CN114702425A - Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate - Google Patents
Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate Download PDFInfo
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- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 150000001294 alanine derivatives Chemical class 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 18
- 230000009471 action Effects 0.000 claims abstract description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- 229910021529 ammonia Inorganic materials 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 102000003929 Transaminases Human genes 0.000 claims description 11
- 108090000340 Transaminases Proteins 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- FRKGSNOMLIYPSH-VKHMYHEASA-N (3s)-3-hydroxypyrrolidin-2-one Chemical compound O[C@H]1CCNC1=O FRKGSNOMLIYPSH-VKHMYHEASA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- -1 sodium alkoxide Chemical class 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 108090000698 Formate Dehydrogenases Proteins 0.000 claims description 6
- 239000005515 coenzyme Substances 0.000 claims description 6
- 238000006114 decarboxylation reaction Methods 0.000 claims description 6
- 150000002430 hydrocarbons Chemical group 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 230000006103 sulfonylation Effects 0.000 claims description 3
- 238000005694 sulfonylation reaction Methods 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 150000008575 L-amino acids Chemical class 0.000 claims description 2
- 229910006080 SO2X Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 31
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 4
- 230000000911 decarboxylating effect Effects 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- ZOKLUHBZBGHBAB-UHFFFAOYSA-N dimethyl 2-oxobutanedioate Chemical compound COC(=O)CC(=O)C(=O)OC ZOKLUHBZBGHBAB-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-OUBTZVSYSA-N sodium-24 Chemical compound [24Na] KEAYESYHFKHZAL-OUBTZVSYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivatives and intermediates, which comprises the steps of reacting a compound C with a compound B under the action of strong base to generate a compound G, then hydrolyzing and decarboxylating the compound G to obtain an intermediate, and then converting the intermediate into the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives. The invention uses the intermediate to prepare the (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivative, has simple preparation method and mild reaction condition, obviously improves the yield of the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative, and is particularly suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivant and intermediate.
Background
PF-07321332 is a new anti-new-corona-virus drug newly introduced by the company of Prey, and has higher anti-new-corona-virus activity through preliminary clinical verification. The chemical structure of PF-07321332 is shown by the following formula:
as can be seen from the above formula, PF-07321332 is mainly composed of three chiral intermediates in the chemical structure (see the following formulas (A), (B), (C)).
Among them, (a) has been commercially produced, (B) has been reported in synthetic literature, and (C) can be obtained by (f) treatment with Burgess Reagent (reference US11124497), and the relevant reaction formula is as follows:
the synthesis of compound (f) has also been reported in the literature, for example, Structure-based design of anti viral drugs targeting the SARS-CoV-2 main protein enzyme, Science (Washington, DC, United States),368(6497), 1331-; 2020a discloses the following synthetic route of (f).
However, the above route has the following disadvantages: firstly, the alkylation reaction of bromoacetonitrile and L-glutamate requires reaction conditions of ultralow temperature of-78 ℃, and the reaction conditions are harsh; secondly, the price of the strong alkali LiHMDS is high, so that the preparation cost is increased undoubtedly; thirdly, the yield of the two steps of alkylation and reduction cyclization is not high (the yield of the two steps is about 22%), and reaction products of the two steps of alkylation and reduction cyclization need to be separated and purified by a column, so that the operation is complex, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates, which has the advantages of mild reaction conditions, simple operation, high purity and high yield and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
in a first aspect, the present invention provides a process for the preparation of an intermediate of the formula
The preparation method comprises the steps of firstly reacting a compound C with a compound B under the action of strong alkali to generate a compound G, and then hydrolyzing and decarboxylating the compound G to obtain the intermediate, wherein the compound C is prepared from the compound CStructural formula is
The structural formula of the compound B is
The structural formula of the compound G is
R in the above formula1、R2Each independently selected from a C1-6 hydrocarbon group, Q2Has the structural formula R3SO2，R3Any one selected from substituted or unsubstituted aryl groups and alkyl groups having 1 to 3 carbon atoms.
Preferably, the strong base is selected from one or more of NaH, sodium alkoxide, potassium alkoxide, DBU, and LiHMDS.
Further preferably, the sodium alkoxide includes, but is not limited to, one or more of sodium methoxide, sodium ethoxide, and the potassium alkoxide includes, but is not limited to, potassium tert-butoxide.
Preferably, the feeding molar ratio of the strong base to the compound C is (0.8-1.2): 1.
further preferably, the feeding molar ratio of the strong base to the compound C is (0.8-1.0): 1.
preferably, the reaction temperature of the compound C and the compound B is controlled to be 0-100 ℃.
Further preferably, the reaction temperature of the compound C and the compound B is controlled to be 10-70 ℃.
Still more preferably, the reaction temperature of the compound C and the compound B is controlled to be 40-70 ℃.
According to some preferred embodiments, the compound C and the strong base are reacted at 15-35 ℃ for 0.1-1 h, and then reacted with the compound B at 40-70 ℃ for 1-5 h to obtain the compound G.
Preferably, said compound C and said compound B are reacted in the presence of an organic solvent selected from one or more of DMF, DMSO, THF, toluene and alcoholic solvents.
Further preferably, said compound C and said strong base are reacted first in the presence of a first organic solvent, then said first organic solvent is distilled off, and then reacted with said compound B in the presence of a second organic solvent, said first organic solvent and said second organic solvent being independently selected from one or more of DMF, DMSO, THF, toluene, and alcoholic solvents, respectively, said first organic solvent and said second organic solvent being different.
Preferably, the hydrolytic decarboxylation comprises reacting the compound G in the presence of sodium hydroxide and an organic solvent, followed by acidification with additional hydrochloric acid to give the intermediate.
More preferably, the sodium hydroxide is fed in the form of a sodium hydroxide aqueous solution with a mass concentration of 5-15%.
Still more preferably, the feeding mass ratio of the sodium hydroxide aqueous solution to the hydrochloric acid is (1.5-3): 1.
more preferably, the feeding mass ratio of the sodium hydroxide aqueous solution to the hydrochloric acid is (2.5-3): 1.
preferably, the organic solvent is selected from one or more of DMF, DMSO, THF, toluene, and alcoholic solvents.
Preferably, the reaction temperature of the hydrolysis decarboxylation is controlled to be 0-100 ℃.
Further preferably, the reaction temperature of the hydrolysis decarboxylation is controlled to be 0-50 ℃.
Still more preferably, the reaction temperature of the hydrolysis decarboxylation is controlled to be 10-30 ℃.
Preferably, the preparation method further comprises the steps of adding an extracting agent into the system after acidification for extraction, concentrating an organic phase obtained by extraction and recrystallizing a concentrate obtained by concentration, wherein the extracting agent is selected from one or more of dichloromethane, ethyl acetate or toluene, a mixed solvent is used for recrystallization, the mixed solvent is ethyl acetate and n-heptane, and the volume ratio of the ethyl acetate to the n-heptane is 1: (3-5).
Preferably, the preparation method further comprises the step of reacting (S) -3-hydroxy-2-pyrrolidone with a sulfonylation reagent under the action of triethylamine to generate the compound B, wherein the formula of the sulfonylation reagent is R3SO2X; wherein, R is3And said Q2R in (1)3Also, the X is selected from any one of fluorine, chlorine, bromine and iodine.
Further preferably, the feeding molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the sulfonylating agent is 1 (1-1.4).
Still more preferably, the molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the sulfonylating agent is 1 (1.1 to 1.3).
Preferably, the feeding molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the triethylamine is 1: (1.2-1.8).
Further preferably, the feeding molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the triethylamine is 1: (1.4-1.6).
Preferably, the reaction temperature is controlled to be 20-50 ℃.
Further preferably, the reaction temperature is controlled to be 25-40 ℃.
A second aspect of the present invention provides (S) -2-amino- (S) -3- [ pyrrolidone-2']Process for the preparation of alanine derivatives by preparation of an intermediate followed by conversion of said intermediate to (S) -2-amino- (S) -3- [ pyrrolidone-2']An alanine derivative; wherein the intermediate (S) -2-amino- (S) -3- [ pyrrolidone-2 'is prepared according to the preparation method']The structural formula of the alanine derivative is shown in the specification
Preferably, the intermediate is converted to (S) -2-amino- (S) -3- [ pyrrolidone-2']Alanine derivatives include: reacting said intermediate with an ammonia donor under the action of a transaminase to form compound e, and then converting said compound e to said (S) -2-amino- (S) -3- [ pyrrolidone-2']An alanine derivative; wherein the structural formula of the compound e is shown in the specification
Preferably, the intermediate is reacted with the ammonia donor in the presence of a formate dehydrogenase, a coenzyme and an auxiliary.
Further preferably, the ammonia donor is selected from ammonium formate and/or an L-amino acid.
Still more preferably, the feeding mass ratio of the intermediate to the ammonia donor is 1 (0.8-1).
Preferably, the feeding mass ratio of the transaminase to the formate dehydrogenase to the coenzyme is 1: (0.1-0.3): (0.05-0.2).
Further preferably, the feeding mass ratio of the transaminase, the formate dehydrogenase and the coenzyme is 1: (0.15-0.25): (0.1-0.15).
Preferably, the feeding mass ratio of the intermediate to the transaminase is 1: (0.01-0.1).
Further preferably, the feeding mass ratio of the intermediate to the transaminase is 1: (0.03-0.08).
Preferably, the auxiliary agent is an aqueous sodium hydroxide solution.
Further preferably, the pH of the reaction system is adjusted to 7.5-8.5 by using the auxiliary agent.
Preferably, the temperature for the reaction of the intermediate and the ammonia donor is controlled to be 20-40 ℃.
Preferably, the conversion of said compound e to said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative comprises: reacting compound e with thionyl chloride and then ammonia to form the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative.
Further preferably, the feeding molar ratio of the compound e to the thionyl chloride is 1 (0.8-1.2).
Further preferably, the mass concentration of ammonia in the system is controlled to be 10-20%.
In a third aspect, the present invention provides an intermediate of the formula
The fourth aspect of the invention provides an application of the intermediate in the field of medicine.
Preferably, the intermediate is used for preparing an anti-neocoronary virus drug.
Further preferably, said intermediate is used for the preparation of PF-07321332.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the preparation method of the intermediate has mild reaction conditions and simple operation, the purity of the prepared intermediate can reach 98% or more, the yield can reach 76% or more, and the prepared intermediate can be used for synthesizing the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative;
the invention uses the intermediate to prepare the (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivative, has simple preparation method and mild reaction condition, obviously improves the yield of the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative, and is particularly suitable for industrial production.
Detailed Description
The synthesis of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives in the prior art mainly has the problems of harsh reaction conditions, complex operation and low yield, and based on the defects of the prior art, the present inventors have made extensive experimental studies to provide the scheme, and further elaboration is made below with respect to the scheme.
A method for preparing (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives, comprising the steps of:
(1) reacting (S) -3-hydroxy-2-pyrrolidone (compound a) with a sulfonylating reagent under the action of triethylamine to generate a compound B;
(2) reacting the compound B with the compound C under the action of strong alkali to generate a compound G, and then hydrolyzing and decarboxylating the compound G to obtain an intermediate (a compound d);
(3) reacting the intermediate with an ammonia donor under the action of transaminase to produce a compound e;
(4) converting compound e to the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative (compound f).
The preparation route of the above steps is shown below.
The invention generates carbanion by the action of the starting material (C) and strong alkali, and then generates SN with the 3-substituted (S) -pyrrolidone (B)2Nucleophilic substitution reaction, hydrolysis and decarboxylation to obtain (d), transaminase catalysis and ammonia donor reaction to generate (e), and final reaction to obtain corresponding target product (f), and the steps are simple, mild in reaction condition, high in product yield and easy in industrial production.
According to the present invention, step (1) is carried out in the presence of a solvent including, but not limited to, dichloromethane.
According to the invention, R1、R2Each independently selected from a C1-6 hydrocarbon group, Q2Has the structural formula R3SO2，R3Any one selected from substituted or unsubstituted aryl groups and alkyl groups having 1 to 3 carbon atoms. The hydrocarbon group in the present invention includes a saturated hydrocarbon group including an alkyl group, a cycloalkyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a n-pentyl group, an isopentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like, as well as an unsaturated hydrocarbon group. Unsaturated alkyl groups include alkenyl, alkyl, cycloalkenyl, phenyl, such as, for example, methyl alkenyl, vinyl, ethynyl, propenyl, allyl, propargyl, hexenyl, cyclopropenyl, phenyl, and the like. Substituted aryl groups include, but are not limited to, tolyl.
According to the invention, the step (1) also comprises the steps of adding water to separate the system after the reaction is finished, then washing the organic layer with water, and then drying the organic layer, wherein the dried organic layer can be directly used for the next reaction or can be dissolved in an organic solvent and then used for the next reaction.
Further, methods of drying the organic layer include, but are not limited to, the use of desiccants and/or concentrated drying. The drying agent may be, for example, anhydrous sodium sulfate.
According to some specific and preferred embodiments, the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative can be prepared by the following route:
wherein the starting material (a) can be synthesized from L-glutamic acid with low cost, and the preparation route is shown in the following preparation method references (EP 430234; CN 1066842; Synlett, (13), 2028-.
The raw material (c) can be obtained by performing claisen ester condensation reaction on oxalate and acetate, and the reaction route is as follows:
or, the reaction route is as follows:
the present invention will be further described with reference to the following examples. However, the present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are conventional conditions in the industry. The technical features of the embodiments of the present invention may be combined with each other as long as they do not conflict with each other.
Unless otherwise specified, the room temperature in the following examples is 20 to 25 ℃.
Example 1
Preparation of Compound (b)
100ml of dichloromethane, 10.1 g (100mmol) of (S) -3-hydroxy-2-pyrrolidone (a) and 22.8 g (120mmol) of p-toluenesulfonyl chloride are added into a reaction bottle, stirred and dissolved, 15 g (148mmol) of triethylamine is dropwise added at room temperature, after dropwise addition, the reaction is carried out at 30-35 ℃ for 5 hours, after the reaction is finished, 50 g of water is added, layers are separated, an organic layer is washed by water, anhydrous sodium sulfate is added into the organic layer for drying, a drying agent is removed by filtration, an organic phase is concentrated to be dry, and 50ml of DMF is added for dilution and is directly used for the next reaction.
Example 2
Preparation of Compound (d)
Adding 50ml of toluene, 7.6 g (140mmol) of sodium methoxide and 24 g (150mmol) of 2-oxo-succinic acid dimethyl ester (c) into another reaction bottle, stirring and reacting for half an hour at room temperature, evaporating the toluene under reduced pressure, adding 50ml of DMF into the residue, stirring uniformly, slowly dripping the DMF solution containing (b) prepared in the example 1, reacting for 3 hours at 60-65 ℃, after the reaction is finished, evaporating the DMF under reduced pressure, recovering DMF, and cooling the residue to room temperature.
Adding 120 g of 10% NaOH aqueous solution and 50ml of toluene into the residue, reacting at room temperature for 2 hours, discarding an organic layer, dropwise adding 45 g of concentrated hydrochloric acid into a water layer, acidifying, adding 100ml of dichloromethane for extraction, concentrating the organic layer, and adding a concentrate into the concentrate, wherein the volume ratio is 2: ethyl acetate of 8: a total of 80ml of n-heptane was recrystallized to yield 13 g of product (d), 76% molar yield, 98% HPLC purity and 97% ee.
Example 3
Preparation of Compound (e)
Weighing 10g of the substrate (d), adding 15ml of water, adjusting the pH to 8 by using 40% NaOH aqueous solution, and preparing substrate liquid; in a 250ml three-neck flask, 9g of ammonium formate and 45ml of water are weighed, 40% NaOH aqueous solution is used for adjusting the pH value to 8.0, the temperature is raised to 30 ℃, 0.5g of transaminase (L-TA, Han enzyme Biotechnology Co., Ltd. in Suzhou), 0.1g of formate dehydrogenase and 0.06g of coenzyme NAD are added, substrate liquid is dripped into the reaction flask by a constant flow pump and is finished in about 5 hours, the reaction is carried out for 24 hours, the conversion rate is 99% by HPLC detection, and the ee% is 99.5%.
Example 4
Preparation of Compound (f)
100ml of methanol, 17.2 g (100mmol) (e) were added to a reaction flask, cooled to 10 ℃ and 12 g (100mmol) SOCl were added dropwise2After the dropwise addition, reacting at room temperature for 20 hours, after the reaction, removing acid and methanol under reduced pressure, then adding 100ml of methanol, cooling to 0 ℃, introducing ammonia to ensure that the mass concentration of the ammonia in the reaction solution reaches 15%, stopping introducing the ammonia, reacting at room temperature for 24 hours, gradually heating and recovering part (about 2/3) of the methanol under normal pressure, separating out a solid product, cooling to-5 ℃, filtering, washing a filter cake with a small amount of cold methanol, and drying to obtain 17.2 g of a product (f), wherein the yield is 83%, HPLC 98% and ee% is 99%.
The present invention has been described in detail in order to enable those skilled in the art to understand the invention and to practice it, and it is not intended to limit the scope of the invention, and all equivalent changes and modifications made according to the spirit of the present invention should be covered by the present invention.
Claims (10)
1. A method for preparing an intermediate, which is characterized in that,
the structural formula of the intermediate is
The preparation method comprises the steps of firstly enabling a compound C and a compound B to react under the action of strong alkali to generate a compound G, then enabling the compound G to be hydrolyzed and decarboxylated to obtain the intermediate,
wherein,
the structural formula of the compound C is
The structural formula of the compound B is
The structural formula of the compound G is
R in the above structural formula1、R2Each independently selected from a C1-6 hydrocarbon group, Q2Of the formula R3SO2，R3Any one selected from substituted or unsubstituted aryl groups and alkyl groups having 1 to 3 carbon atoms.
2. The preparation method of the intermediate as claimed in claim 1, wherein the strong base is selected from one or more of NaH, sodium alkoxide, potassium alkoxide, DBU and LiHMDS, and the feeding molar ratio of the strong base to the compound C is (0.8-1.2): 1;
and/or controlling the reaction temperature of the compound C and the compound B to be 0-100 ℃;
and/or, reacting said compound C and said compound B in the presence of an organic solvent selected from one or more of DMF, DMSO, THF, toluene, and alcoholic solvents.
3. The preparation method of the intermediate as claimed in claim 2, wherein the compound C and the strong base are reacted at 15-35 ℃ for 0.1-1 h, and then reacted with the compound B at 40-70 ℃ for 1-5 h to obtain the compound G.
4. The method for preparing the intermediate according to claim 1, wherein the hydrolysis decarboxylation comprises reacting the compound G in the presence of sodium hydroxide and an organic solvent, and then adding hydrochloric acid to acidify to obtain the intermediate;
wherein the sodium hydroxide is fed in the form of a sodium hydroxide aqueous solution with the mass concentration of 5-15%, the organic solvent is one or more of DMF, DMSO, THF, toluene and alcohol solvents, and the reaction temperature is controlled to be 0-100 ℃.
5. The method for preparing the intermediate according to claim 4, further comprising the steps of adding an extractant selected from one or more of dichloromethane, ethyl acetate and toluene to the system after the acidification, concentrating the organic phase obtained by the extraction, and recrystallizing the concentrate obtained by the concentration, wherein the mixed solvent is ethyl acetate and n-heptane, and the volume ratio of the ethyl acetate to the n-heptane is 1: (3-5).
6. The process for preparing an intermediate as claimed in claim 1, further comprising reacting (S) -3-hydroxy-2-pyrrolidone with a sulfonylating agent having a formula of R to produce the compound B under the action of triethylamine3SO2X；
Wherein, R is3And said Q2R in (1)3And X is selected from any one of fluorine, chlorine, bromine and iodine, the feeding molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the sulfonylation reagent is 1 (1-1.4), the feeding molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the triethylamine is 1: (1.2-1.8) and controlling the reaction temperature to be 20-50 ℃.
7. A process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivatives, which comprises preparing an intermediate and then converting said intermediate into (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives; wherein the intermediate is produced according to the production method described in any one of claims 1 to 6,
the (S) -2-amino- (S) -3- [ pyrrolidone-2']The structural formula of the alanine derivative is shown in the specification
8. The process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivatives according to claim 7, wherein the conversion of the intermediate into (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives comprises: reacting said intermediate with an ammonia donor under the action of a transaminase to form compound e, and then converting said compound e into said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative;
wherein,
the structural formula of the compound e is
9. The process for producing (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives according to claim 8, wherein the intermediate is reacted with the ammonia donor in the presence of formate dehydrogenase, a coenzyme and an auxiliary;
wherein the ammonia donor is selected from ammonium formate and/or L-amino acid, and the feeding mass ratio of the intermediate to the ammonia donor is 1 (0.8-1);
the feeding mass ratio of the transaminase to the formate dehydrogenase to the coenzyme is 1: (0.1-0.3): (0.05 to 0.2) of,
the feeding mass ratio of the intermediate to the transaminase is 1: (0.01-0.1);
the auxiliary agent is sodium hydroxide aqueous solution, the pH of the reaction system is adjusted to 7.5-8.5 by using the auxiliary agent,
controlling the reaction temperature to be 20-40 ℃;
and/or, the conversion of said compound e to said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative comprises: reacting compound e with thionyl chloride and then ammonia to form the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative;
wherein the feeding molar ratio of the compound e to the thionyl chloride is 1 (0.8-1.2), and the mass concentration of ammonia in the system is controlled to be 10-20%.
10. An intermediate, characterized in that the structural formula of the intermediate is
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