CN111574473A - Method for synthesizing aminothiazole compound - Google Patents
Method for synthesizing aminothiazole compound Download PDFInfo
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- CN111574473A CN111574473A CN202010499806.5A CN202010499806A CN111574473A CN 111574473 A CN111574473 A CN 111574473A CN 202010499806 A CN202010499806 A CN 202010499806A CN 111574473 A CN111574473 A CN 111574473A
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- -1 aminothiazole compound Chemical class 0.000 title claims abstract description 17
- 229950003476 aminothiazole Drugs 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims abstract description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 28
- 239000003054 catalyst Substances 0.000 claims description 21
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 230000009471 action Effects 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical group C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003456 ion exchange resin Substances 0.000 claims description 6
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 6
- 229920001429 chelating resin Polymers 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 abstract description 8
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 17
- 239000012267 brine Substances 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 239000002132 β-lactam antibiotic Substances 0.000 description 6
- 229940124586 β-lactam antibiotics Drugs 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 3
- 229960003644 aztreonam Drugs 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241001214789 Basilea Species 0.000 description 1
- ZMJOVJSTYLQINE-UHFFFAOYSA-N Dichloroacetylene Chemical compound ClC#CCl ZMJOVJSTYLQINE-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KLFSEZJCLYBFKQ-WXYNYTDUSA-N [(3s)-3-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-[(1,5-dihydroxy-4-oxopyridin-2-yl)methoxyimino]acetyl]amino]-2,2-dimethyl-4-oxoazetidin-1-yl] hydrogen sulfate Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(\C=1N=C(N)SC=1)=N/OCC1=CC(=O)C(O)=CN1O KLFSEZJCLYBFKQ-WXYNYTDUSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001775 anti-pathogenic effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a synthesis method of aminothiazole compounds, belonging to the technical field of medicine synthesis. The synthesis method comprises the following steps: f) reacting the compound with the structure of the formula (VI) with selenium dioxide to obtain a compound with the structure of the formula (VII);
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of an aminothiazole compound.
Background
Antibiotics are a class of secondary metabolites with antipathogenic or other activities produced by microorganisms (bacteria, fungi, actinomycetes, etc.) or higher animals and plants during life, and chemical substances capable of interfering with other life cell development functions. Antibiotics commonly used in clinical practice include extracts from microbial cultures, chemically synthesized or semi-synthesized compounds. Antibiotics are in a wide variety, and among them, monocyclic β -lactam antibiotics are one of the hot areas of antibiotic development.
Aztreonam (Aztreonam), the first monocyclic β -lactam antibiotic used clinically, was approved by the FDA in 1984 and marketed, and is currently the most widely used monocyclic β -lactam antibiotic.
Monobactam 1, the Basilea pharmaceutical group of California, Switzerland BAL-30072 and LYS228, Nowa, are outstanding in this field.
Researches show that the side chains formed by aminothiazole compounds mostly exist in the monocyclic beta-lactam antibiotics, and the structure only needs oximation and N-acylation to obtain the beta-lactam antibiotics. However, the conventional method for synthesizing aminothiazole compounds is complicated in operation and requires post-treatment after most reactions.
Disclosure of Invention
The invention provides a synthesis method of aminothiazole compounds, which is easy to operate, simple in post-treatment, mild in reaction condition and high in yield.
The invention provides a synthesis method of an aminothiazole compound, wherein the aminothiazole compound has a structure shown as a formula (VII); the method comprises the following steps:
d) reacting a compound with a structure shown in a formula (IV) with thiourea to obtain a compound with a structure shown in a formula (V);
e) reacting a compound with a structure shown in a formula (V) with di-tert-butyl carbonate under the action of a catalyst to obtain a compound with a structure shown in a formula (VI);
f) reacting the compound with the structure of the formula (VI) with selenium dioxide to obtain a compound with the structure of the formula (VII);
further, the compound with the structure of formula (IV) is prepared according to the following steps:
c) reacting a compound with a structure shown in a formula (III) with bromine to obtain a compound with a structure shown in a formula (IV);
further, the compound with the structure of the formula (III) is prepared according to the following steps:
b) reacting the compound with the structure of the formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine to obtain a compound with the structure of the formula (III);
further, the compound with the structure of the formula (II) is prepared according to the following steps:
a) reacting a compound with a structure shown in a formula (I) under the action of a catalyst to obtain a compound with a structure shown in a formula (II);
further, in step f):
a compound having a structure of formula (VI) and selenium dioxide (SeO)2) The molar ratio of (1) to (0.5-2);
the solvent for the reaction is 1, 4-dioxane; the reaction temperature is 0-40 ℃.
Further, in step e):
the mol ratio of the compound with the structure of formula (V) to the di-tert-butyl carbonate is 1: (0.5 to 2);
the catalyst for the reaction is 4-Dimethylaminopyridine (DMAP); the molar ratio of the compound with the structure of the formula (V) to the catalyst is 1: 0.1; the reaction temperature is 0-40 ℃.
Further, in step d):
the molar ratio of the compound with the structure of formula (IV) to thiourea is 1: (0.5 to 2); the reaction temperature is 0-40 ℃;
further, in step c):
the molar ratio of the compound with the structure of formula (III) to bromine is 1 (0.5-2); mixing the reaction raw materials at 0 ℃; the reaction temperature is 0-40 ℃.
Further, in step b):
the mol ratio of the compound with the structure of formula (II), oxalyl chloride, dimethyl sulfoxide and triethylamine is (2-6): (2 to 6), (8 to 10) and (22 to 26); mixing the reaction raw materials at-70 to-80 ℃;
further, in step a):
the mass ratio of the compound with the structure of formula (I) to the catalyst is 3-5: 1; the catalyst is ion exchange resin; the ion exchange resin is Amberlyst A-15.
The invention has the following advantages:
the synthesis method of the aminothiazole compound provided by the invention is easy to operate, simple in post-treatment, mild in reaction condition and high in final product yield. The aminothiazole compound obtained by the method can be used as an intermediate for preparing monocyclic beta-lactam antibiotics.
Detailed Description
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict. And the source of the raw material used in the present invention is not particularly limited.
The embodiment of the invention provides a synthesis method of an aminothiazole compound, wherein the aminothiazole compound has a structure shown as a formula (VII); the method comprises the following steps:
d) reacting a compound with a structure shown in a formula (IV) with thiourea to obtain a compound with a structure shown in a formula (V);
e) reacting a compound with a structure shown in a formula (V) with di-tert-butyl carbonate under the action of a catalyst to obtain a compound with a structure shown in a formula (VI);
f) reacting the compound with the structure of the formula (VI) with selenium dioxide to obtain a compound with the structure of the formula (VII);
specifically, in step f):
a compound having a structure of formula (VI) and selenium dioxide (SeO)2) The molar ratio of (1) to (0.5-2); preferably, the compound having the structure of formula (VI) is reacted with selenium dioxide (SeO)2) The molar ratio of (1) to (1-1.2); the solvent of the reaction is organic solvent; preferably, the solvent for the reaction is 1, 4-dioxane.
The reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the reaction temperature is normal temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: the reaction mixture was filtered through a celite layer, and the solvent was distilled under reduced pressure, and the resulting mixture was subjected to chromatography on a silica gel column to obtain a compound having a structure of formula (vii).
Specifically, in step e):
the mol ratio of the compound with the structure of formula (V) to the di-tert-butyl carbonate is 1: (0.5 to 2); preferably, the molar ratio of the compound with the structure of the formula (V) to the di-tert-butyl carbonate is 1: (1-1.2); in some embodiments of the invention, the compound having the structure of formula (v) has a molar ratio of di-tert-butyl carbonate of 6.99: 7.69; the solvent of the reaction is organic solvent; preferably, the solvent of the reaction is dichloromethane; the catalyst for the reaction is 4-Dimethylaminopyridine (DMAP); the molar ratio of the compound having the structure of formula (v) to the catalyst was 1: 0.1.
The reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the reaction temperature is normal temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: the reaction mixture was treated with HCl and diluted with EtOAc, washed with water, brine and dried. The organic phase is concentrated and chromatographed on a column of silica gel to give the compound having the structure of formula (VI).
Specifically, in step d):
the molar ratio of the compound with the structure of formula (IV) to thiourea is 1: (0.5 to 2); preferably, the molar ratio of the compound with the structure of formula (IV) to the thiourea is 1: (1-1.2); in some embodiments of the invention, the molar ratio of the compound having the structure of formula (iv) to thiourea is 24.39: 26.83; the solvent of the reaction is organic solvent; preferably, the solvent of the reaction is absolute ethanol.
The reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the reaction temperature is normal temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: the reaction mixture was evaporated to dryness and diluted with ethyl acetate, then the reaction mixture was washed with water, brine and Na2SO4And (5) drying. The organic phase is concentrated and chromatographed using petroleum ether: ethyl acetate (volume ratio 2: 8) was used as eluent to obtain the desired compound of formula (v).
In one embodiment of the invention, the compound having the structure of formula (IV) is prepared by the following steps:
c) reacting a compound with a structure shown in a formula (III) with bromine to obtain a compound with a structure shown in a formula (IV);
specifically, in step c):
the molar ratio of the compound with the structure of formula (III) to bromine is 1 (0.5-2); preferably, the molar ratio of the compound with the structure of the formula (III) to bromine is 1: 1-1.2; the solvent of the reaction is organic solvent; preferably, the solvent for the reaction is anhydrous dichloromethane.
Mixing the reaction raw materials at 0 ℃; the reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the reaction temperature is normal temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The post-treatment of the reaction includes: with saturated Na2CO3The solution was quenched, stirred, extracted with DCM, brine and dried over anhydrous sodium sulfate and the organic phase was concentrated to give a mixture of compounds having the structure of formula (iv). Purification is not needed, and the post-treatment of the reaction is simplified.
In one embodiment of the present invention, the compound having the structure of formula (iii) is prepared as follows:
b) reacting the compound with the structure of the formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine to obtain a compound with the structure of the formula (III);
specifically, in step b):
the mol ratio of the compound with the structure of formula (II), oxalyl chloride, dimethyl sulfoxide and triethylamine is (2-6): (2 to 6), (8 to 10) and (22 to 26); preferably, the mole ratio of the compound with the structure of formula (II), oxalyl chloride, dimethyl sulfoxide and triethylamine is (3-5): (3-5), (8-10), (23-25); in some embodiments of the invention, the compound having the structure of formula (ii), oxalyl chloride, dimethyl sulfoxide, and triethylamine are present in a molar ratio of 4.24: 4.6: 9.3: 24.5; the reaction solvent is an organic solvent; preferably, the reaction solvent is dichloromethane.
Mixing the reaction raw materials at-70 to-80 ℃; preferably, the reaction raw materials are mixed at-78 ℃; the reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the reaction temperature is normal temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC).
The reaction of the compound with the structure of the formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine specifically comprises the following steps:
mixing the compound with the structure of formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine at-70 to-80 ℃, and heating to the reaction temperature for reaction.
Preferably, the reaction of the compound with the structure of formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine specifically comprises the following steps: at the temperature of-70 to-80 ℃, adding oxalyl chloride into dimethyl sulfoxide dropwise, mixing, adding a compound with a structure shown in a formula (II), mixing, adding triethylamine, mixing, and heating to the reaction temperature for reaction;
the post-treatment of the reaction includes: quenching the reaction mixture with cold water; the reaction was extracted with DCM, brine and Na2SO4Drying and concentrating the organic phase to obtain a mixture of the compound with the structure of the formula (III), without purification, thereby simplifying the post-treatment of the reaction.
In one embodiment of the present invention, the compound having the structure of formula (ii) is prepared as follows:
a) reacting a compound with a structure shown in a formula (I) under the action of a catalyst to obtain a compound with a structure shown in a formula (II);
specifically, in step a):
the mass ratio of the compound with the structure of formula (I) to the catalyst is 3-5: 1; in some embodiments of the invention, the mass ratio of the compound having the structure of formula (i) to the catalyst is 20: 5; the catalyst is ion exchange resin; the ion exchange resin is Amberlyst A-15. Amberlyst A-15 is available from Alfa Aesar, Inc., among others. The reaction solvent is absolute ethyl alcohol; the concentration of the compound with the structure of formula (I) in absolute ethyl alcohol is 3-6 mol/L; in some embodiments of the invention, the concentration of the compound having the structure of formula (I) in absolute ethanol is 4.6 mol/L.
The reaction temperature is 0-40 ℃; preferably, the reaction temperature is 10-30 ℃; in some embodiments of the invention, the reaction temperature is normal temperature; the reaction time is not limited, and the completion of the reaction can be monitored (TLC). No post-treatment and purification are needed, and the reaction operation is simplified.
The present invention will be described in detail with reference to examples.
Example 1
a) Reacting a compound 1 with a structure shown in a formula (I) under the action of a catalyst to obtain a compound 2 (4-ethyl hydroxybutyrate (2)) with a structure shown in a formula (II);
the chemical reaction formula is as follows:
to a solution of Compound 1 (. gamma. -butyrolactone) (20g, 232.23mmol) having the structure of formula (I) in absolute ethanol (50mL) was added, with stirring, 5g of Amberlyst A-15. The reaction mixture was stirred at room temperature overnight. After completion of the TLC monitoring reaction, the reaction mixture was filtered after overnight consumption, and then the solvent was concentrated to give compound 2 expected to have the structure of formula (ii) as a mixture which was used in the next reaction without further purification.
b) Reacting the compound 2 with the structure of formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine to obtain a compound 3 (4-oxoethyl butyrate) with the structure of formula (III);
the chemical reaction formula is as follows:
to a stirred solution of oxalyl chloride (0.54mL, 4.6mmol) in Dichloromethane (DCM) (30mL) was slowly added dimethyl sulfoxide (DMSO) (0.6mL, 9.3mmol) dropwise at-78 deg.C. After stirring the reaction mixture for two minutes, a mixture of compound 2 having the structure of formula (II) (0.5g, 4.24mmol) dissolved in 10mL of DCM was added. The reaction mixture was then stirred at-78 ℃ for 50 minutes. Triethylamine (2.97mL, 24.5mmol) was then added and stirred at-78 deg.C for 15 minutes. The reaction mixture was allowed to warm to room temperature overnight and after TLC monitoring the reaction was complete, it was quenched with cold water. The reaction was extracted with DCM, brine and Na2SO4And (5) drying. The organic phase is then concentrated to give the desired mixture 3 of compound 3 having the structure of formula (III), which is used in the next reaction without purification due to its instability.
c) Reacting a compound 3 with a structure shown in a formula (III) with bromine to obtain a compound 4 (3-bromine-4-oxoethyl butyrate) with a structure shown in a formula (IV);
the chemical reaction formula is as follows:
to a stirred solution of compound 3(4g, 30.77mmol) having the structure of formula (III) in anhydrous CH at 0 deg.C2Cl2(25mL), bromine (1.6mL, 30.77mmol) was added dropwise. The reaction mixture was then warmed to room temperature and stirred at room temperature overnight. After TLC monitoring of the reaction completion, saturated Na was used2CO3The reaction was quenched with water, stirred for 15 min, extracted with DCM, brine and filtered over Na2SO2And (5) drying. The organic phase is concentrated to give the desired mixture of compound 4 having the structure of formula (IV), which is used in the next reaction without further purification.
d) Reacting a compound 4 with a structure shown in a formula (IV) with thiourea to obtain a compound 5(2- (2-aminothiazole-5-yl) ethyl acetate) with a structure shown in a formula (V);
the chemical reaction formula is as follows:
to a stirred solution of compound 4 having a structure of formula (IV) (5g, 24.39mmol) in absolute ethanol (30mL) at room temperature was added thiourea (2.04g, 26.83 mmol). After six hours of reaction, TLC monitored completion of reaction, the reaction mixture was evaporated to dryness and diluted with ethyl acetate (40mL), then the reaction mixture was washed with water, brine 3 times and Na2SO4And (5) drying. The organic phase is concentrated and chromatographed using petroleum ether: ethyl acetate (2: 8) was used as the eluent to give the desired compound 5 having the structure of formula (v) as a yellow solid (1.54g, 30.8%, total yield from four steps) with nuclear magnetic characterization as follows:
1H NMR(400MHz,DMSO-d6)H1.18(t,J＝7.1Hz,3H),4.08(q,J＝7.1Hz,2H),6.72(s,1H),6.80(s,2H)。
e) reacting a compound 5 with a structure shown in a formula (V) with di-tert-butyl carbonate under the action of a catalyst to obtain a compound 6(2- (2- (((tert-butoxycarbonyl) amino) thiazol-5-yl) ethyl acetate) with a structure shown in a formula (VI);
the chemical reaction formula is as follows:
to a stirred solution of compound 5 having a structure of formula (V) (1.3g, 6.99mmol) in dichloromethane (20mL) at room temperature were added di-tert-butyl carbonate (1.68g, 7.69mmol) and 4-Dimethylaminopyridine (DMAP) (0.1g, 0.699mmol), and the reaction mixture was refluxed for 6 hours. After TLC to monitor completion of the reaction, the reaction mixture was treated with 1N HCl and diluted with EtOAc (30mL), washed with water, brine and Na2SO4And (5) drying. The organic phase was concentrated and chromatographed on a column of silica gel to give the desired compound 6 of formula (vi) as a yellow solid (0.82g, 63%) with nuclear magnetic characterization as follows:
1H NMR(400MHz,DMSO-d6)H1.20(t,J＝7.1Hz,3H),1.47(s,9H),3.83(s,2H),4.10(q,J＝7.1Hz,2H),7.15(s,1H),11.32(s,1H).
f) reacting the compound 6 with the structure shown in the formula (VI) with selenium dioxide to obtain a compound 7(2- (2- (((tert-butoxycarbonyl) amino) thiazole-5-yl) -2-oxyacetic acid ethyl ester) with the structure shown in the formula (VII);
the chemical reaction formula is as follows:
SeO was added to a stirred solution of compound 6 having the structure of formula (VI) (0.19g, 0.66mmol) in 1, 4-dioxane (20mL) at room temperature2(0.07g, 0.66mmol), the reaction mixture was then refluxed at 105 ℃ for 24 hours, TLC monitored for completion of the reaction, the reaction mixture was filtered through a celite layer, and the solvent was distilled under reduced pressure, and the resulting mixture was chromatographed on a silica gel column to give compound 7 having the structure of formula (vii) as a yellow solid (0.21g, 100%). Nuclear magnetic characterization was as follows:
1H NMR(400MHz,DMSO-d6)H1.33(t,J＝7.1Hz,3H),1.51(s,9H),4.36(q,J＝7.1Hz,2H),8.45(s,1H),12.36(s,1H).
the present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for synthesizing an aminothiazole compound, wherein the aminothiazole compound has a structure shown as a formula (VII); the method comprises the following steps:
d) reacting a compound with a structure shown in a formula (IV) with thiourea to obtain a compound with a structure shown in a formula (V);
e) reacting a compound with a structure shown in a formula (V) with di-tert-butyl carbonate under the action of a catalyst to obtain a compound with a structure shown in a formula (VI);
f) reacting the compound with the structure of the formula (VI) with selenium dioxide to obtain a compound with the structure of the formula (VII);
2. the method of claim 1, wherein the compound having the structure of formula (iv) is prepared by the following steps:
c) reacting a compound with a structure shown in a formula (III) with bromine to obtain a compound with a structure shown in a formula (IV);
3. the method of claim 2, wherein the compound having the structure of formula (iii) is prepared by the steps of:
b) reacting the compound with the structure of the formula (II) with oxalyl chloride, dimethyl sulfoxide and triethylamine to obtain a compound with the structure of the formula (III);
4. the method of claim 3, wherein the compound having the structure of formula (II) is prepared by the following steps:
a) reacting a compound with a structure shown in a formula (I) under the action of a catalyst to obtain a compound with a structure shown in a formula (II);
5. method according to claim 1, characterized in that in step f):
a compound having a structure of formula (VI) and selenium dioxide (SeO)2) The molar ratio of (1) to (0.5-2);
the solvent for the reaction is 1, 4-dioxane; the reaction temperature is 0-40 ℃.
6. Method according to claim 1, characterized in that in step e):
the mol ratio of the compound with the structure of formula (V) to the di-tert-butyl carbonate is 1: (0.5 to 2);
the catalyst for the reaction is 4-Dimethylaminopyridine (DMAP); the molar ratio of the compound with the structure of the formula (V) to the catalyst is 1: 0.1; the reaction temperature is 0-40 ℃.
7. Method according to claim 1, characterized in that in step d):
the molar ratio of the compound with the structure of formula (IV) to thiourea is 1: (0.5 to 2); the reaction temperature is 0-40 ℃.
8. Method according to claim 2, characterized in that in step c):
the molar ratio of the compound with the structure of formula (III) to bromine is 1 (0.5-2); mixing the reaction raw materials at 0 ℃; the reaction temperature is 0-40 ℃.
9. A method according to claim 3, characterized in that in step b):
the mol ratio of the compound with the structure of formula (II), oxalyl chloride, dimethyl sulfoxide and triethylamine is (2-6): (2 to 6), (8 to 10) and (22 to 26); the reaction raw materials are mixed at the temperature of-70 to-80 ℃.
10. Method according to claim 4, characterized in that in step a):
the mass ratio of the compound with the structure of formula (I) to the catalyst is 3-5: 1; the catalyst is ion exchange resin; the ion exchange resin is Amberlyst A-15.
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| CN1496364A (en) * | 2000-06-28 | 2004-05-12 | Substituted quinazoline derivatives and their use as inhibitors | |
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