CN112779304A - Preparation method of polycyclic pyridone compound - Google Patents
Preparation method of polycyclic pyridone compound Download PDFInfo
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- CN112779304A CN112779304A CN201911077448.2A CN201911077448A CN112779304A CN 112779304 A CN112779304 A CN 112779304A CN 201911077448 A CN201911077448 A CN 201911077448A CN 112779304 A CN112779304 A CN 112779304A
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- 238000002360 preparation method Methods 0.000 title abstract description 7
- -1 polycyclic pyridone compound Chemical class 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 102000004190 Enzymes Human genes 0.000 claims abstract description 11
- 108090000790 Enzymes Proteins 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 229940125782 compound 2 Drugs 0.000 claims description 21
- 229940126214 compound 3 Drugs 0.000 claims description 19
- 229940125904 compound 1 Drugs 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 13
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 108090001060 Lipase Proteins 0.000 claims description 5
- 239000004367 Lipase Substances 0.000 claims description 5
- 102000004882 Lipase Human genes 0.000 claims description 5
- 235000019421 lipase Nutrition 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 241000228212 Aspergillus Species 0.000 claims description 3
- 241000589513 Burkholderia cepacia Species 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 108010093096 Immobilized Enzymes Proteins 0.000 claims description 3
- 108091005804 Peptidases Proteins 0.000 claims description 3
- 239000004365 Protease Substances 0.000 claims description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 3
- 101000968489 Rhizomucor miehei Lipase Proteins 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000002538 fungal effect Effects 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 3
- 241001453380 Burkholderia Species 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000001035 drying Methods 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WNMORWGTPVWAIB-UHFFFAOYSA-N ethenyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC=C WNMORWGTPVWAIB-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229940123734 Endonuclease inhibitor Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PIZOACXKIKXRDJ-UHFFFAOYSA-N phenyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC=CC=C1 PIZOACXKIKXRDJ-UHFFFAOYSA-N 0.000 description 1
- LSJFMTWFOIHWKQ-UHFFFAOYSA-N prop-1-en-2-yl 2-methylpropanoate Chemical compound CC(C)C(=O)OC(C)=C LSJFMTWFOIHWKQ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
Abstract
The invention relates to a preparation method of a polycyclic pyridone compound, belonging to the field of pharmaceutical chemistry. The method adopts enzyme catalysis reaction, can realize dynamic kinetic resolution, converts racemates and the like into compounds with single configuration, avoids the waste of isomers and reduces the recovery of the isomers, and is more economic and environment-friendly and has higher production and application values.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a heterocyclic-fused pyridone compound.
Background
BaloxavirMarvoxil (formerly S-033188, tradename Xofluza) is an innovative Cap-dependent endonuclease inhibitor that is able to inhibit transcription of influenza virus self-mRNA. BaloxavirMarvoxil was first described in PCT patent WO2016175224 and has the following structural formula:
compound 3 is an important fragment in the structure of BaloxavirMarvoxil, and the preparation and the acquisition thereof are very important for obtaining the medicine
The compound 3 has one chiral center and 3 rings, which is difficult to obtain the compound 3 with a single configuration. At present, the conventional methods are chiral synthesis or resolution. In the chiral synthesis method, a special chiral catalyst and the like are required, in the resolution method, in the common method using a resolution reagent, the theoretical yield of the product is only 50%, and the methods are not favorable for obtaining the target compound 3 at low cost, and particularly, half of isomers need to be discarded or recycled, thereby causing unnecessary waste or burden. Therefore, a simple, low-cost, environmentally friendly, and easily controlled method for reducing isomer recovery is needed to prepare intermediate compound 3 of baloxavirrmorvoxil. The enzyme catalysis is a green, environment-friendly and economic method, and has a good application prospect.
Disclosure of Invention
The invention provides a preparation method of a compound 3. A process for the preparation of compound 3,
the method comprises the following steps: in an organic solvent, in the presence of alkali and enzyme, the compound 1 reacts with an acyl donor, and after post-treatment, the compound 2 is prepared
Wherein the dotted line indicates that the bond is down (S configuration) or that the bond is planar (racemate); r is alkyl, alkoxy, phenyl, alkyl optionally substituted by halogen, alkoxy optionally substituted by halogen, or phenyl optionally substituted by halogen.
Compound 1 can be in the racemic or S configuration.
In the above method, the enzyme may be at least one of Burkholderia lipase, Pseudomonas cepacia lipase, Rhizomucor miehei lipase immobilized enzyme, and Aspergillus fungal protease.
In the above process, the acyl donor may be any suitable compound including, but not limited to, di-tert-butyl dicarbonate, vinyl isobutyrate, isopropenyl isobutyrate, or compound 6 of the formula; wherein R is alkyl, alkoxy, phenyl, alkyl optionally substituted by halogen, alkoxy optionally substituted by halogen, or phenyl optionally substituted by halogen; r1Is halogen or nitro at any position and in any number;
in the method, the base is at least one of potassium carbonate, cesium fluoride, cesium carbonate and barium hydroxide.
In the above method, the organic solvent is at least one of DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), acetonitrile, THF (tetrahydrofuran), toluene, ester solvents such as isopropyl acetate, ethyl acetate, and the like, ether solvents such as isopropyl ether, methyl t-butyl ether, and the like. In some embodiments, the organic solvent is at least one of DMSO, acetonitrile, toluene, isopropyl acetate, methyl tert-butyl ether, which facilitates the reaction and the formation of the product.
In the above method, the mass ratio of the enzyme to the compound 1 may be 0.1:1 to 10: 1. In some embodiments, the mass ratio of enzyme to compound 1 can be from 0.2:1 to 5:1, which facilitates reaction control and product formation.
In the above process, the molar ratio of the base to the compound 1 is 0.5:1 to 10: 1. In some embodiments, the molar ratio of base to compound 1 is from 1:1 to 10:1, which facilitates reaction control and product formation. In some embodiments, the molar ratio of base to compound 1 is from 2:1 to 8:1, which is more favorable for reaction control and product formation.
In the above method, the molar ratio of the acyl donor to the compound 1 is 1:1 to 10: 1. In some embodiments, the molar ratio of acyl donor to compound 1 is 2:1 to 8:1, which facilitates reaction control and product formation.
In the above method, the reaction temperature may be 10 ℃ to 100 ℃. In some embodiments, the reaction temperature may be from 20 ℃ to 80 ℃. In some embodiments, the reaction temperature may be from 30 ℃ to 60 ℃, which is more favorable for the reaction and the production of the product.
In some embodiments, in compound 2 or compound 6,
the structure is as follows:
The post-processing may include: controlling the temperature of the reaction solution to be 0-30 ℃, filtering, evaporating the filtrate to dryness, and crystallizing the residue by using an ester solvent or an alcohol solvent or a combined solvent thereof to obtain a compound 2; the ester solvent may be ethyl acetate, isopropyl acetate, or a combination thereof, and the alcohol solvent is ethanol or isopropanol, or a combination thereof. In some embodiments, the post-processing may include: controlling the temperature of the reaction solution to 15-30 ℃, filtering, evaporating the filtrate to dryness, and crystallizing the residue by using an ester solvent to obtain the compound 2, wherein the ester solvent can be ethyl acetate, isopropyl acetate or a combination thereof.
In the method provided by the invention, the compound 1 can be converted into the compound 2 with a single configuration under the action of enzyme and alkali, dynamic kinetic resolution is realized, the theoretical yield of the compound 2 is 100%, the actual yield is also more than 60%, and is higher than the theoretical yield (50%) of the conventional resolution method, the waste of isomers can be avoided, the recovery of the isomers is reduced, and the method is more economic and environment-friendly and is more favorable for production.
In some embodiments, a method of preparing compound 3 can further comprise: in a reaction solvent, reacting the compound 2 under the action of an alkaline reagent, and performing post-treatment to prepare a compound 3
Wherein R is alkyl, alkoxy, phenyl, alkyl optionally substituted by halogen, alkoxy optionally substituted by halogen, or phenyl optionally substituted by halogen.
In some embodiments, a method of making compound 3, comprises: in an organic solvent, in the presence of alkali and enzyme, reacting the compound 1 with an acyl donor, and performing post-treatment to prepare a compound 2; in a reaction solvent, reacting the compound 2 under the action of an alkaline reagent, and performing post-treatment to prepare a compound 3
Wherein R is alkyl, alkoxy, phenyl, alkyl optionally substituted by halogen, alkoxy optionally substituted by halogen, or phenyl optionally substituted by halogen.
The alkaline agent is DBU, diisopropylethylamine, triethanolamine, or a combination thereof.
The reaction solvent may be ethyl acetate, isopropyl acetate, or a combination thereof.
The compound 2 reacts under the action of an alkaline reagent, and the reaction temperature can be 0-60 ℃. In some embodiments, compound 2 is reacted under the action of a basic reagent, and the reaction temperature may be from 0 ℃ to 45 ℃. In some embodiments, compound 2 is reacted under the action of a basic reagent, and the reaction temperature may be 20 ℃ to 40 ℃. In some embodiments, compound 2 is reacted under the action of a basic reagent, and the reaction temperature may be 40 ℃ to 60 ℃.
In the present invention, the halogen is fluorine, chlorine, bromine, or iodine.
After the compound 2 is reacted, controlling the temperature of reaction liquid to be 0-30 ℃, filtering, optionally crystallizing the obtained solid by using an ester solvent or a mixed solvent of the ester solvent and water, and drying the obtained solid to constant weight to obtain a compound 3; the ester solvent may be ethyl acetate, isopropyl acetate, or a combination thereof. In some embodiments, after the compound 2 is reacted, controlling the temperature of the reaction solution to 10-30 ℃, filtering, optionally crystallizing the obtained solid by using an ester solvent or a mixed solvent of the ester solvent and water, and drying the obtained solid to constant weight to obtain a compound 3; the ester solvent may be ethyl acetate, isopropyl acetate, or a combination thereof.
The method is different from the conventional resolution dynamic resolution method, can obtain the intermediate compound 2 with a single configuration, further obtain the compound 3 with a single configuration, is simple and convenient, economic and environment-friendly, can reduce the steps of isomer recovery and re-racemization, and has higher industrialization advantages.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means h, min means min, g means g, ml means ml, DBU means 1, 8-diazabicycloundec-7-ene, CDCl3Represents deuterated chloroform;1h NMR represents nuclear magnetic resonance hydrogen spectrum;
LC-MS: liquid phase-mass spectrometry;
ee value: enantiomeric excess, which means the excess of a certain enantiomer, can be calculated as ee ═ 100% (R- [ S ]/[ R ] + [ S ]).
In the present invention, the reaction is considered to be completed when the remaining amount of the raw materials is less than 2%, 1% or 0.5% of the charged amount thereof during the reaction.
In the invention, the room temperature refers to the ambient temperature and is 20-30 ℃, or 25-28 ℃.
In the present invention, when referring to numerical values, there is a deviation of ± 10% for each numerical value, whether about or about used.
Example 1-1:
adding 1.0g of compound 1, 3.0g of phenol isobutyrate, 3.7g of cesium fluoride and 30ml of acetonitrile to a reaction flask, adding 500mg of Pseudomonas cepacia lipase while stirring at room temperature, stirring, heating the reaction flask to 50 ℃, cooling to room temperature after the reaction is finished, filtering, drying the filtrate, and recrystallizing the residue with ethyl acetate to obtain compound 2-01: 884mg, yield 70%, purity 95%, ee value 85%; and (3) detection:
LC-MS:[M+H]＝398.1；
1H NMR(400MHz,DMSO)δ7.65(d,J＝7.5Hz,1H),7.51(d,J＝6.8Hz,2H),7.39–7.25(m,3H),6.30(d,J＝7.7Hz,1H),5.83(dd,J＝9.8,2.9Hz,1H),5.22–5.06(m,2H),4.34(d,J＝12.5Hz,1H),4.05(dd,J＝10.6,2.6Hz,1H),3.73(dd,J＝11.2,2.1Hz,1H),3.53(t,J＝10.3Hz,1H),3.43–3.34(m,1H),3.32–3.19(m,2H),1.08(dd,J＝11.6,6.7Hz,6H)。
examples 1 to 2:
adding 884mg of compound 2-01, 9ml of ethyl acetate and 25mg of 1, 8-diazabicyclo [5.4.0] undec-7-ene to a reaction flask, stirring, and heating the reaction flask to 30 ℃; after the reaction is finished, cooling to room temperature, filtering, and drying a filter cake to obtain a compound 3: 616mg, yield 89%, purity 98%, ee value 95%; and (3) detection:
LC-MS：[M+H]＝328.4；
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.6Hz,2H),7.41–7.30(m,3H),6.33(d,J＝7.7Hz,1H),5.63(d,J＝13.1Hz,1H),5.35(d,J＝9.8Hz,1H),5.04(d,J＝9.9Hz,1H),4.55–4.41(m,1H),4.03–3.87(m,2H),3.80(dd,J＝11.5,4.5Hz,1H),3.56(dd,J＝12.0,9.3Hz,1H),2.99–2.91(m,1H),2.83(td,J＝13.3,4.4Hz,1H)。
example 2-1
Adding 1.0g of compound 1, 2.7g of vinyl isobutyrate, 3.8g of barium hydroxide and 30ml of methyl tert-ether to a reaction flask, adding 600mg of Aspergillus fungal protease at room temperature under stirring, and heating to 50 ℃; after the reaction is finished, cooling to room temperature, filtering, spin-drying the filtrate, and recrystallizing the residue with 5ml of ethyl acetate to obtain a compound 2-01: 947mg, 75% yield, 95% purity, 87% ee; and (3) detection:
LC-MS：[M+H]＝398.1；
1H NMR(400MHz,DMSO)δ7.65(d,J＝7.5Hz,1H),7.51(d,J＝6.8Hz,2H),7.39–7.25(m,3H),6.30(d,J＝7.7Hz,1H),5.83(dd,J＝9.8,2.9Hz,1H),5.22–5.06(m,2H),4.34(d,J＝12.5Hz,1H),4.05(dd,J＝10.6,2.6Hz,1H),3.73(dd,J＝11.2,2.1Hz,1H),3.53(t,J＝10.3Hz,1H),3.43–3.34(m,1H),3.32–3.19(m,2H),1.08(dd,J＝11.6,6.7Hz,6H)。
example 2-2:
947mg of compound 2-01, 10ml of ethyl acetate and 28mg of DBU were added to a reaction flask, and stirred, and the reaction flask was heated to 30 ℃; after the reaction is finished, cooling to room temperature, filtering, and drying a filter cake to obtain a compound 3: 667mg, yield 90%, purity 98%, ee value 96%; and (3) detection: LC-MS: [ M + H ] ═ 328.4;
1H NMR(400MHz,CDCl3)δ7.59(d,J＝6.6Hz,2H),7.41–7.30(m,3H),6.33(d,J＝7.7Hz,1H),5.63(d,J＝13.1Hz,1H),5.35(d,J＝9.8Hz,1H),5.04(d,J＝9.9Hz,1H),4.55–4.41(m,1H),4.03–3.87(m,2H),3.80(dd,J＝11.5,4.5Hz,1H),3.56(dd,J＝12.0,9.3Hz,1H),2.99–2.91(m,1H),2.83(td,J＝13.3,4.4Hz,1H)。
example 3-1:
adding 1.0g of compound 1, 3.3g of compound II, 5.5g of cesium carbonate and 30ml of isopropyl acetate into a reaction flask, adding 800mg of Rhizomucor miehei lipase immobilized enzyme under stirring at room temperature, heating the reaction flask to 50 ℃, cooling to room temperature after the reaction is finished, filtering, drying the filtrate in a spinning mode, and recrystallizing the residue with 5ml of ethyl acetate to obtain compound 2-02: 884mg, yield 70%, purity 94%, ee value 85%; and (3) detection:
LC-MS：[M+H]＝414.2；
1H NMR(400MHz,DMSO)δ7.76(d,J＝7.8Hz,1H),7.51(d,J＝7.0Hz,2H),7.39–7.25(m,3H),6.28(d,J＝7.8Hz,1H),5.65(dd,J＝10.2,2.8Hz,1H),5.18(d,J＝10.8Hz,1H),5.10(d,J＝10.7Hz,1H),4.98–4.83(m,1H),4.43–4.30(m,1H),3.98(dd,J＝10.6,2.7Hz,1H),3.79–3.66(m,1H),3.53(t,J＝10.5Hz,1H),3.27(dt,J＝16.7,8.3Hz,2H),1.19(dd,J＝19.3,6.2Hz,6H)。
example 3-2:
adding 884mg of compound 02-2, 10ml of ethyl acetate and 28mg of DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene) to a reaction flask, stirring, and heating the reaction flask to 35 ℃; and after the reaction is finished, cooling to room temperature, filtering, and drying a filter cake to obtain a compound 3: 592mg, yield 90%, purity 98%, ee value 94%; and (3) detection: LC-MS: [ M + H ] ═ 328.4.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. Method for preparing compound 2
The method comprises the following steps: in an organic solvent, in the presence of alkali and enzyme, the compound 1 reacts with an acyl donor, and after post-treatment, the compound 2 is prepared
Wherein the dotted line indicates that the bond is down or that the bond is planar; r is alkyl, alkoxy, phenyl, alkyl optionally substituted by halogen, alkoxy optionally substituted by halogen, or phenyl optionally substituted by halogen.
2. A method of preparing compound 3, comprising: compound 2 prepared according to the process of claim 1; in a reaction solvent, reacting a compound 2 under the action of an alkaline reagent, and performing post-treatment to prepare a compound 3; wherein R is alkyl, alkoxy, phenyl, alkyl optionally substituted by halogen, alkoxy optionally substituted by halogen, or phenyl optionally substituted by halogen;
3. the method according to claim 1, wherein the enzyme is at least one of burkholderia lipase, pseudomonas cepacia lipase, rhizomucor miehei lipase immobilized enzyme, aspergillus fungal protease.
4. The method of claim 1, wherein the base is at least one of potassium carbonate, cesium fluoride, cesium carbonate, and barium hydroxide.
5. The method according to claim 1, wherein the organic solvent is at least one of DMF, DMSO, acetonitrile, THF, toluene, an ester solvent, and an ether solvent.
6. The method according to claim 1, wherein the mass ratio of enzyme to compound 1 is 0.1:1-10:1, or the molar ratio of base to compound 1 is 0.5:1-10:1, or the molar ratio of acyl donor to compound 1 is 1:1-10: 1.
7. The method of claim 1 or 2,
the structure is as follows:
R1is halogen or nitro at any position and in any number.
8. The method of claim 1, wherein post-processing comprises: controlling the temperature of the reaction solution to be 0-30 ℃, filtering, evaporating the filtrate to dryness, and crystallizing the residue by using an ester solvent or an alcohol solvent to obtain a compound 2; the ester solvent is ethyl acetate, isopropyl acetate or a combination thereof, and the alcohol solvent is ethanol or isopropanol or a combination thereof.
9. The process of claim 1, wherein the temperature of the reaction is from 10 ℃ to 100 ℃.
10. The method of claim 2, the basic agent is DBU, diisopropylethylamine, triethanolamine, or a combination thereof.
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| CN102925529A (en) * | 2011-10-26 | 2013-02-13 | 苏州同力生物医药有限公司 | Method for producing intermediate of levo-praziquantel and levo-praziquantel |
| US9427355B1 (en) * | 2014-05-12 | 2016-08-30 | Gholam A. Peyman | Corneal transplantation with a cross-linked cornea |
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