烷基或烷氧基取代喹啉基；
在一实施例中，R 24和R 25各自独立地选自：H、C 1-6烷基或苯基；
在一实施例中，R 23和R 24可相互连接形成五元含氮杂环；
在一实施例中，R 23、R 24和R 25可相互连接形成
Figure PCTCN2020109818-appb-000020
结构。
在一实施例中，
Figure PCTCN2020109818-appb-000021
为
Figure PCTCN2020109818-appb-000022
本发明还提供了上述中间体的制备方法，包括以下步骤：
将待拆分化合物、第一试剂、第二试剂和非质子性溶剂混合，加热回流，反应完成后，结晶获得式(IVa-1)或式(IVa-2)所示结构的中间体；其中，待拆分化合物为式(IVa)和式(IVa')组成的混合物；
Figure PCTCN2020109818-appb-000023
可理解的，上述反应的反应过程不应理解为对本发明的限制，上述反应可以先使待拆分化合物和第一试剂反应生成式(IVa-3)和式(IVa-4)所示结构的混合物，然后式(IVa-3)和式(IVa-4)所示结构的混合物与第二试剂反应，制得式(IVa-1)或式(IVa-2)所示结构的中间体。其中，可以对式(IVa-3)和式(IVa-4)所示结构的混合物进行分离，也可以不分离，应理解为均在本发明的保护范围内。
进一步地，上述反应包括以下步骤：
S001:将待拆分化合物溶解于非质子性溶剂中；
进一步地，步骤S001中非质子性溶剂选自：四氢呋喃(THF)、2-甲基四氢呋喃(2-MeTHF)、乙腈(ACN)、甲苯(toluene)、苯(benzene)、1,4-二氧六环(1，4-diox)和丙酮(Acetone)中的一种或多种，以增大不同构型中间体的溶解度差异，且使所需构型中间体(式(IVa-1))以沉淀的形式析出，进一步地降低分离难度，与此同时提高产品的产率和ee值；更进一步地，非质子性溶剂选自乙腈。
进一步地，每1g待拆分化合物加入1-100mL非质子性溶剂；更进一步地，每1g待拆分化合物加入20-80mL非质子性溶剂；更进一步地，每1g待拆分化合物加入30-60mL非质子性溶剂。
S002:加入第一试剂和第二试剂，加热回流反应预定时间；
通过加入第一试剂和第二试剂，使得非对映体引入新的手性中心，获得一对非对映体，最终通过结晶即可实现拆分；且该方法所获得的式(IVa-1)为制备L-赤型生物蝶呤类化合物的关键中间体，其在大部分常规非质子性溶剂中均是以固体的形式析出，能够显著降低分离难度，提高产物的ee值；例如：当采用硼酸酯和手性氨基醇时，具体地反应机理如下：
Figure PCTCN2020109818-appb-000024
进一步地，第一试剂为硼酸酯或硼酸；
进一步地，第二试剂为手性氨基醇、手性氨基酸、手性氨基酸酯或手性二醇；更进一步地，第二试剂为手性氨基醇；
第一试剂和第二试剂如上所述，在此不再进行赘述。
更进一步地，硼酸酯为硼酸三异丙酯，手性氨基醇为L-脯氨醇，溶剂为乙腈。
进一步地，待拆分化合物和硼酸酯的摩尔比小于或等于1；
进一步地，第一试剂和第二试剂的摩尔比为1：(1.0-1.3)；进一步地，第一试剂和第二试剂的摩尔比为1：1；
可理解的，步骤S002中试剂的添加顺序无特别限定，不应理解为对本发明的限制，例如：可以先加入第一试剂再加入第二试剂，也可以将第一试剂和第二试剂同时加入；另外，步骤S002的反应时间无特别限定，根据所采用的试剂种类进行调节，不应理解为对本发明的限制；
进一步地，步骤S002中先加入第一试剂反应25min～50min，再加入第二试剂反应8h～24h；
S003：结晶，获得式(IVa-1)或式(IVa-2)所示结构的中间体；
可理解的，可以采用现有的方法进行结晶，且结晶中的固液分离的温度可以根据所选择的具体溶剂进行调节，不应理解为对本发明的限制；在一实施例中，采用以下方法进行结晶：待反应完成后，将反应液降温，有固体析出固液分离，所需构型产物为固相产物或液相产物。
上述通式(IVa-1)或式(IVa-2)所示结构的中间体的制备方法具有以下优点：
由于通式(IVa-1)或式(IVa-2)所示结构的中间体在非质子性溶剂中的溶解度不同，故仅需进行结晶，则可使通式(IVa-1)和式(IVa-2)所示结构的中间体中一种溶解在溶剂中，一种通过沉淀的方式析出来，如此通过简单的固液分离即可实现不同构型产品的分离，有效地降低了分离难度，特别适用于工业生产；
上述第一试剂和第二试剂组成的拆分试剂组条件温和，且对底物的质量纯度要求范围宽泛，拆分后产品ee值dr值以及纯度极高，即使待拆分化合物的纯度在70％仍然可以实现拆分，同时所获得的产品纯度可以提高至99％，有效地实现了一锅拆分、纯化的效果；
上述方法所得到的式(IVa-1)或式(IVa-2)所示结构的中间体可以不用解离，可直接用于下一步反应的生产，且经下一步合成，ee值和dr值可以进一步提升，经实验，当使用88％ee的产品(IVa-1/IVa-2＝94/6)进行下一步反应时，终产品ee仍然可以提升至99.9％以上，手性纯度与天然手性引入的效果相当；
且所获得的式(IVa-1)或式(IVa-2)所示结构的中间体都为固体，结构稳定，易于质量控制、生产，便于贮存和运输。
本发明还涉及一种手性拆分试剂组，包括第一试剂和第二试剂，第一试剂为硼酸酯或硼酸；第二试剂为手性氨基醇、手性氨基酸、手性氨基酸酯或手性二醇；其中，上述试剂如上所述，在此不再进行赘述。
本发明还涉及一种手性拆分试剂组，由手性氨基醇和硼酸酯组成。
进一步地，上述手性拆分试剂组由硼酸酯和L-脯氨酸组成。进一步地，上述手性拆分试剂组由硼酸酯和L-苯甘氨醇组成。进一步地，上述手性拆分试剂组由硼酸酯和(S)-(-)-α,α-二苯基脯氨醇组成。进一步地，上述手性拆分试剂组由硼酸酯和奎宁组成。进一步地，上述手性拆分试剂组由硼酸酯和辛可尼组成。
本发明还涉及上述手性拆分试剂组在制备L-赤型生物蝶呤类化合物中的应用。
本发明一实施方式的L-赤型生物蝶呤类化合物的制备方法，主要由式(II)所示化合物或式(III)所示化合物通过双羟化反应制备而成。其中，L-赤型生物蝶呤类化合物具有式(I)所示的结构：
Figure PCTCN2020109818-appb-000025
其中，Y为O或不存在；在一实施例中，Y不存在。
Z为氢原子或离去基团；其中，离去基团包括但不限于：卤素(例如：Cl、Br、I)、OSO nR 9、OCOR 10或OPO 2R 11；R 9、R 10或R 11各自独立地选自：-CF 3、烷基、苯基、或烷基取代苯基(例如甲苯基)，n为0、1或2，硅烷基可以为甲硅烷基等。
R 1为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
R 2和R 3各自独立地为氢原子或氨基保护基，其中，氨基保护基团包括但不限于：-Boc、-Cbz、-Ac、-Ts、-Ms、-Bz、-Bn、-PMB、或schiff碱。
且R 2和R 3可和与R 2、R 3相连的氮原子一起形成环状内酰亚胺基，例如：戊二酰亚胺、琥珀酰亚胺。可理解的，R 2和R 3不必然和其相连的氮原子一起形成环状内酰亚胺基，根据需要进行选择。
R 4为-COOR 5、-CONR 6或-CN；在一实施例中，R 4为-CN。
R 5和R 6各自独立地为氢原子、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基。
上述L-赤型生物蝶呤类化合物的制备方法创新性地采用式(II)或式(III)所示烯烃类化合物作为原料，并利用双羟化反应构建所需构型的双羟基，有效地避免了5-脱氧-L-阿拉伯糖(D)等中间体的使用，进而避免具有浓重臭味的乙硫醇等的使用，有效地降低了环境污染，绿色环保。此外，烯烃双羟化反应条件较为温和，操作方便，产率较高，且式(II)或式(III)所示结构的原料易得，可以大幅度缩短反应路线，进一步提高效率，降低生产成本，适宜工业生产应用。
可理解的，在进行本发明所述反应的同时，利用本领域常见反应(例如氧化反应、还原反应等)，将原料转化为所需化合物(如式(II)所示化合物或式(III)所示化合物)，无论是否将所需化合物(如式(II)所示化合物或式(III)所示化合物)进行分离，还是直接进行后续反应，应理解为均在本发明的保护范围内。例如：
Figure PCTCN2020109818-appb-000026
(R 4为-CHO)进行环化反应，在环化反应之前或进行环化反应的同时加入氧化剂，将醛基转化为羧酸或羧酸酯，然后进行环化反应。应理解为，其等同于R 4为羧酸或羧酸酯的技术方案，无论是否对含羧酸或羧酸酯的化合物进行分离，应理解为均在本发明的保护范围内。
在一实施例中，R 1选自C 1-6烷基、3-8元环烷基、3-10元芳基、3-10元杂芳基、TMS、TBS、或-CH 2X；X为离去基团。在一实施例中，C 1-6烷基、环丙基、苯基、吡啶基、TMS、TBS、或-CH 2X；X为离去基团。在一实施例中，R 1为甲基。
R 5和R 6各自独立地为氢原子、或取代或未取代的C 1-20烷基。其中，C 1-20烷基被进一步取代时，取代基可以为C 1-6烷基、3-8元环烷基、3-10元芳基、3-10元杂芳基、羟基、卤素、氨基、氰基或C 1-4烷氧基。
R 7为-OH或-NH 2。当R 7为-NH 2，可以在碱性条件下进行水解，获得R 7为-OH的化合物。
可理解的，“双羟化反应”应做本领域的常规理解，指使烯烃的双键部位(例如式(II)或式(III) 中
Figure PCTCN2020109818-appb-000027
)进行反应，生成邻二羟基化合物，双羟化反应的方法包括但不限于：Sharpless不对称双羟化反应、碱性KMnO 4双羟化反应、Fe催化双羟基化反应或不对称环氧化后水解开环。优选采用Sharpless不对称双羟化反应。发明人在研究的过程中发现，若采用式(II)所示化合物或式(III)所示化合物作为反应物，并采用Sharpless不对称双羟化反应可以以较高产率获得所需构型的产物，大幅度降低分离难度，提高生产效率。
需要说明的是，式(II)或式(III)中烯烃基团
Figure PCTCN2020109818-appb-000028
表示可以为顺式结构也可以为反式结构。
可理解的，在反应中，式(II)或式(III)所示化合物可以为纯物质，即仅含有顺式结构的式(II)或式(III)所示化合物，或仅含有反式结构的式(II)或式(III)所示化合物，也可以为混合物，即为顺式结构和反式结构的混合物，在此不做特别限定(优选采用顺式结构的式(II)所示化合物)，反应后经手性分离即可，手性分离方法无特别限定，可以为现有的分离方法。式(II)所示的化合物经双羟化反应后，进行环化即可获得(I)所示的L-赤型生物蝶呤类化合物。其中，环化方法可以采用现有的方法，例如：Journal of Organic Chemistry 1987,52(18),3997-4000和Journal of Organic Chemistry 1988,53(1),35–38等。
一、式(II)所示化合物制L-赤型生物蝶呤类化合物
1.1顺式烯烃制L-赤型生物蝶呤类化合物
当式(II)所示化合物中烯烃为顺式结构时，由式(II)所示化合物制备式(I)所示的L-赤型生物蝶呤类化合物的步骤包括以下步骤：
S111：将式(IIa)所示化合物进行双羟化反应，制得式(IVa)所示化合物。
Figure PCTCN2020109818-appb-000029
其中，步骤S111中双羟化反应包括但不限于：Sharpless不对称双羟化反应、碱性KMnO 4双羟化反应、Fe催化双羟基化反应或不对称环氧化后水解开环，优选采用Sharpless不对称双羟化反应。
①采用Sharpless不对称双羟基化反应进行反应时，步骤S111可以包括以下步骤：将式(IIa)所示化合物、氧化剂、双羟基化试剂、碱和配体混合进行反应，反应完成后淬灭反应，分离，即得。优选在0-25℃下进行反应，反应完成后，可以采用亚硫酸钠淬灭反应，淬灭后，过滤不溶物，收集有机相，并对有机相进行手性分离，得到单一手性的式(IVa)所示化合物(R,S)。
优选双羟基化试剂选自：OsO 4、K 2OsO 4、OsO 4水合物和K 2OsO 4水合物中的一种或多种；氧化剂选自：K 3[Fe(CN) 6]或NMO以及中的一种或多种；碱选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、NaOH、KOH、LiOH、NH 4OH，t-BuONa、t-BuOK、t-BuOLi、碳酸铯、三乙胺、二异丙基乙基氨、DBU、吡啶和对二甲氨基吡啶中的一种或多种；配体选自：(DHQ) 2PHAL、(DHQD) 2PHAL、DHQ-IND和DHQD-IND中的一种或多种；溶剂可以为丙酮、甲醇、乙醇、1,4-二氧六环、叔丁醇和THF中的一种或多种。
另外，上述步骤S111还可以加入锇酸酯水解剂，该锇酸酯水解剂包括但不限定为甲磺酰胺。
另外，优选式(IIa)所示化合物与溶剂的用量比为1g：(10～100mL)；式(IIa)所示化合物与氧化剂的摩尔比为1：(0.1％～20％)；式(IIa)所示化合物与碱的摩尔比为1：(1～10)；式(IIa)所示化合物与甲磺酰胺的摩尔比为1：(1～10)。
②采用碱性KMnO 4双羟化反应进行反应时，步骤S111可以包括以下步骤：将式(IIa)所示化合物、双羟基化试剂、碱和溶剂混合，进行反应，反应完成后手性分离，即得。
优选，双羟基化试剂为KMnO 4；碱可以为碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、NaOH、KOH、LiOH、NH 4OH、t-BuONa、t-BuOK、t-BuOLi、碳酸铯、三乙胺、二异丙基乙基氨、DBU、吡啶和对二甲氨基吡啶中的一种或多种；溶剂为丙酮、甲醇、乙醇、1,4-二氧六环、叔丁醇和THF中的一种或多种。
③采用Fe催化双羟基化反应进行反应时，步骤S111可以包括以下步骤：将式(IIa)所示化合物、双羟基化试剂、催化剂和溶剂混合，进行反应，反应完成后手性分离，即得。
优选双羟化试剂为双氧水；催化剂为Fe(ClO 4) 2、Fe(OTf) 2、FeCl 2和FeBr 2中的一种或多种；溶剂可以为丙酮、甲醇、乙醇、1,4-二氧六环、叔丁醇和THF中的一种或多种。
④采用环氧化反应进行反应时，步骤S111可以包括以下步骤，将式(II)所示化合物和环氧化试剂进行反应获得环氧化中间体，再通酸或者碱开环、手性分离，获得所需双羟基化产品。
优选环氧化试剂为m-CPBA、DMDO、salen-Mn(III)/NaOCl中的一种或者几种；溶剂可以为二氯甲烷、四氢呋喃、1,4-二氧六环、叔丁醇中的一种或者几种。开环所用的酸可以为稀盐酸、稀硫酸、稀磷酸等，所用碱可以为KHCO 3、K 2CO 3、KOH等。
可理解的，上述双羟化反应后“手性分离”可以采用手性柱进行分离，也可以采用化学拆分的方法进行手性分离，优选采用手性拆分试剂组拆分待拆分化合物，其中，手性拆分试剂组包括第一试剂和第二试剂，第一试剂为硼酸酯或硼酸；第二试剂为手性氨基醇、手性氨基酸、手性氨基酸酯或手性二醇；其中各试剂如上所述，在此不再进行赘述；
进一步地，步骤S111包括以下步骤：
S1111:将式(IIa)所示化合物进行双羟化反应，获得式(IVa)和式(IVa')所示化合物组成的待拆分化合物；
Figure PCTCN2020109818-appb-000030
进一步地，双羟化反应如上所述，在此不再进行赘述。
S1112：采用手性拆分试剂组拆分待拆分化合物，得到式(IVa-1)所示化合物；
其中，步骤S1112中的手性拆分试剂组包括第一试剂和第二试剂，第一试剂为硼酸酯或硼酸；第二试剂为手性氨基醇、手性氨基酸、手性氨基酸酯或手性二醇；具体地，步骤S1112中的拆分方法如上述式(IVa-1)或式(IVa-2)所示结构的中间体的制备方法，在此不再进行赘述。
S112：与
Figure PCTCN2020109818-appb-000031
盐进行环化反应，制得式(I)所示的L-赤型生物蝶呤类化合物；
具体地，可以按以下S112a和S112b制备式(I)所示的L-赤型生物蝶呤类化合物；
S112a：将式(IVa)所示化合物与
Figure PCTCN2020109818-appb-000032
盐进行环化反应，制得式(I)所示的L-赤型生物蝶呤类化合物；
Figure PCTCN2020109818-appb-000033
S112b：将式(IVa-1)所示化合物与
Figure PCTCN2020109818-appb-000034
盐进行环化反应，制得式(I)所示的L-赤型生物蝶呤类化合物；
Figure PCTCN2020109818-appb-000035
E为卤素、C 1-4烷氧基、C 1-4烷硫基或-NH 2；进一步地，E为甲氧基、氯、甲硫基、或-NH 2；
由于式(IVa-1)所示化合物在质子性溶剂中能够快速释放出式(IVa)所示化合物，而在与
Figure PCTCN2020109818-appb-000036
Figure PCTCN2020109818-appb-000037
盐进行环化反应时采用的溶剂为质子性溶剂，故可以直接将式(IVa-1)所示化合物投入后续反应中，而无需解离，能够有效地降低操作难度，节约成本，且通过环化反应还可以进一步提高所需构型产物的ee值，具有较大应用前景。
需要说明的是，步骤S112b中直接将式(IVa-1)所示化合物用于后续反应，但不应理解为对本发明的限制，同样可以先采用质子性溶剂将式(IVa-1)所示化合物进行处理，获得了式(IVa)所示化合物后，再使式(IVa)所示化合物进行后续反应，此时同步骤S112a。
步骤S112中的
Figure PCTCN2020109818-appb-000038
盐是指含有
Figure PCTCN2020109818-appb-000039
的盐，可以为本领域可接受的盐，如盐酸盐等。可理解的，该
Figure PCTCN2020109818-appb-000040
盐可以含有本领域可接受保护基，应理解为均在本发明的保护范围内。
步骤S112a与S112b基本相同，不同之处在于，采用式(IVa)所示化合物代替步骤S112b中的式(IVa-1)所示化合物，现以步骤S112b为例进行进一步说明；
进一步地，步骤S112b包括以下步骤进行：
S1121：环化步骤，将式(IVa-1)所示化合物、
Figure PCTCN2020109818-appb-000041
盐、碱和溶剂混合，加热至50-100℃，待反应完成后，冷却，有固体析出，过滤获得的固体物质(即式(I-1)所示化合物)。
Figure PCTCN2020109818-appb-000042
Y、Z、R 1、R 2、R 3、R 4的定义如上所述，在此不再赘述。R 7为-OH或-NH 2。
更进一步地，上述环化步骤包括以下步骤：将Na加入至MeOH中，搅拌至完全反应后加入
Figure PCTCN2020109818-appb-000043
Figure PCTCN2020109818-appb-000044
盐，在N 2保护，室温搅拌预定时间(优选3-10min)。然后，将体系中的不溶物过滤，加入式(IVa-1)所示化合物，加热至回流，待反应完成后，冷却至室温搅拌40min-80min，过滤析出的固体物质。
上述环化步骤中，溶剂为质子性溶剂，优选为醇溶剂，包括但不限于：甲醇、乙醇和异丙醇中的一种或多种。碱可以为乙醇钠、甲醇钠、t-BuONa、t-BuOK和t-BuOLi中的一种或多种；优选为强碱，例如甲醇钠等。式(IVa-1)所示化合物与
Figure PCTCN2020109818-appb-000045
盐的摩尔比为1：(1～3)；式(IVa-1)所示化合物与碱的摩尔比为1：(2～5)；式(IVa-1)所示化合物与溶剂的比例为1g：(5～100mL)。
上述环化步骤中，采用R 4为-COOR 5、-CONR 6或-CN的原料，并创新性地利用
Figure PCTCN2020109818-appb-000046
盐进行环化反应，形成所需并环，首次应用到生物蝶呤类化合物的合成中，相比于传统方法具有明显 的优势：原子利用度高，转化率高，反应干净；副产物溶于反应溶剂，而产物难溶，易于纯化，本工艺只需过滤产品和简单洗涤即可获得高纯度产品(98％-99％)；
Figure PCTCN2020109818-appb-000047
盐成本相对较低，可以进一步降低生产成本。而传统环化工艺中采用
Figure PCTCN2020109818-appb-000048
为原料，需要准确调整反应体系的pH值，并精确控制温度，来水解乙酰基，以防止6-位侧链在水解时断裂，操作难度较大，不适宜工业生产应用。
S1122：水解步骤，将环化步骤中所获得的固体物质(即式(I-1)所示化合物)加入碱性溶液中，待反应完成，加入酸，调pH至5～6，有晶体析出，过滤干燥，即得式(I)所示的L-赤型生物蝶呤类化合物。
Figure PCTCN2020109818-appb-000049
R 1的定义如上所述，在此不再赘述。R 7为-OH或-NH 2。
更进一步地，上述水解步骤包括以下步骤：将式(I-1)所示化合物悬浮于碱性溶液中，加热至50℃-100℃，搅拌2h-5h；冷却至室温，再加入酸调pH至5-6，有晶体析出，过滤干燥，即得式(I)所示的L-赤型生物蝶呤类化合物。
其中，碱性溶液可以为无机碱溶液，例如氢氧化钠溶液、氢氧化钾溶液等，优选质量百分含量为5％-40％的氢氧化钠溶液。优选式(I-1)所示化合物和碱的摩尔比为1：(5～20)，更优选1：(5～10)。酸可以为有机酸或无机酸，例如甲酸，盐酸，硫酸，氢溴酸等，优选为甲酸。
可理解的，当R 4为-COOR 5或-CONR 6时，可以省去水解步骤。
可理解的，当将式(IVa-1)所示化合物进行处理获得式(IVa)所示化合物，使式(IVa)所示化合物与
Figure PCTCN2020109818-appb-000050
盐进行反应的步骤与上述方法基本相同，仅需将式(IVa)所示化合物替换式(IVa-1)所示化合物即可，在此不再进行赘述。
1.2反式烯烃制L-赤型生物蝶呤类化合物
当式(II)所示化合物中烯烃为反式结构时，由式(II)所示化合物制备式(I)所示化合物的步骤包括以下步骤：
S121：将式(IIb)所示化合物进行双羟化反应，制得式(IVb-1)和/或式(IVb-2)所示化合物。
Figure PCTCN2020109818-appb-000051
步骤S121中的双羟化反应同步骤S111，在此不再赘述。
S122：将式(IVb-1)和/或式(IVb-2)所示化合物进行乙酰化反应，制得式(VIIb-1)和/或式(VIIb-2)所示化合物。
Figure PCTCN2020109818-appb-000052
其中，步骤S122中的乙酰化反应可以包括以下步骤：
将式(Ⅳb-1)所示化合物和/或式(Ⅳb-2)所示化合物、乙酰化试剂和对甲苯磺酰胺(PTSA)溶于溶剂中，搅拌20min-50min，然后加入水继续搅拌，待反应完成，分离即得式(Ⅶb-1)和/或式(Ⅶb-2)所示化合物。其中，乙酰化试剂包括但不限于：醋酐、原乙酸三甲酯和乙酰氯中的一种或多种；溶剂可以为乙腈、THF、二氧六环、DCM和MTBE中的一种或多种等。
S123：将式(VIIb-1)和/或式(VIIb-2)所示化合物进行Mitsunobu反应，制得式(VIIb-3)和/或式(VIIb-4)所示化合物。
Figure PCTCN2020109818-appb-000053
具体地可以包括以下步骤：
将式(Ⅶb-1)所示化合物和/或式(Ⅶb-2)、亲核试剂
Figure PCTCN2020109818-appb-000054
PPh 3或Bu 3P、偶氮二甲酸二异丙酯(DIAD)或偶氮二甲酸二乙酸酯(DEAD)溶于溶剂中进行反应，反应完成后，分离即得所需产物。具体地试剂组合包括但不限于：DEAD/PPh 3、DIAD/PPh 3、DEAD/n-Bu 3P、或DIAD/n-Bu 3P等。
其中，R 10为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；优选R 10取代或未取代芳基，当芳基被进一步取代时，取代基选自C 1-6烷基或C 1-6烷氧基。更优选R 10为
Figure PCTCN2020109818-appb-000055
表示连接位点。
R 11为H、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；优选R 11为H或C 1-6烷基。
在一实施例中，
Figure PCTCN2020109818-appb-000056
为
Figure PCTCN2020109818-appb-000057
(萘普生)。
S124：将式(VIIb-3)和/或式(VIIb-4)所示化合物与
Figure PCTCN2020109818-appb-000058
盐(优选胍盐)进行环化反应，并水解，制得式(I)所示的L-赤型生物蝶呤类化合物。
Figure PCTCN2020109818-appb-000059
步骤S124同步骤S112，在此不再赘述，Y、Z、R 1、R 2、R 3、R 4和R 10的定义如上所述，在此不再赘述。E为卤素、C 1-4烷氧基、C 1-4烷硫基或-NH 2；进一步地，E为甲氧基、氯、甲硫基、或-NH 2；
当式(II)所示化合物中烯烃为顺式结构，通过采用双羟化反应和环化反应，两步即可高产率地获得所需构型的产物，可以大幅度地缩短反应路线，提高生产效率，降低生产成本。当式(II)所示化合物中烯烃为反式结构，先利用双羟化反应构建双羟基，形成两个手性中心，然后创新性的使用高选择性的邻二醇的单乙酰化反应，实现其中一个羟基乙酰化，并用Mitsunobu反应实现另一个羟基的手性翻转，获得所需构型的中间体，进而环化获得所需产物，大幅度地提高了原料的选择范围，进而可以选择相对廉价的原料。此外，乙酰化反应和Mitsunobu反应等步骤均具有较高的产率，且单乙酰化的副产物以及在Mitsunobu反应中未发生翻转的副产物亦可以通过简单地水解回收成为原料再次利用，保证了整个路线的经济性，符合工业生产的要求。
二、式(III)所示化合物制L-赤型生物蝶呤类化合物
可理解的，式(III)所示化合物可以为市售原料，或由式(II)所示化合物通过环化反应制得，例如可以采用式(II)所示化合物和
Figure PCTCN2020109818-appb-000060
盐进行环化。
2.1顺式烯烃制L-赤型生物蝶呤类化合物
进一步地，当式(III)所示化合物中烯烃为顺式结构时，由式(III)所示化合物制备式(I)所示的L-赤型生物蝶呤类化合物的步骤包括以下步骤：
S211：将式(III)所示化合物进行双羟化反应，制得式(I-1)所示化合物。
Figure PCTCN2020109818-appb-000061
步骤S211中的双羟化反应的反应试剂及其反应条件如步骤S111所述，在此不再赘述。
可理解的，步骤S211中也可以采用上述手性拆分试剂组进行拆分，拆分方法和手性拆分试剂组如上所述，仅需将步骤S111中的待拆分化合物替换为式(III)所示底物双羟基化反应后生成的待拆分化合物(
Figure PCTCN2020109818-appb-000062
的混合物)即可，在此不再进行赘述，应理解为均在本发明的保护范围内。
S212：式(I-1)所示化合物在碱性条件(如氢氧化钠等条件)下水解获得式(I)所示L-赤型生物蝶呤类化合物。
Figure PCTCN2020109818-appb-000063
步骤S212同步骤S1122，在此不再赘述。
2.2反式烯烃制L-赤型生物蝶呤类化合物
当式(III)所示化合物中烯烃为反式结构时，可以由式(III)所示化合物先进行双羟化反应，形成双羟基，然后进行乙酰化反应，然后进行Mitsunobu反应，即获得所需构型的产物。具体方法和步骤同S121～S124，在此不再赘述。
当式(III)所示化合物中烯烃为顺式结构，通过采用双羟化反应，即可高产率地获得所需构型的产物，可以大幅度地缩短反应路线，提高生产效率，降低生产成本。当(III)所示化合物中烯烃为反式结构，先利用双羟化反应构建双羟基，形成两个手性中心，然后创新性的使用高选择性的邻二醇的单乙酰化反应，实现其中一个羟基乙酰化，并用Mitsunobu反应实现另一个羟基的手性翻转，水解即可获得所需产物，大幅度地提高了原料的选择范围，进而可以选择相对廉价的原料。此外，乙酰化反应和Mitsunobu反应等步骤均具有较高的产率，且单乙酰化的副产物以及在Mitsunobu反应中未发生翻转的副产物亦可以通过简单地水解回收成为原料再次利用，保证了整个路线的经济性，符合工业生产的要求。
三、式(II)所示化合物和式(III)所示化合物的制备
需要说明的是，式(II)或式(III)所示化合物可以通过现有的方法合成，例如：Heck反应(参见J.Chem.Soc.,Chem.Commun.1983,15,793-794)，格式反应(参见Chemistry Letters 2014,43(6),922–924)，烷基锂脱溴与丙烯基溴反应(参见Chemistry-An Asian Journal 2012,7(5),1061–1068)，Stille反应(参见J.Org.Chem.1990,55,3019)，Negishi偶联(参见J.Chem.Soc.,Chem.Commun.1977,683-684)。也可以为市购原料，应理解为均在本发明的保护范围内。
但申请人在研究中发现，Heck反应制式(II)或式(III)所示化合物顺反选择和区域选择较差；格氏反应，虽然可以控制顺反，但需要制作较不稳定的芳基溴化镁，工业化难度较大；烷基锂脱溴与丙烯基溴反应，条件苛刻，转化率低；Stille反应，使用烯基锡试剂与底物发生偶联，需要合成剧毒有机锡，不适用工业生产；Negishi偶联，需要制作不稳定的且易燃的有机锌试剂，后处理复杂，不适宜工业生产应用。优选按以下方法合成，以更进一步提高生产效率，降低生产成本。
3.1式(II)所示化合物的合成
3.1.1顺式结构式(II)所示化合物的合成
当式(II)所示化合物中烯烃为顺式结构的式(IIa)所示化合物时，式(IIa)所示化合物由式(V)所示化合物通过催化氢化制得：
Figure PCTCN2020109818-appb-000064
具体地可以包括以下步骤：
将式(V)所示化合物、催化剂和溶剂混合，在氢气氛围下反应，待反应完成后，过滤，浓缩，得到顺式结构的式(IIa)所示化合物。
其中，催化剂可以选自：Lindlar催化剂、钯/碳、Raney镍、铂黑和二氧化铂中的一种或多种。溶剂可以选自：四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚、甲基环戊基醚、甲醇、乙醇、异丙 醇、乙腈和甲苯中的一种或多种。
优选式(V)所示化合物与溶剂的用量比为1g：(1～100mL)，更优选1g：(5～60mL)。式(V)所示化合物与催化剂的重量比为1：0.005～0.2，更优选0.01％～0.1。通入的氢气压力0.1-10MPa，更优选0.1-5MPa；反应温度优选0-50℃。
其中，式(V)所示化合物可以为市售原料，也可以采用现有的方法合成，优选采用以下方法合成：
S311：式(V)所示化合物由式(VI)所示化合物通过Sonogashira反应制得：
Figure PCTCN2020109818-appb-000065
其中，M为H或离去基团，优选M为卤素、磺酸酯、羧酸酯或磷酸酯，离去基团包括但不限于：卤素(例如：Cl、Br、I)、OSO nR 9、OCOR 10或OPO 2R 11；R 9、R 10或R 11各自独立地选自：-CF 3、烷基、苯基、或烷基取代苯基(例如甲苯基)，n为0、1或2，硅烷基可以为甲硅烷基等。其中，磺酸酯可以为：甲基苯磺酸酯、甲磺酸酯、三氟甲磺酸酯等。更优选，M为溴。
采用上述反应制备式(V)所示化合物，则可采用市场上广泛存在的式(VI)所示化合物作为原料，显著降低生产成本，且该反应收率高(>95％)，室温反应条件温和，可通过常规重结晶的方式获得产品。
具体地，可以包括以下步骤：
S3111：将式(VI)所示化合物、催化剂、配体和溶剂混合；
S3112：加入碱和
Figure PCTCN2020109818-appb-000066
反应完成后，淬灭反应，分离得到式(V)所示化合物。
上述步骤S3111中优选在0-35℃的条件下溶解，催化剂优选为铜催化剂和钯催化剂的组合，配体为磷配体。其中，铜催化剂可以为氯化亚铜、溴化亚铜和碘化亚铜中的一种或多种，优选碘化亚铜。钯催化剂可以为氯化钯、醋酸、PdCl 2(dppf)、Pd 2(dba) 3和Pd(PPh 3) 4中的一种或多种。
另外，上述步骤S3111中溶剂可以为四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚、甲基环戊基醚和乙腈中的一种或多种，优选为2-甲基四氢呋喃。步骤S3111中，碱可以为碳酸钾、碳酸钠、碳酸铯、三乙胺、二异丙基乙基氨、DBU、吡啶和对二甲氨基吡啶中的一种或多种。
另外，优选式(VI)所示化合物与溶剂的用量比为1g:(1～20mL)，优选1g:(5～15mL)。式(VI)所示化合物与催化剂的摩尔比为1:(1％～15％)，优选为1:(1％～10％)。式(VI)所示化合物与配体的摩尔比为1:(2％～30％)，优选1:(2～20％)；式(VI)所示化合物与碱的摩尔比为1:(5～15)。
3.1.2反式结构式(II)所示化合物的合成
当式(II)所示化合物中烯烃为反式结构的式(IIb)所示化合物时，式(IIb)所示化合物由式(VI)所示化合物通过偶联反应(如：Suzuki偶联反应)制得；
Figure PCTCN2020109818-appb-000067
其中M为H或离去基团，优选M为卤素、磺酸酯、羧酸酯或磷酸酯，离去基团包括但不限于：卤素(例如：Cl、Br、I)、OSO nR 9、OCOR 10或OPO 2R 11；R 9、R 10或R 11各自独立地选自：-CF 3、烷基、苯基、或烷基取代苯基(例如甲苯基)，n为0、1或2，硅烷基可以为甲硅烷基等。其中，磺酸酯可以为：甲基苯磺酸酯、甲磺酸酯、三氟甲磺酸酯等。更优选，M为溴。
具体地，可以包括以下步骤：
将式(VI)所示化合物、反式-1-丙烯基硼酸类试剂、催化剂、溶剂和配体混合，待反应完成后， 分离得到反式结构的式(IIb)所示化合物。
可理解的，其中，反式-1-丙烯基硼酸类试剂是指含有反式-1-丙烯基团的硼酸类试剂，包括但不限于：反式-1-丙烯基硼酸硼酸频哪醇酯、反式-1-丙烯基硼酸、或反式-1-丙烯基氟硼酸盐。
另外，优选催化剂选自：5％Pd/C、10％Pd/C、Pd(OAc) 2、PdCl 2(PPh 3) 2、Pd(PPh 3) 4、PdCl 2(dppf)、PdCl 2(MeCN) 2和Pd 2(dba) 3中一种或多种。溶剂选自：甲醇、乙醇、异丙醇、丁醇、水、四氢呋喃、2-甲基四氢呋喃、1.4-二氧六环、DME、DMF、DMSO、NMP、乙腈、二氯甲烷、1，2-二氯乙烷、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙醚、甲基叔丁基醚、甲苯、二甲苯、丙酮、甲基乙基酮和甲基环戊烷中的一种或多种。配体选自：PPh 3、BINAP、dppf、Xantphos、Xphos单磷及双磷配体中的一种或多种。
其中，式(VI)所示化合物可以为市售原料，也可以采用现有的方法制得。式(VI)所示化合物为吡嗪类化合物，为目前市场上广泛销售的化合物，例如：CAS：6966-01-4、612835-51-5、17890-77-6、17231-51-5等，成本较低，可以进一步降低整个工艺路线的制备成本。
3.2式(III)所示化合物的合成
式(III)所示化合物可以采用市售原料，也可以采用现有方法制备得到，优选式(III)所示化合物由式(II)所示化合物经环化反应制，即可以先进行环化反应，然后再进行双羟化反应，也可以经双羟化反应再进行环化反应。
3.2.1顺式结构式(III)所示化合物的合成
当式(III)所示化合物中烯烃为顺式结构的式(IIIa)所示化合物时，式(IIIa)所示化合物由式(VIII)所示化合物通过催化氢化制得：
Figure PCTCN2020109818-appb-000068
具体地可以包括以下步骤：
将式(VIII)所示化合物、催化剂和溶剂混合，在氢气氛围下反应，待反应完成后，过滤，浓缩得到顺式结构的式(IIIa)所示化合物。
其中，优选催化剂可以选自：Lindlar催化剂、钯/碳、Raney镍、铂黑和二氧化铂中的一种或多种；溶剂可以选自：四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚、甲基环戊基醚、甲醇、乙醇、异丙醇、乙腈和甲苯中的一种或多种。
优选式(VIII)所示化合物与溶剂的用量比为1g：(1～100mL)，更优选1g：(5～60mL)；式(VIII)所示化合物与催化剂的重量比为1：0.005～0.2，更优选0.01％～0.1；通入的氢气压力0.1-10MPa，更优选0.1-5MPa；反应温度优选0-50℃。
其中，式(VIII)所示化合物可以为市售原料，也可以采用现有方法制得，优选采用以下方法制备而成：
S3211：由式(VI)所示化合物通过Sonogashira反应制得式(V)所示化合物。
Figure PCTCN2020109818-appb-000069
具体地，可以采用S3111～S3112的方法制备式(V)所示化合物，在此不再赘述。
S3212：由式(V)所示化合物经环化反应制得式(VIII)所示化合物。
Figure PCTCN2020109818-appb-000070
具体地，可以采用以下方法进行环化：
式(V)所示化合物与
Figure PCTCN2020109818-appb-000071
盐(优选为胍盐)进行环化反应，可理解的，该
Figure PCTCN2020109818-appb-000072
Figure PCTCN2020109818-appb-000073
盐如上所述，在此不再进行赘述。
进一步地，步骤S3212可以包括以下步骤进行：将式(V)所示化合物、
Figure PCTCN2020109818-appb-000074
盐、碱和溶剂混合，加热至50-100℃，待反应完成后，过滤，即得式(VIII)所示化合物。其中，溶剂为醇类溶剂，优选为甲醇、乙醇和异丙醇中的一种或多种；碱可以为乙醇钠、甲醇钠、t-BuONa、t-BuOK和t-BuOLi中的一种或多种；优选为强碱，例如甲醇钠等。
进一步地，步骤S3212可以包括以下步骤：将Na加入至MeOH中搅拌至完全反应后加入
Figure PCTCN2020109818-appb-000075
Figure PCTCN2020109818-appb-000076
盐，在N 2保护，室温搅拌3-10min。然后，将体系中的不溶物过滤，加入式(V)所示化合物，加热至回流，待反应完成后，冷却至室温搅拌40min-80min，过滤析出的固体物质，即得式(VIII)所示化合物。
3.2.2反式结构式(III)所示化合物的合成
当式(III)所示化合物中烯烃为反式结构时，式(III)所示化合物可以由以下方法制得：
S3221：式(VI)所示化合物通过偶联反应制得式(II)所示化合物；
Figure PCTCN2020109818-appb-000077
M为H或离去基团；优选M为卤素、磺酸酯、羧酸酯或磷酸酯，其中，磺酸酯可以为：甲基苯磺酸酯、甲磺酸酯、三氟甲磺酸酯等；
步骤S3221的偶联反应同上，在此不再赘述。
S3222：式(II)所示化合物经环化反应制得式(IIIb)所示化合物；
Figure PCTCN2020109818-appb-000078
步骤S3222的环化反应步骤同上，在此不再赘述。
三、优选反应路线
路线一
Figure PCTCN2020109818-appb-000079
其中，各取代基的定义如上所述，在此不再赘述。式(I)所示L-赤型生物蝶呤类化合物的制备方法包括以下步骤：
(1)式(VI)所示化合物和
Figure PCTCN2020109818-appb-000080
进行Sonogashira反应，制得式(V)所示化合物；
(2)式(V)所示化合物经催化氢化，制得式(IIa)所示化合物；
(3)式(IIa)所示化合物经双羟化反应，制得式(IVa)所示化合物；优选地采用手性拆分试剂组进行手性拆分，手性拆分试剂组及拆分方法如上所述；
(4)式(IVa)所示化合物或式(IVa-1)所示化合物
Figure PCTCN2020109818-appb-000081
进行环化反应，制得式(I-1)所示化合物，将式(I-1)所示化合物进行水解，制得式(I)所示L-赤型生物蝶呤类化合物。
上述(1)～(4)中，各反应的具体介绍如上所述，在此不再赘述。可理解的，当R 4为-COOR 5或-CONR 6时，可以省去步骤(4)中的水解步骤。
本实施例中，以(VI)所示化合物为起始原料，与炔发生交叉偶联反应，催化氢化获得顺式烯烃。然后创新性地采用系统双羟基化反应构建两个手性中心，随后通过手性分离纯化，获得单一对映体(R,S)-吡嗪丙二醇类化合物。随后经环合，获得L-赤型生物蝶呤蝶呤类化合物。大幅度缩短反应路线，且各步产率较高，原子利用率高，避免采用传统的5-脱氧-L-阿拉伯糖与2，4，5-三氨基-6-羟基嘧啶(TAP)缩合制备L-赤式生物蝶呤，进而全面克服现有工业制法存在的低效、低收率、高成本、高污染的缺点。
路线二
Figure PCTCN2020109818-appb-000082
(1)式(VI)所示化合物和
Figure PCTCN2020109818-appb-000083
进行Sonogashira反应，制得式(V)所示化合物；
(2)式(V)所示化合物经环化反应，制得式(VIII)所示化合物；
(3)式(VIII)所示化合物催化氢化制得式(III)所示化合物；
(4)式(III)所示化合物经双羟化反应，制得式(I-1)所示化合物；
(5)式(I-1)所示化合物在碱性条件下水解获得式(I)所示L-赤型生物蝶呤类化合物。
上述(1)～(5)中，各反应的具体介绍如上所述，在此不再赘述。可理解的，当R 4为-COOR 5或-CONR 6时，可以省去步骤(5)中的水解步骤。
本实施例中，以(VI)所示化合物为起始原料，与炔发生交叉偶联反应，然后依次环化、催化氢化，获得所需顺式烯烃。双羟基化后构建两个手性中心，随后通过手性分离纯化，即可获得所需L-赤型生物蝶呤蝶呤类化合物，大幅度缩短反应路线，且各步产率较高，原子利用率高，避免采用传统的5-脱氧-L-阿拉伯糖与2，4，5-三氨基-6-羟基嘧啶(TAP)缩合制备L-赤式生物蝶呤，进而全面克服现有工业制法存在的低效、低收率、高成本、高污染的缺点。
路线三
Figure PCTCN2020109818-appb-000084
(1)式(VI)所示化合物进行偶联反应，制得式(IIb)所示化合物；
(2)式(IIb)所示化合物经双羟化反应，制得式(IVb-1)和/或式(IVb-2)所示化合物；
(3)将式(IVb-1)和/或式(IVb-2)所示化合物进行乙酰化反应，制得式(VIIb-1)和/或式(VIIb-2)所示化合物；
(4)将式(VIIb-1)和/或式(VIIb-2)所示化合物进行Mitsunobu反应，制得式(VIIb-3)和/或式(VIIb-4)所示化合物；
(5)将所述(VIIb-3)和/或式(VIIb-4)所示化合物与
Figure PCTCN2020109818-appb-000085
盐(优选为胍盐)进行环化反应，并水解，制得式(I)所示的L-赤型生物蝶呤类化合物。
上述(1)～(4)中，各反应的具体介绍如上所述，在此不再赘述。可理解的，当R 4为-COOR 5或-CONR 6时，可以省去步骤(5)中的水解步骤。
上述方法以(VI)所示化合物为起始原料，利用偶联反应构建烯烃，并创新性地对烯烃进行双羟化反应、乙酰化反应和Mitsunobu反应，获得所需构型的产物。充分利用了各反应的性质，提高立体选择性，扩大原料选择范围，且单乙酰化的副产物以及在Mitsunobu反应中未发生翻转的副产物亦可以通过简单地水解回收成为原料再次利用，保证了整个路线的经济性。且避免采用传统的5-脱氧-L-阿拉伯 糖与2，4，5-三氨基-6-羟基嘧啶(TAP)缩合制备L-赤式生物蝶呤，避免了环境污染的同时，提高了生产安全性。
下面列举具体实施例来对本发明进行说明。
实施例1
Figure PCTCN2020109818-appb-000086
称取200mg化合物8，11mg CuI，10mg PdCl 2，30mg PPh 3置于25mL三口烧瓶中，加入5mL乙腈。室温搅拌下加入0.7mL三乙胺和1.1mL丙炔(1M in THF)，反应搅拌16h。加入10mL水淬灭反应，分液，有机层干燥浓缩获得163mg化合物6粗品，用于下一步反应。IR(cm -1)ν3400,2226,1647,1487,1192； 1H NMR(400MHz,DMSO-d 6)δ8.26(s,1H),7.54(s,2H),2.01(s,3H), 13C NMR(101MHz,DMSO)δ155.61,150.33,128.08,115.71,111.16,88.27,76.62,4.18.HRMS m/z(ESI+)C 8H 7N 4 +requires:159.0667；found:159.0671.
Figure PCTCN2020109818-appb-000087
将62mg Na加入至10mL MeOH中搅拌至完全反应后加入226mg盐酸胍N 2保护，室温搅拌5min。将体系中的不溶物过滤，加入163mg化合物6。加热至回流搅拌18h。将反应体系冷却至室温搅拌1h，过滤体系中析出的黄色晶体，得144mg化合物5(纯度>99％，两步收率71.6％)；IR(cm -1)ν3421,3102,1635,1456,1507,1063； 1H NMR(500MHz,DMSO-d6)δ8.91(s,1H),7.08(s,2H),6.33(s,2H),2.06(s,3H)； 13C NMR(125MHz,DMSO)δ163.83,162.42,155.36,146.65,136.10,119.12,91.24,83.52,4.73.HRMS m/z(ESI+)C 9H 9N 6 +requires:201.4358；found:201.4359.
Figure PCTCN2020109818-appb-000088
将144mg化合物5加入20mL THF中加热50℃溶解，加入150mg Lindlar Pd并置换H 2在1atm下搅拌3天，过滤催化剂，浓缩获得化合物4(120mg，纯度90％收率83％)；IR(cm -1)ν3294,1646,1508,1479,1380,1046； 1H NMR(500MHz,DMSO)δ8.49(s,1H),7.28(d,J＝9.0Hz,1H),7.07(d,J＝9.5Hz,1H),6.75–6.69(m,1H),6.58(s,2H),6.23(dq,J＝10.5,6.0Hz,1H),1.92(dd,J＝6.0,1.1Hz,3H). 13C NMR(125MHz,DMSO)δ161.42,154.82,147.13,144.39,129.56,126.01,118.45,17.04,16.95.HRMS m/z(ESI+)C 9H 11N 6 +requires:203.2210；found:203.2208.
Figure PCTCN2020109818-appb-000089
将化合物4进行双羟化反应，包括以下方法：
1)Sharpless不对称双羟化反应
称取5.2g AD-mix-α，置于250mL的三口瓶中，加入10mL水和10mL叔丁醇。搅拌下，加入143mg MsNH 2和120mg化合物4。反应升至室温，搅拌16h。过滤不溶物。分液，水相用乙酸乙酯萃取三次(30mL x 3)，合并有机相，加NaSO 4干燥，浓缩得到151mg深棕色油状物。将该粗品通过手 性制备获得单一手性中间体2(54mg收率42％)。
2)使用KMnO 4完成双羟基化反应
往10mL THF中加入100mg化合物4，将体系冷却至0℃，加入10mL pH＝12 1％的高锰酸钾的水溶液，并加入5mg四丁基氯化铵，反应保持0℃搅拌过夜。分液，水相用EA 5mLx3萃取，合并油相，使用Na 2SO 4干燥后过滤，浓缩，甲醇洗涤后获得黄色固体86mg将该粗品通过手性制备获得单一手性中间体2(28mg收率22％)。
3)使用Fe催化完成双羟基化反应
取100mg化合物4用10mL THF溶解，加入催化剂[FeIII(L-N4Me 2)Cl 2]+3.5mol％oxone(2equiv)and NaHCO 3(6equiv)的水溶液5mL，反应室温搅拌过夜。分液，收集油相，浓缩后用甲醇洗涤获得黄色固体粗品76mg。将该粗品通过手性制备获得单一手性中间体2(16mg收率12.4％)。
IR(cm -1)ν3288,1655,1514,1469,1379,1058； 1H NMR(500MHz,DMSO-d 6)δ8.72(s,1H),7.63(s,2H),6.58(s,2H),5.45(s,1H),4.68(s,1H),4.41(d,J＝6.3Hz,1H),3.84(p,J＝6.2Hz,1H),1.11(d,J＝6.2Hz,3H)； 13C NMR(126MHz,DMSO)δ162.93,162.81,155.25,149.73,149.60,120.48,76.43,69.73,19.55；HRMS m/z(ESI+)C 9H 13N 6O 2 +requires:237.1095；found:237.1094.
Figure PCTCN2020109818-appb-000090
将获得的54mg化合物2悬浮于5mL NaOH(80mg)水溶液中，反应加热至78℃搅拌3h。冷却至室温，滴加HCOOH调节pH＝5～6，冷却至室温过滤析出的晶体，获得化合物1，即L-赤型生物蝶呤(51mg,纯度>99％,收率>99％)；IR(cm -1)ν3249,1701,1537,1490,1367,1127； 1H NMR(500MHz,DMSO-d 6)δ11.42(s,1H),8.70(s,1H),6.87(s,2H),5.58(d,J＝4.9Hz,1H),4.69(d,J＝5.3Hz,1H),4.43(t,J＝5.3Hz,1H),3.90(h,J＝6.1Hz,1H),1.05(d,J＝6.3Hz,3H)； 13C NMR(126MHz,DMSO)δ161.03,156.55,153.61,151.86,148.98,127.08,76.85,69.42,19.11.HRMS m/z(ESI+)C 9H 12O 3N 5 +requires:238.0935；found:238.0935.
实施例2
Figure PCTCN2020109818-appb-000091
将200mg化合物5置于分散于5mL含有50mg NaOH的水溶液中，并加热至78℃，搅拌1h，滴加醋酸将体系中和至pH＝5-6，过滤析出的固体，用甲醇洗涤，获得化合物5-1(152mg，纯度98％，收率76％)；
将152mg化合物5-1溶解于5mL MeOH/DCM＝1/1的组合溶液中，充分搅拌溶解，加入Lindlar Pd100mg，置换H 2(1atm)室温搅拌3天。过滤催化剂后，浓缩溶剂获得化合物3(150mg，纯度95％，收率93％)； 1H NMR(500MHz,DMSO)δ12.3(s,1H),8.53(s,1H),6.49(s,2H),2.04(s,3H). 13C NMR(125MHz,DMSO)δ161.85,156.13,150.79,148.55,136.37,127.07,92.12,85.24,4.59.HRMS m/z(ESI+)C 9H 10N 5O +requires:203.2050,found:203.2051
Figure PCTCN2020109818-appb-000092
将化合物3进行双羟化反应，包括以下方法：
1)Sharpless不对称双羟化反应
称取2.6g AD-mix-α，置于100mL的三口瓶中，加入5mLH2O和5mL t-BuOH。搅拌下，加入70mg MsNH 2和150mg化合物3。反应升至室温，搅拌16h。过滤不溶物。分液，水相用2-MeTHF萃取三次(30mL x 3)，合并有机相，加NaSO 4干燥，浓缩得到56mg深棕色油状物。将该粗品通过手性制备获得单一手性化合物1(19mg，收率11％)。
2)使用KMnO 4完成双羟基化反应
配制10mL pH＝12 1％的高锰酸钾的水溶液，加入150mg化合物3，反应保持0℃搅拌过夜。加入Na 2SO 3淬灭反应，并加入醋酸调节pH＝5-7，过滤产物，将该粗品通过手性制备获得单一手性化合物1(40mg，收率21％)。
3)使用Fe催化完成双羟基化反应
将化合物3 150mg加入含有催化剂[FeIII(L-N4Me 2)Cl 2]+3.5mol％oxone(2equiv)and NaHCO3(6equiv)的水溶液5mL中，反应室温搅拌过夜。加入Na 2SO 3淬灭反应，并加醋酸调节pH＝5-7，将析出的产品过滤。将该粗品通过手性制备获得单一手性化合物1(15mg，收率8.7％)。
IR(cm -1)ν3249,1701,1537,1490,1367,1127； 1H NMR(500MHz,DMSO-d 6)δ11.42(s,1H),8.70(s,1H),6.87(s,2H),5.58(d,J＝4.9Hz,1H),4.69(d,J＝5.3Hz,1H),4.43(t,J＝5.3Hz,1H),3.90(h,J＝6.1Hz,1H),1.05(d,J＝6.3Hz,3H)； 13C NMR(126MHz,DMSO)δ161.03,156.55,153.61,151.86,148.98,127.08,76.85,69.42,19.11.HRMS m/z(ESI+)C 9H 12O 3N 5 +requires:238.0935；found:238.0935.
实施例3
Figure PCTCN2020109818-appb-000093
称取200mg化合物8，11mg CuI，10mg PdCl 2，30mg PPh 3置于25mL三口烧瓶中，加入5mL乙腈。室温搅拌下加入0.7mL三乙胺和1.1mL丙炔(1M in THF)，反应搅拌16h。加入10mL水淬灭反应，分液，有机层干燥浓缩获得160mg化合物6粗品，用于下一步反应。
Figure PCTCN2020109818-appb-000094
将得到的500mg化合物6加入高压釜中，加入500mg Lindlar催化剂和10mL THF，置换H 2三次，于室温搅拌16小时。过滤催化剂，浓缩得到400mg化合物5a；IR(cm -1)ν3401,3202,2222,1644,1492,1515,1172； 1H NMR(500MHz,DMSO-d 6)δ8.27(s,1H),7.33(s,2H),6.30(dq,J＝11.7,1.8Hz,1H),5.88(dq,J＝11.7,7.3Hz,1H),2.01(dd,J＝7.3,1.8Hz,3H)； 13C NMR(126MHz,DMSO)δ154.87,147.91,141.32,129.95,124.29,116.05,109.58,14.88；HRMS m/z(ESI+)C 8H 9N 4 +requires:161.0822；found:161.0821.
Figure PCTCN2020109818-appb-000095
将化合物5a进行双羟化反应，包括以下方法：
1)Sharpless不对称双羟化反应
称取6.5g AD-mix-α，置于250mL的三口瓶中，加入10mL水和10mL叔丁醇。搅拌下，加入180mg MsNH 2和350mg化合物5a。反应升至室温，搅拌16h。过滤不溶物。分液，水相用乙酸乙酯萃取三次(30mL x 3)，合并有机相，加NaSO 4干燥，浓缩得到200mg深棕色油状物。将该粗品通过手性制备获得单一手性中间体4a；IR(cm -1)ν3374,3196,2236,1655,1572,1496,1065； 1H NMR(500 MHz,DMSO-d 6)δ8.30(s,1H),7.17(s,2H),5.42(d,J＝5.1Hz,1H),4.57(d,J＝5.3Hz,1H),4.21(dd,J＝6.0,5.1Hz,1H),3.84–3.75(m,1H),1.04(d,J＝6.2Hz,3H)； 13C NMR(126MHz,DMSO)δ156.21,146.77,146.63,116.26,108.70,76.21,69.18,19.34；HRMS m/z(ESI+)C 8H 11N 4O 2 +requires:195.0877；found:195.0878.
2)使用KMnO 4完成双羟基化反应：往10mL THF中加入80mg化合物5a，将体系冷却至0℃，加入10mL pH＝12 1％的高锰酸钾的水溶液，并加入5mg四丁基氯化铵，反应保持0℃搅拌过夜。分液，水相用EA 5mLx3萃取，合并油相，使用Na 2SO 4干燥后过滤，浓缩，甲醇洗涤后获得黄色固体88mg将该粗品通过手性制备获得单一手性中间体4a(31mg，收率32％)。
3)使用Fe催化完成双羟基化反应
取80mg化合物5a用10mL THF溶解，加入催化剂[FeIII(L-N4Me 2)Cl 2]+3.5mol％oxone(2equiv)和NaHCO 3(6equiv)的水溶液5mL，反应室温搅拌过夜。分液，收集油相，浓缩后用甲醇洗涤获得黄色固体粗品64mg。将该粗品通过手性制备获得单一手性中间体4a(13mg收率17％)。
Figure PCTCN2020109818-appb-000096
将62mg Na加入至10mL MeOH中搅拌至完全反应后加入226mg盐酸胍N 2保护，室温搅拌5min。将体系中的不溶物过滤，加入200mg单一手性中间体4a。加热至回流搅拌18h。将反应体系冷却至室温搅拌1h，过滤体系中析出的黄色晶体，得150mg化合物2(纯度>99％，收率68％)。
Figure PCTCN2020109818-appb-000097
将获得的100mg化合物2悬浮于10mL NaOH(160mg)水溶液中，反应加热至78℃搅拌3h。冷却至室温，滴加HCOOH调节pH＝5～6，冷却至室温过滤析出的晶体，获得化合物1，即L-赤型生物蝶呤(100mg,纯度>99％,收率>99％)；IR(cm -1)ν3249,1701,1537,1490,1367,1127； 1H NMR(500MHz,DMSO-d 6)δ11.42(s,1H),8.70(s,1H),6.87(s,2H),5.58(d,J＝4.9Hz,1H),4.69(d,J＝5.3Hz,1H),4.43(t,J＝5.3Hz,1H),3.90(h,J＝6.1Hz,1H),1.05(d,J＝6.3Hz,3H)； 13C NMR(126MHz,DMSO)δ161.03,156.55,153.61,151.86,148.98,127.08,76.85,69.42,19.11.HRMS m/z(ESI+)C 9H 12O 3N 5 +requires:238.0935；found:238.0935.
实施例4
Figure PCTCN2020109818-appb-000098
称取化合物8 200mg,E-丙烯基硼酸104mg,Pd(dppf)Cl 2 37mg,K 2CO 3 500mg溶解于1,4-diox/H 2O(v/v＝3mL/2mL)，反应加热至回流，搅拌3h，经TLC检测鉴定反应完全。分液，水相用EA萃取合并油相后，Na 2SO 4干燥，浓缩柱层析(EA/heptane＝1/5-1/3)获得黄色固体5b(100mg)；IR(cm -1)ν3384,2231,1667,1574,1498,1316,1166； 1H NMR(500MHz,DMSO-d 6)δ8.31(s,1H),7.18(s,2H),5.35(d,J＝5.4Hz,1H),4.54(d,J＝5.4Hz,1H),4.26(t,J＝5.0Hz,1H),3.81–3.71(m,1H),1.00(d,J＝6.4Hz,3H)； 13C NMR(126MHz,DMSO)δ156.14,146.56,146.40,116.20,108.75,75.85,69.04,19.22；HRMS m/z(ESI+)C 8H 11N 4O 2 +requires:195.0879；found:195.0877.
Figure PCTCN2020109818-appb-000099
将化合物5b进行双羟化反应，包括以下方法：
1)Sharpless不对称双羟化反应
称取AD-mix-α,7.0g分散于t-BuOH/H 2O(30mL/30mL),置于0℃下搅拌5min后，加入MsNH 2475mg，置于0℃下搅拌5min，加入化合物5b 800mg升温至4℃，反应搅拌2d，HPLC检测反应完全，将10g Na 2SO 3加入体系中，并在室温下搅拌30min，过滤，滤渣用50mL EA洗涤，滤液分液后，水相用EA 50mL x 3萃取，合并有机相，用Na2SO4干燥后，使用柱层析提纯，(HEP:EA＝5:1-0:1)获得浅黄色固体4b(1.08g收率>99％,纯度＝98％ee＝94％)；IR(cm -1)ν3384,2231,1667,1574,1498,1316,1166； 1H NMR(500MHz,DMSO-d 6)δ8.31(s,1H),7.18(s,2H),5.35(d,J＝5.4Hz,1H),4.54(d,J＝5.4Hz,1H),4.26(t,J＝5.0Hz,1H),3.81–3.71(m,1H),1.00(d,J＝6.4Hz,3H)； 13C NMR(126MHz,DMSO)δ156.14,146.56,146.40,116.20,108.75,75.85,69.04,19.22；HRMS m/z(ESI+)C 8H 11N 4O 2 +requires:195.0879；found:195.0877.
2)使用KMnO 4完成双羟基化反应
往10mL THF中加入80mg化合物5b，将体系冷却至0℃，加入10mL pH＝12 1％的高锰酸钾的水溶液，并加入5mg四丁基氯化铵，反应保持0℃搅拌过夜。分液，水相用EA 5mLx3萃取，合并油相，使用Na2SO4干燥后过滤，浓缩，甲醇洗涤后获得黄色固体91mg将该粗品通过手性制备获得单一手性中间体4b(33mg收率34％)。
4)使用Fe催化完成双羟基化反应
取80mg化合物5b用10mL THF溶解，加入催化剂[FeIII(L-N4Me 2)Cl 2]+3.5mol％oxone(2equiv)and NaHCO3(6equiv)的水溶液5mL，反应室温搅拌过夜。分液，收集油相，浓缩后用甲醇洗涤获得黄色固体粗品64mg。将该粗品通过手性制备获得单一手性中间体4b(15mg收率20％)。
IR(cm -1)ν3384,2231,1667,1574,1498,1316,1166； 1H NMR(500MHz,DMSO-d 6)δ8.31(s,1H),7.18(s,2H),5.35(d,J＝5.4Hz,1H),4.54(d,J＝5.4Hz,1H),4.26(t,J＝5.0Hz,1H),3.81–3.71(m,1H),1.00(d,J＝6.4Hz,3H)； 13C NMR(126MHz,DMSO)δ156.14,146.56,146.40,116.20,108.75,75.85,69.04,19.22；HRMS m/z(ESI+)C 8H 11N 4O 2 +requires:195.0879；found:195.0877.
Figure PCTCN2020109818-appb-000100
将化合物4b 800mg分散ACN 100mL中充分搅拌，加入1.48g H 3CC(OEt) 3 39mg PTSA搅拌至完全溶解后继续搅拌30min后往体系中加入1mL H 2O体系继续搅拌30min，TLC检测原料完全反应，生成两种产物直接往体系中加入硅胶拌样后柱层析获得化合物3b-2 400mg，以及化合物3b-1和化合物3b-2的混合物421mg，将化合物3b-1和化合物3b-2的混合物加入至NH 3/MeOH溶液中，搅拌30min后生成化合物4b重复上述单乙酰化过程，得到化合物3b-2 260mg，两次反应得到的化合物3b-2共660mg，纯度90％，收率61％；
化合物3b-2谱图数据：IR(cm -1)ν3452,3340,2223,1697,1616,1482,1372,1044； 1H NMR(500MHz,DMSO-d 6)δ8.33(s,1H),7.29(s,2H),5.77(d,J＝5.3Hz,1H),5.03(qd,J＝6.5,5.1Hz,1H),4.53(t,J＝5.3Hz,1H),1.93(s,3H),1.10(d,J＝6.5Hz,3H). 13C NMR(126MHz,DMSO)δ169.75,156.23,146.23,144.84,115.98,109.15,73.02,72.05,20.88,16.00.HRMS m/z(ESI+)C 10H 12O 3N 4Na +requires:259.0802；found:259.0801.
Figure PCTCN2020109818-appb-000101
称取化合物3b-2 500mg,萘普生732mg,PPh 3 834mg,溶解于THF 30mL中，0℃下滴加DIAD 0.63mL,反应搅拌过夜。HPLC检测反应完全，将体系加饱和NaHCO3水溶液，淬灭，分液，水相用EA 20mLx2萃取。合并油相后，Na 2SO 4干燥，浓缩柱层析(EA/Heptane＝1/2)分别获得化合物2b-1(272mg，纯度97％，收率28％)。生成化合物2b-2 610mg加入至NH 3/MeOH溶液中，搅拌1h可再次生成化合物4b 260mg回收做为上游反应原料。
化合物2b-1谱图数据：IR(cm -1)ν3331,2224,1740,1630,1233  1H NMR(500MHz,DMSO-d 6)δ7.90-7.69(m,4H),7.48-7.36(m,3H),7.34–7.23(m,1H),7.19–7.10(m,1H),5.69(d,J＝4.2Hz,1H),5.28–5.13(m,1H),4.05(q,J＝7.0Hz,1H),3.86(s,3H),1.89(s,3H),1.51(d,J＝7.1Hz,3H),1.09(d,J＝6.6Hz,3H)； 13C NMR(126MHz,DMSO)δ172.77,169.44,157.23,156.29,145.61,139.20,134.99,133.36,129.14,128.36,126.92,126.27,125.81,118.82,115.55,109.62,105.74,74.45,69.72,55.15,44.36,20.64,17.80,14.74.HRMS m/z(ESI+)C 24H 24O 5N 4Na +requires:471.1639；found:471.1637.
Figure PCTCN2020109818-appb-000102
称取Na 77mg加入至30mL甲醇中，充分搅拌至完全反应。取其中3mL，加入盐酸胍32mg N 2保护下搅拌5min，过滤不溶物后，加入化合物2b-1 50mg，反应加热至回流搅拌过夜,此时析出亮黄色晶体，过滤析出的晶体，获得化合物2(15.3mg，收率58％)；IR(cm -1)ν3288,1655,1514,1469,1379,1058； 1H NMR(500MHz,DMSO-d 6)δ8.72(s,1H),7.63(s,2H),6.58(s,2H),5.45(s,1H),4.68(s,1H),4.41(d,J＝6.3Hz,1H),3.84(p,J＝6.2Hz,1H),1.11(d,J＝6.2Hz,3H)； 13C NMR(126MHz,DMSO)δ162.93,162.81,155.25,149.73,149.60,120.48,76.43,69.73,19.55；HRMS m/z(ESI+)C 9H 13N 6O 2 +requires:237.1095；found:237.1094.
Figure PCTCN2020109818-appb-000103
将获得的100mg化合物2悬浮于10mL NaOH(160mg)水溶液中，反应加热至78℃搅拌3h。冷却至室温，滴加HCOOH调节pH＝5～6，冷却至室温过滤析出的晶体，获得化合物1，即L-赤型生物蝶呤(100mg,纯度>99％,收率>99％).
实施例5
Figure PCTCN2020109818-appb-000104
将化合物5b进行双羟化反应，包括以下方法：
1)Sharpless不对称双羟化反应
称取AD-mix-β,7.0g分散于t-BuOH/H 2O(30mL/30mL),置于0℃下搅拌5min后，加入MsNH 2475mg，置于0℃下搅拌5min，加入化合物5b 800mg升温至4℃，反应搅拌2d，HPLC检测反应完全，将10g Na 2SO 3加入体系中，并在室温下搅拌30min，过滤，滤渣用50mL EA洗涤，滤液分液后，水相用EA 50mL x 3萃取，合并有机相，用Na2SO4干燥后，使用柱层析提纯，(HEP:EA＝5:1-0:1)获得浅黄色固体4b-1(979mg，收率>99％，纯度＝98％，ee＝92％)
IR(cm -1)ν3374,2230,1668,1570,1486,1166； 1H NMR(500MHz,DMSO-d 6)δ8.31(s,1H),7.18(s,2H),5.35(d,J＝5.4Hz,1H),4.54(d,J＝5.4Hz,1H),4.26(t,J＝5.0Hz,1H),3.81–3.71(m,1H),1.00(d,J＝6.4Hz,3H)； 13C NMR(126MHz,DMSO)δ156.14,146.56,146.40,116.20,108.75,75.85,69.04,19.22；HRMS m/z(ESI+)C 8H 11N 4O 2 +requires:195.0879；found:195.0877.
2)使用KMnO 4完成双羟基化反应
往10mL THF中加入80mg化合物5b，将体系冷却至0℃，加入10mL pH＝12 1％的高锰酸钾的水溶液，并加入5mg四丁基氯化铵，反应保持0℃搅拌过夜。分液，水相用EA 5mLx3萃取，合并油相，使用Na 2SO 4干燥后过滤，浓缩，甲醇洗涤后获得黄色固体91mg将该粗品通过手性制备获得单一手性中间体4b-1(29mg，收率30％)。
3)使用Fe催化完成双羟基化反应
取80mg化合物5b用10mL THF溶解，加入催化剂[FeIII(L-N4Me 2)Cl 2]+3.5mol％oxone(2equiv)and NaHCO3(6equiv)的水溶液5mL，反应室温搅拌过夜。分液，收集油相，浓缩后用甲醇洗涤获得黄色固体粗品64mg。将该粗品通过手性制备获得单一手性中间体化合物4b-1(12mg，收率16％)；IR(cm -1)ν3384,2231,1667,1574,1498,1316,1166； 1H NMR(500MHz,DMSO-d 6)δ8.31(s,1H),7.18(s,2H),5.35(d,J＝5.4Hz,1H),4.54(d,J＝5.4Hz,1H),4.26(t,J＝5.0Hz,1H),3.81–3.71(m,1H),1.00(d,J＝6.4Hz,3H)； 13C NMR(126MHz,DMSO)δ156.14,146.56,146.40,116.20,108.75,75.85,69.04,19.22；HRMS m/z(ESI+)C 8H 11N 4O 2 +requires:195.0879；found:195.0877.
Figure PCTCN2020109818-appb-000105
将化合物4b-1 800mg分散ACN 100mL中充分搅拌，加入1.48g H 3CC(OEt) 3 39mg PTSA搅拌至完全溶解后继续搅拌30min后往体系中加入1mL H 2O体系继续搅拌30min，TLC检测原料完全反应，生成两种产物直接往体系中加入硅胶拌样后柱层析获得化合物3b-3 200mg，以及化合物3b-4和化合物3b-3的混合物611mg，将化合物3b-4和化合物3b-3的混合物加入至NH 3/MeOH溶液中，搅拌30min后生成化合物4b-1重复上述单乙酰化过程，得到化合物3b-3 240mg，两次反应得到的化合物3b-4共440mg，纯度90％，收率41％；IR(cm -1)ν3426,2220,1683,1606,1485,1373； 1H NMR(500MHz,DMSO-d 6)δ8.28(s,1H),7.38(s,2H),5.38(d,J＝6.0Hz,1H),4.04-3.96(m,1H),2.08(s,3H),0.98(d,J＝6.4Hz,3H)； 13C NMR(126MHz,DMSO)δ170.00,156.37,146.69,141.44,115.84,109.67,77.50,66.91,20.81,19.06.HRMS m/z(ESI+)C 10H 12O 3N 4Na +requires:259.0802；found:259.0803.
Figure PCTCN2020109818-appb-000106
称取化合物3b-3 100mg,萘普生147mg,PPh 3167mg,溶解于THF 10mL中，0℃下滴加DIAD 0.2mL,反应搅拌过夜。HPLC检测反应完全，将体系加饱和NaHCO 3水溶液，淬灭，分液，水相用EA 20mLx2萃取。合并油相后，Na 2SO 4干燥，浓缩柱层析(EA/Heptane＝1/2)分别获得化合物2b-3(52m，纯度97％，收率27％)。
Figure PCTCN2020109818-appb-000107
称取Na 77mg加入至30mL甲醇中，充分搅拌至完全反应。取其中3mL，加入盐酸胍32mg N 2保护下搅拌5min，过滤不溶物后，加入化合物2b-3 50mg,反应加热至回流搅拌过夜,此时析出亮黄色晶体，过滤析出的晶体，获得化合物2(16.8mg，收率64％)；IR(cm -1)ν3329,2222,1736,1625,1225  1H NMR(500MHz,DMSO-d 6)δ7.99-7.65(m,4H),7.51-7.36(m,3H),7.34–7.21(m,1H),7.20–7.08(m,1H),5.58(d,J＝4.2Hz,1H),5.31–5.10(m,1H),4.09(q,J＝7.0Hz,1H),3.74(s,3H),1.56(s,3H),1.49(d,J＝7.1Hz,3H),1.10(d,J＝6.6Hz,3H)； 13C NMR(126MHz,DMSO)δ174.53,167.36,157.37,156.89,148.58,138.26,134.93,130.35,129.54,127.87,126.92,126.27,123.21,117.72,112.51,106.42,103.14,73.25,66.71,55.36,47.63,21.64,19.83,12.79.HRMS m/z(ESI+)C 24H 24O 5N 4Na +requires:471.1639；found:471.1638.
Figure PCTCN2020109818-appb-000108
将获得的100mg化合物2悬浮于10mL NaOH(160mg)水溶液中，反应加热至78℃搅拌3h。冷却至室温，滴加HCOOH调节pH＝5～6，冷却至室温过滤析出的晶体，获得化合物1，即L-赤型生物蝶呤(100mg,纯度>99％,收率>99％).
实施例6
Figure PCTCN2020109818-appb-000109
取10g(50mmol)化合物8，CuI 475mg(2.5mmol),PdCl 2(440mg 2.5mmol),TPP 1.3g(5mmol),TEA(25.3g 250mmol)以及丙炔55mL(1M),溶解于250mL乙腈中，反应室温搅拌16h，HPLC检测原料完全转化为产物后，加100mLH 2O洗涤，分液，水相用25mL x3 EA萃取，收集油相，Na 2SO 4干燥后，柱层析(EA:Heptane＝3:1)获得化合物6，黄色晶体7.8g，收率98.7％。
Figure PCTCN2020109818-appb-000110
取2g(12.5mmol)化合物6，置于氢化釜中，加入20mL 2-MeTHF溶解，加入20mg Lindlar Pd，置换H 2并加压0.2MPa,室温搅拌，通过HPLC监控反应至原料刚好消失反应，过滤Lindlar Pd，并浓缩， 柱层析(EA:Heptane＝1:3)获得化合物5a,黄色晶体1.9g。IR(cm -1)ν3401,3202,2222,1644,1492,1515,1172； 1H NMR(500MHz,DMSO-d 6)δ8.27(s,1H),7.33(s,2H),6.30(dq,J＝11.7,1.8Hz,1H),5.88(dq,J＝11.7,7.3Hz,1H),2.01(dd,J＝7.3,1.8Hz,3H)； 13C NMR(126MHz,DMSO)δ154.87,147.91,141.32,129.95,124.29,116.05,109.58,14.88；HRMS m/z(ESI+)C 8H 9N 4 +requires:161.0822；found:161.0821.
Figure PCTCN2020109818-appb-000111
取K 2OsO 4·2H 2O 1.5mg(4μmol)，DHQ-IND 20mg(40μmol)，K 2CO 3 840mg(6mmol),K 3[Fe(CN) 6]2g(6mmol)溶解于H 2O/t-BuOH(10mL/10mL)室温搅拌至完全溶解，加入化合物5a，反应室温搅拌过夜约18h,HPLC检测反应完毕后,分液,收集油相，水相用2-MeTHF萃取至无残留后，Na 2SO 4干燥，过滤，浓缩，柱层析获得白色晶体110mg，为4a和4b混合物(er＝62:38)。
Figure PCTCN2020109818-appb-000112
取以上获得的4a和4b混合物220mg(er＝62:38)，分散于5mL甲苯中，加热至回流，加入225mg硼酸异丙酯，体系溶清，继续回流30min后，注射入121mg脯氨醇，回流30min后冷却至室温，将析出的固体过滤，用2-MeTHF充分洗涤滤饼后收集滤饼，得到化合物3a，白色晶体144mg，收率42％，化学纯度99％，非对映体比例(dr)为3a:3b＝96:4。
Figure PCTCN2020109818-appb-000113
将1g化合物3a(dr＝99:1),用10mL 2-MeTHF分散，加入5mL饱和K 2CO 3，搅拌至完全溶解，分液，水相用10mLx3 2-MeTHF萃取，合并有机相，Na 2SO 4干燥，过滤，浓缩，柱层析(EA：Heptane＝1:3)获得化合物4a，白色晶体620mg(纯度99％，98％ee)。
Figure PCTCN2020109818-appb-000114
将盐酸胍638mg(7.3mmol)用7mL甲醇溶解，加入1.4mL甲醇钠(5M in MeOH)，搅拌10min后，过滤析出的固体，收集滤液，加入320mg化合物4a(1.67mmol,>99％ee),加热回流过夜。降至室温后，过滤收集滤饼，获得化合物2，黄色晶体250mg(>99.9％ee,纯度99％,收率64％)。
Figure PCTCN2020109818-appb-000115
将盐酸胍638mg(7.3mmol)用7mL甲醇溶解，加入1.4mL甲醇钠(5M in MeOH),搅拌10min后，过滤析出的固体，收集滤液，加入500mg 3a(1.65mmol,3a:3b＝94:6)，加热回流过夜。降至室温后，过 滤收集滤饼，获得化合物2，黄色晶体244mg(>99.9％ee,纯度99％,收率63％)。
IR(cm -1)ν3249,1701,1537,1490,1367,1127； 1H NMR(500MHz,DMSO-d 6)δ11.42(s,1H),8.70(s,1H),6.87(s,2H),5.58(d,J＝4.9Hz,1H),4.69(d,J＝5.3Hz,1H),4.43(t,J＝5.3Hz,1H),3.90(h,J＝6.1Hz,1H),1.05(d,J＝6.3Hz,3H)； 13C NMR(126MHz,DMSO)δ161.03,156.55,153.61,151.86,148.98,127.08,76.85,69.42,19.11.HRMS m/z(ESI+)C 9H 12O 3N 5 +requires:238.0935；found:238.0935.
Figure PCTCN2020109818-appb-000116
将89mg(纯度99％，99.9％ee)化合物2分散于5mL的NaOH(15mg)水溶液中，加热至50℃搅拌4h,HPLC中控反应转化约90％，补加100mgNaOH，升温至78℃，反应完毕，加入10mg活性炭脱色，过滤，并用1mL正丁醇洗涤，分液收集水相，用1M稀盐酸中和至pH＝7，获得化合物1，白色固体78mg，收率87％，纯度99％，99.9％ee。IR(cm -1)ν3249,1701,1537,1490,1367,1127； 1H NMR(500MHz,DMSO-d 6)δ11.42(s,1H),8.70(s,1H),6.87(s,2H),5.58(d,J＝4.9Hz,1H),4.69(d,J＝5.3Hz,1H),4.43(t,J＝5.3Hz,1H),3.90(h,J＝6.1Hz,1H),1.05(d,J＝6.3Hz,3H)； 13C NMR(126MHz,DMSO)δ161.03,156.55,153.61,151.86,148.98,127.08,76.85,69.42,19.11.HRMS m/z(ESI+)C 9H 12O 3N 5 +requires:238.0935；found:238.0935.
实施例7
将4a和4b消旋体混合物的制备同实施例1；
Figure PCTCN2020109818-appb-000117
将4a和4b消旋体混合物100mg，溶解于5mL乙腈中，同时加入117mg硼酸异丙酯，回流搅拌30min。将93.4mg L-苯丙氨醇用乙腈溶解后，加到反应体系中。继续回流约15min，产生沉淀，将沉淀过滤，获得72mg产品9a，为白色晶体，化学纯度99％，非对映体比例(dr)9a:9b＝99.2:0.8。
构型验证试验
获取L-脯氨醇拆分后形成产品(化合物3a，
Figure PCTCN2020109818-appb-000118
)的XRD数据
检测仪器为D8 Venture，仪器参数如下表1：
表1
Figure PCTCN2020109818-appb-000119
结构解析与精修过程：
采用SAINT程序对衍射数据进行积分还原后，采用SADABS程序对数据进行经验吸收校正；采用SHELXT2014通过直接法解析单晶结构，并采用最小二乘法对结构进行精修，氢原子精修过程采取各向同性计算处理获得，C-H上氢原子通过计算加氢获得，并采用骑式模型对其精修处理。
用D8 Venture衍射仪收集衍射强度数据，Cu靶
Figure PCTCN2020109818-appb-000120
石墨单色器，单导管直径Φ＝0.50mm，晶体与COMS探测器距离d＝40mm，分辨率：
Figure PCTCN2020109818-appb-000121
管压50KV，管流1.2mA，扫描方式：Φ和ω扫描，收集总衍射点数为6738个，独立衍射点数2751个，可观察点数(|F|2≥2σ|F|2)为2709个。Flack常数为-0.03(7)，手性中心如图1所示；晶体数据如下表2，数据收集如表3，精修参数如表4，其他具体参数结果如表5-表7。
表2 Crystal data(晶体数据)
Figure PCTCN2020109818-appb-000122
表3 Data collection(数据收集)
Figure PCTCN2020109818-appb-000123
表4
Figure PCTCN2020109818-appb-000124
Figure PCTCN2020109818-appb-000125
表5 Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters
Figure PCTCN2020109818-appb-000126
(分数原子坐标和各向同性或等效各向同性位移参数)
  x Y z Uiso*/Ueq
O2 0.64183(7) 0.3466(2) 0.90349(10) 0.0284(3)
O3 0.73919(7) 0.53879(18) 0.88836(11) 0.0272(3)
O1 0.64514(6) 0.3533(2) 0.71733(10) 0.0250(3)
N2 0.44700(8) 0.4545(2) 0.59248(13) 0.0261(3)
N1 0.75403(8) 0.1845(2) 0.88956(13) 0.0257(3)
N3 0.50499(9) 0.8426(3) 0.63775(16) 0.0343(4)
N5 0.25974(10) 0.5638(3) 0.44136(17) 0.0421(4)
N4 0.38641(10) 0.9765(3) 0.53837(19) 0.0418(4)
H4A 0.34431 0.959052 0.54561 0.050*
H4B 0.409931 1.082673 0.580823 0.050*
C9 0.52051(9) 0.4867(3) 0.65153(14) 0.0247(3)
C10 0.54820(10) 0.6817(3) 0.67279(16) 0.0302(4)
H10 0.600853 0.700135 0.714619 0.036*
C6 0.57060(10) 0.3066(3) 0.69661(15) 0.0258(4)
H6 0.550774 0.195661 0.636741 0.031*
C11 0.40272(10) 0.6161(3) 0.55589(15) 0.0263(4)
C1 0.80696(10) 0.4983(3) 0.87991(16) 0.0288(4)
H1A 0.846548 0.593573 0.92966 0.035*
H1B 0.799391 0.509148 0.795464 0.035*
C7 0.57939(10) 0.2340(3) 0.82101(16) 0.0298(4)
H7 0.593762 0.089638 0.829854 0.036*
C2 0.82872(10) 0.2853(3) 0.92620(17) 0.0301(4)
H2 0.85831 0.284276 1.015667 0.036*
C13 0.32331(10) 0.5819(3) 0.49092(16) 0.0307(4)
C12 0.43054(10) 0.8133(3) 0.57820(16) 0.0303(4)
C5 0.74743(12) 0.0217(3) 0.80192(18) 0.0365(4)
H5A 0.696253 0.017265 0.735234 0.044*
H5B 0.759279 -0.110065 0.842316 0.044*
C8 0.51302(12) 0.2583(4) 0.84878(19) 0.0442(5)
H8A 0.524991 0.201813 0.928255 0.066*
H8B 0.469703 0.188319 0.787783 0.066*
H8C 0.501252 0.400526 0.848327 0.066*
B1 0.69082(11) 0.3664(3) 0.84626(16) 0.0242(4)
C3 0.86852(13) 0.1659(4) 0.8665(2) 0.0454(5)
H3A 0.900125 0.059633 0.920509 0.054*
H3B 0.900172 0.253516 0.843131 0.054*
C4 0.80418(16) 0.0773(4) 0.7561(2) 0.0474(6)
H4C 0.783299 0.176608 0.690291 0.057*
H4D 0.82071 -0.041813 0.726658 0.057*
H1 0.7538(12) 0.131(3) 0.954(2) 0.019(5)
表6 Atomic displacement parameters(原子位移参数)
U11 U22 U33 U12 U13 U23
O2 0.0275(6) 0.0368(7) 0.0209(6) 0.0011(5) 0.0104(5) -0.0008(5)
O3 0.0266(6) 0.0268(6) 0.0262(6) 0.0009(5) 0.0098(5) -0.0030(5)
O1 0.0217(5) 0.0321(6) 0.0200(5) 0.0001(5) 0.0079(4) 0.0013(5)
N2 0.0241(7) 0.0331(8) 0.0208(6) -0.0024(6) 0.0094(5) 0.0003(6)
N1 0.0295(7) 0.0266(7) 0.0208(7) 0.0026(6) 0.0109(5) 0.0016(6)
N3 0.0259(7) 0.0318(8) 0.0422(9) -0.0017(7) 0.0122(6) -0.0002(7)
N5 0.0254(8) 0.0602(12) 0.0388(9) -0.0039(8) 0.0122(7) -0.0088(8)
N4 0.0276(8) 0.0350(9) 0.0615(11) 0.0030(7) 0.0181(8) 0.0029(9)
C9 0.0226(8) 0.0319(9) 0.0189(7) -0.0019(7) 0.0083(6) 0.0003(7)
C10 0.0221(8) 0.0333(9) 0.0318(9) -0.0025(7) 0.0087(7) -0.0027(8)
C6 0.0241(8) 0.0296(9) 0.0224(7) -0.0022(7) 0.0089(6) -0.0013(6)
C11 0.0213(8) 0.0341(9) 0.0235(8) -0.0010(6) 0.0097(6) -0.0002(7)
C1 0.0275(8) 0.0332(9) 0.0267(8) -0.0015(7) 0.0127(7) -0.0029(7)
C7 0.0282(8) 0.0353(9) 0.0251(8) -0.0007(7) 0.0111(7) 0.0031(7)
C2 0.0256(8) 0.0378(10) 0.0260(8) 0.0033(7) 0.0103(7) 0.0017(7)
C13 0.0263(9) 0.0393(9) 0.0271(8) -0.0008(7) 0.0123(7) -0.0026(8)
C12 0.0254(8) 0.0347(10) 0.0319(9) 0.0001(7) 0.0134(7) 0.0004(7)
C5 0.0476(11) 0.0272(9) 0.0324(9) 0.0068(8) 0.0152(9) -0.0026(8)
C8 0.0336(10) 0.0711(15) 0.0318(9) -0.0015(10) 0.0180(8) 0.0100(10)
B1 0.0260(8) 0.0251(9) 0.0199(8) 0.0038(7) 0.0086(7) 0.0012(7)
C3 0.0426(11) 0.0460(12) 0.0595(13) 0.0105(10) 0.0333(10) 0.0038(11)
C4 0.0762(16) 0.0385(11) 0.0413(11) 0.0140(11) 0.0385(12) 0.0026(10
表7 Geometric parameters
Figure PCTCN2020109818-appb-000127
(几何参数)
O2—C7 1.428(2) C6—C7 1.548(2)
O2—B1 1.437(2) C11—C13 1.441(2)
O3—C1 1.420(2) C11—C12 1.411(3)
O3—B1 1.445(2) C1—H1A 0.99
O1—C6 1.422(2) C1—H1B 0.99
O1—B1 1.451(2) C1—C2 1.527(3)
N2—C9 1.333(2) C7—H7 1
N2—C11 1.342(2) C7—C8 1.508(3)
N1—C2 1.507(2) C2—H2 1
N1—C5 1.502(2) C2—C3 1.523(3)
N1—B1 1.660(2) C5—H5A 0.99
N1—H1 0.88(2) C5—H5B 0.99
N3—C10 1.327(3) C5—C4 1.513(3)
N3—C12 1.346(2) C8—H8A 0.9800
N5—C13 1.143(3) C8—H8B 0.9800
N4—H4A 0.8861 C8—H8C 0.9800
N4—H4B 0.8860 C3—H3A 0.9900
N4—C12 1.351(3) C3—H3B 0.9900
C9—C10 1.396(3) C3—C4 1.524(4)
C9—C6 1.506(2) C4—H4C 0.9900
C10—H10 0.9500 C4—H4D 0.9900
C6—H6 1.0000    
       
C7—O2—B1 105.08(13) N1—C2—C1 103.04(13)
C1—O3—B1 108.83(14) N1—C2—H2 110.7
C6—O1—B1 108.20(13) N1—C2—C3 105.66(17)
C9—N2—C11 116.93(16) C1—C2—H2 110.7
C2—N1—B1 105.90(14) C3—C2—C1 115.48(17)
C2—N1—H1 107.7(14) C3—C2—H2 110.7
C5—N1—C2 107.82(15) N5—C13—C11 176.6(2)
C5—N1—B1 118.98(13) N3—C12—N4 117.58(18)
C5—N1—H1 109.2(14) N3—C12—C11 119.05(17)
B1—N1—H1 106.7(14) N4—C12—C11 123.31(16)
C10—N3—C12 117.29(17) N1—C5—H5A 110.9
H4A—N4—H4B 108.8 N1—C5—H5B 110.9
C12—N4—H4A 110.3 N1—C5—C4 104.31(17)
C12—N4—H4B 110.1 H5A—C5—H5B 108.9
N2—C9—C10 120.07(17) C4—C5—H5A 110.9
N2—C9—C6 117.42(16) C4—C5—H5B 110.9
C10—C9—C6 122.48(15) C7—C8—H8A 109.5
N3—C10—C9 123.57(16) C7—C8—H8B 109.5
N3—C10—H10 118.2 C7—C8—H8C 109.5
C9—C10—H10 118.2 H8A—C8—H8B 109.5
O1—C6—C9 110.96(14) H8A—C8—H8C 109.5
O1—C6—H6 109.8 H8B—C8—H8C 109.5
O1—C6—C7 103.51(13) O2—B1—O3 112.50(14)
C9—C6—H6 109.8 O2—B1—O1 107.61(14)
C9—C6—C7 112.86(15) O2—B1—N1 110.64(14)
C7—C6—H6 109.8 O3—B1—O1 116.20(15)
N2—C11—C13 117.11(17) O3—B1—N1 100.38(13)
N2—C11—C12 123.09(15) O1—B1—N1 109.33(14)
C12—C11—C13 119.80(17) C2—C3—H3A 111.1
O3—C1—H1A 110.6 C2—C3—H3B 111.1
O3—C1—H1B 110.6 C2—C3—C4 103.25(17)
O3—C1—C2 105.82(14) H3A—C3—H3B 109.1
H1A—C1—H1B 108.7 C4—C3—H3A 111.1
C2—C1—H1A 110.6 C4—C3—H3B 111.1
C2—C1—H1B 110.6 C5—C4—C3 103.32(17)
O2—C7—C6 103.23(14) C5—C4—H4C 111.1
O2—C7—H7 108.4 C5—C4—H4D 111.1
O2—C7—C8 110.64(16) C3—C4—H4C 111.1
C6—C7—H7 108.4 C3—C4—H4D 111.1
C8—C7—C6 117.49(16) H4C—C4—H4D 109.1
C8—C7—H7 108.4    
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (29)

  1. 具有式(IVa-1)、式(IVa-2)、式(IVa-3)、式(IVa-4)、式(IVa)或式(IVa')所示结构的中间体：
    Figure PCTCN2020109818-appb-100001
    其中，
    Figure PCTCN2020109818-appb-100002
    表示双羟基、第一试剂和第二试剂反应生成的结构；
    Figure PCTCN2020109818-appb-100003
    表述双羟基与第一试剂反应生成的结构；
    所述第一试剂为硼酸酯或硼酸；
    所述第二试剂为手性氨基醇；
    W为NH x，X为0、1或2；
    R 1为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
    R 2和R 3各自独立地为氢原子或氨基保护基；且R 2和R 3可和与所述R 2、R 3相连的氮原子一起形成环状内酰亚胺基；
    R 4为-COOR 5、-CONR 6或-CN；
    R 5和R 6各自独立地为氢原子、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
    Z为氢原子或离去基团；
    Y为O或不存在。
  2. 根据权利要求1所述的中间体，其特征在于，所述Y不存在，Z为氢原子，R 4为氰基，R 1为甲基。
  3. 根据权利要求1所述的中间体，其特征在于，所述第一试剂为硼酸酯；所述第二试剂为手性氨基醇。
  4. 根据权利要求3所述的中间体，其特征在于，R 8为取代或未取代的C 1-10烷基、取代或未取代的C 3-10环烷基；和/或
    Figure PCTCN2020109818-appb-100004
    具有以下结构：
    Figure PCTCN2020109818-appb-100005
    其中，与R 20和R 21相连的碳原子、与R 22和R 23相连的碳原子中至少有一个碳原子为手性碳；
    R 20、R 21、R 22和R 23各自独立地选自：H、取代或未取代C 1-6烷基、取代或未取代苯基、取代或未取代萘基、或取代或未取代喹啉基；
    R 24和R 25各自独立地选自：H、取代或未取代C 1-6烷基、或取代或未取代苯基；
    R 23和R 24可相互连接形成环状结构；
    R 23、R 24和R 25可相互连接形成桥环结构。
  5. 根据权利要求4所述的中间体，其特征在于，R 20、R 21、R 22和R 23各自独立地选自H、苯基、C 1-6烷基或C 1-6烷氧基取代喹啉基；
    R 24和R 25各自独立地选自：H、C 1-6烷基或苯基；
    R 23和R 24可相互连接形成五元含氮杂环；
    R 23、R 24和R 25可相互连接形成
    Figure PCTCN2020109818-appb-100006
    结构。
  6. 根据权利要求1所述的中间体，其特征在于，所述硼酸酯选自：硼酸三甲酯、硼酸三乙酯、硼酸三异丙酯或硼酸异丙醇频那醇酯；
    所述手性氨基醇选自：L-苯甘氨醇、L-脯氨醇、L-苯丙胺醇、(S)-(-)-α,α-二苯基脯氨醇、奎宁或辛可尼。
  7. 权利要求1-6任一项所述的中间体的制备方法，其特征在于，包括以下步骤：
    将待拆分化合物、第一试剂、第二试剂和非质子性溶剂混合，加热回流，反应完成后，结晶获得式(IVa-1)或式(IVa-2)所示结构的中间体；其中，所述待拆分化合物为式(IVa)和式(IVa')组成的混合物；
    Figure PCTCN2020109818-appb-100007
  8. 根据权利要求7所述的制备方法，其特征在于，所述待拆分化合物和所述第一试剂反应，生成式(IVa-3)和式(IVa-4)所示结构的混合物；所述式(IVa-3)和式(IVa-4)所示结构的混合物与所述第二试剂反应，制得式(IVa-1)或式(IVa-2)所示结构的中间体。
  9. 根据权利要求7所述的制备方法，其特征在于，所述非质子性溶剂选自：四氢呋喃、2-甲基四氢呋喃、环戊基甲基醚、乙腈、甲苯、苯、二甲苯、1,4-二氧六环、丙酮和MIBK中的一种或多种；和/或
    所述待拆分化合物和所述第二试剂的摩尔比为小于或等于1；和/或
    所述第一试剂和所述第二试剂的摩尔比为1：(1.0-1.3)；和/或
    每1g所述待拆分化合物加入1-100mL所述非质子性溶剂。
  10. 权利要求1-6任一项所述的中间体的在制备L-赤型生物蝶呤类化合物中的应用。
  11. 一种L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述L-赤型生物蝶呤类化合物具有式(I)所示的结构，且所述式(I)所示的L-赤型生物蝶呤类化合物由式(II)所示化合物或式(III)所示化合物通过双羟化反应制备而成；
    Figure PCTCN2020109818-appb-100008
    其中，
    Y为O或不存在；
    Z为氢原子或离去基团；
    R 1为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
    R 2和R 3各自独立地为氢原子或氨基保护基；且R 2和R 3可和与所述R 2、R 3相连的氮原子一起形成环状内酰亚胺基；
    R 4为-COOR 5、-CONR 6或-CN；
    R 5和R 6各自独立地为氢原子、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代或未取代的杂芳基；
    R 7为-OH或-NH 2。
  12. 根据权利要求11所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述R 5和R 6各自独立地选自：氢原子、或取代或未取代的C 1-20烷基；
    所述R 1选自：C 1-6烷基、3-8元环烷基、3-10元芳基、3-10元杂芳基、TMS、TBS、或-CH 2X；X为离去基团。
  13. 根据权利要求12所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述离去基团选自：硅烷基、卤素、OSO nR 9、OCOR 10或OPO 2R 11；其中R 9、R 10或R 11各自独立地选自：-CF 3、烷基、苯基、或烷基取代苯基，n为0、1或2；和/或
    所述氨基保护基选自：-Boc、-Cbz、-Ac、-Ts、-Ms、-Bz、-Bn、-PMB、或schiff碱。
  14. 根据权利要求13所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述Y不存在，Z为氢原子，R 4为氰基，R 1为甲基。
  15. 根据权利要求11所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，当所述式(II)所示化合物中烯烃为顺式结构，其结构式为式(IIa)所示时，由式(IIa)所示化合物制备式(I)所示的L-赤型生物蝶呤类化合物的步骤包括以下步骤：
    将所述式(IIa)所示化合物进行双羟化反应，获得式(IVa)和式(IVa')所示化合物组成的待拆分化合物；
    采用手性拆分试剂组拆分所述待拆分化合物，得到式(IVa-1)所示化合物；
    将所述式(IVa-1)所示化合物与
    Figure PCTCN2020109818-appb-100009
    和/或
    Figure PCTCN2020109818-appb-100010
    盐依次进行环化反应和水解反应，制得式(I)所示的L-赤型生物蝶呤类化合物；
    其中，所述手性拆分试剂组包括第一试剂和第二试剂，所述第一试剂为硼酸酯或硼酸；
    所述第二试剂为手性氨基醇；
    Figure PCTCN2020109818-appb-100011
    W、Z、Y、R 1、R 2、R 3、R 4、R 5和R 6如权利要求1所定义；
    E为卤素、C 1-4烷氧基、C 1-4烷硫基或-NH 2；
    Figure PCTCN2020109818-appb-100012
  16. 根据权利要求15所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，得到式(IVa-1)所示化合物的步骤后还包括以下步骤：
    将式(IVa-1)所示化合物与质子性溶剂混合，制得式(IVa)所示化合物；
    将式(IVa)所示化合物与
    Figure PCTCN2020109818-appb-100013
    和/或
    Figure PCTCN2020109818-appb-100014
    盐依次进行环化反应和水解反应，制得式(I)所示的L-赤型生物蝶呤类化合物；
    Figure PCTCN2020109818-appb-100015
  17. 根据权利要求15所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，将式(IVa-1)所示化合物与
    Figure PCTCN2020109818-appb-100016
    和/或
    Figure PCTCN2020109818-appb-100017
    盐依次进行环化反应和所述水解反应的步骤包括以下步骤：
    将式(IVa-1)所示化合物、
    Figure PCTCN2020109818-appb-100018
    和/或
    Figure PCTCN2020109818-appb-100019
    盐、碱和质子性溶剂混合，加热至50-100℃，待反应完成后，冷却，有固体析出，过滤获得式(I-1)所示化合物；
    将所述式(I-1)所示化合物加入碱性溶液中，待反应完成，加入酸，调pH至5～6，有晶体析出，过滤干燥，即得式(I)所示的L-赤型生物蝶呤类化合物；
    Figure PCTCN2020109818-appb-100020
    R 7为-OH或-NH 2。
  18. 根据权利要求15所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述硼酸酯选自：硼酸三甲酯、硼酸三乙酯、硼酸三异丙酯或硼酸异丙醇频那醇酯；
    所述手性氨基醇选自：L-苯甘氨醇、L-脯氨醇、L-苯丙胺醇、(S)-(-)-α,α-二苯基脯氨醇、奎宁或辛可尼。
  19. 根据权利要求11所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，当所述式(II)所示化合物中烯烃为反式结构，其结构式为式(IIb)所示时，由式(IIb)所示化合物制备式(I)所示的L-赤型生物蝶呤类化合物的步骤包括以下步骤：
    将所述式(IIb)所示化合物进行双羟化反应，制得式(IVb-1)和/或式(IVb-2)所示化合物；
    将所述式(IVb-1)和/或式(IVb-2)所示化合物进行乙酰化反应，制得式(VIIb-1)和/或式(VIIb-2)所示化合物；
    将所述式(VIIb-1)和/或式(VIIb-2)所示化合物进行Mitsunobu反应，制得式(VIIb-3)和/或式 (VIIb-4)所示化合物；
    将所述(VIIb-3)和/或式(VIIb-4)所示化合物与
    Figure PCTCN2020109818-appb-100021
    和/或
    Figure PCTCN2020109818-appb-100022
    盐进行环化反应，制得式(I)所示的L-赤型生物蝶呤类化合物；
    Figure PCTCN2020109818-appb-100023
    其中，R 10为取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代芳基、或取代未取代的杂芳基；
    E为卤素、C 1-4烷氧基、C 1-4烷硫基或-NH 2。
  20. 根据权利要求11-19任一项所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述双羟化反应方法为Sharpless不对称双羟化反应、碱性KMnO 4双羟化反应、Fe催化双羟基化反应或不对称环氧化后水解开环。
  21. 根据权利要求20所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，采用Sharpless不对称双羟化反应将式(IIa)所示化合物和/或所述式(IIb)所示化合物进行双羟化反应，所述Sharpless不对称双羟化反应的步骤包括以下步骤：
    将所述式(IIa)所示化合物和/或所述式(IIb)所示化合物、氧化剂、双羟基化试剂、碱、配体和溶剂混合进行反应，反应完成后淬灭反应，分离，即得；
    其中，所述双羟基化试剂选自：OsO 4、K 2OsO 4、OsO 4水合物和K 2OsO 4水合物中的一种或多种；
    所述氧化剂选自：K 3[Fe(CN) 6]或NMO以及中的一种或多种；
    所述碱选自碳酸钾、碳酸钠、碳酸铯、碳酸氢钾、碳酸氢钠、NaOH、KOH、LiOH、NH 4OH，t-BuONa、t-BuOK、t-BuOLi、碳酸铯、三乙胺、二异丙基乙基氨、DBU、吡啶和对二甲氨基吡啶中的一种或多种；
    所述配体选自：(DHQ) 2PHAL、(DHQD) 2PHAL、DHQ-IND和DHQD-IND中的一种或多种。
  22. 根据权利要求11所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，
    当所述式(II)所示化合物中烯烃为顺式结构，其结构式为式(IIa)所示化合物时，所述式(IIa)所示化合物由式(V)所示化合物通过催化氢化反应制得：
    Figure PCTCN2020109818-appb-100024
    当所述式(II)所示化合物中烯烃为反式结构，其结构式为式(IIb)所示化合物时，所述式(IIb)所示化合物由式(VI)所示化合物通过偶联反应制得；
    Figure PCTCN2020109818-appb-100025
    其中，M为H或离去基团。
  23. 根据权利要求22所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述催化氢化反应的步骤包括以下步骤：
    将所述式(V)所示化合物、催化剂和溶剂混合，在氢气氛围下反应，待反应完成后，过滤，浓缩得到所述式(IIa)所示化合物；
    所述催化剂选自：Lindlar催化剂、钯/碳、Raney镍、铂黑和二氧化铂中的一种或多种；
    所述溶剂选自：四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚、甲基环戊基醚、甲醇、乙醇、异丙醇、乙腈和甲苯中的一种或多种。
  24. 根据权利要求22所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述偶联反应的步骤包括以下步骤：
    将所述式(VI)所示化合物、反式-1-丙烯基硼酸类试剂、催化剂、溶剂和配体混合，待反应完成后，分离得到所述式(IIb)所示化合物；
    所述反式-1-丙烯基硼酸类试剂选自：反式-1-丙烯基硼酸频哪醇酯、反式-1-丙烯基硼酸或反式-1-丙烯基氟硼酸盐；
    所述催化剂选自：5％Pd/C、10％Pd/C、Pd(OAc) 2、PdCl 2(PPh 3) 2、Pd(PPh 3) 4、PdCl 2(dppf)、PdCl 2(MeCN) 2和Pd 2(dba) 3中一种或多种；
    所述溶剂选自：甲醇、乙醇、异丙醇、丁醇、水、四氢呋喃、2-甲基四氢呋喃、1.4-二氧六环、DME、DMF、DMSO、NMP、乙腈、二氯甲烷、1，2-二氯乙烷、乙酸甲酯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、乙醚、甲基叔丁基醚、甲苯、二甲苯、丙酮、甲基乙基酮和甲基环戊烷中的一种或多种；
    所述配体选自：PPh 3、BINAP、dppf、Xantphos、Xphos单磷及双磷配体中的一种或多种。
  25. 根据权利要求22所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述式(V)所示化合物由式(VI)所示化合物通过Sonogashira反应制得；
    Figure PCTCN2020109818-appb-100026
  26. 根据权利要求25所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述Sonogashira反应的步骤包括以下步骤：
    将所述式(VI)所示化合物、催化剂、配体和溶剂混合；
    加入碱和
    Figure PCTCN2020109818-appb-100027
    反应完成后，淬灭反应，分离得到所述式(V)所示化合物。
  27. 根据权利要求11所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述式(III)所 示化合物由式(II)所示化合物和
    Figure PCTCN2020109818-appb-100028
    和/或
    Figure PCTCN2020109818-appb-100029
    盐进行环化反应制得；
    Figure PCTCN2020109818-appb-100030
    E为卤素、C 1-4烷氧基、C 1-4烷硫基或-NH 2。
  28. 根据权利要求11所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，
    当所述式(III)所示化合物中烯烃为顺式结构，其结构式为式(IIIa)所示化合物时，所述式(IIIa)所示化合物由式(VIII)所示化合物通过催化氢化反应制得：
    Figure PCTCN2020109818-appb-100031
  29. 根据权利要求28所述的L-赤型生物蝶呤类化合物的制备方法，其特征在于，所述式(VIII)所示化合物由以下步骤制得：
    式(VI)所示化合物通过Sonogashira反应制得式(V)所示化合物；
    所述式(V)所示化合物经环化制得所述式(VIII)所示化合物；
    Figure PCTCN2020109818-appb-100032
    其中，M为H或离去基团。
PCT/CN2020/109818 2019-08-19 2020-08-18 L-赤型生物蝶呤类化合物的制备方法 Ceased WO2021032088A1 (zh)

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