CN117720540A - Sitagliptin intermediate and preparation method of sitagliptin - Google Patents
Sitagliptin intermediate and preparation method of sitagliptin Download PDFInfo
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- CN117720540A CN117720540A CN202311202909.0A CN202311202909A CN117720540A CN 117720540 A CN117720540 A CN 117720540A CN 202311202909 A CN202311202909 A CN 202311202909A CN 117720540 A CN117720540 A CN 117720540A
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- compound
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- reaction
- sitagliptin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229960004034 sitagliptin Drugs 0.000 title abstract description 32
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title abstract description 21
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 title abstract description 5
- -1 amine compounds Chemical class 0.000 claims abstract description 55
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 16
- 102000003929 Transaminases Human genes 0.000 claims abstract description 10
- 108090000340 Transaminases Proteins 0.000 claims abstract description 10
- OFUCCBIWEUKISP-UHFFFAOYSA-N 2,2,2-trifluoroacetohydrazide Chemical group NNC(=O)C(F)(F)F OFUCCBIWEUKISP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001408 amides Chemical class 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 102
- 238000006243 chemical reaction Methods 0.000 claims description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000007810 chemical reaction solvent Substances 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 15
- 230000003213 activating effect Effects 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000005515 coenzyme Substances 0.000 claims description 5
- 239000003223 protective agent Substances 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000001769 aryl amino group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 4
- 125000005544 phthalimido group Chemical group 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
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 4
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- NGFFLHMFSINFGB-UHFFFAOYSA-N [chloro(methoxy)phosphoryl]oxymethane Chemical compound COP(Cl)(=O)OC NGFFLHMFSINFGB-UHFFFAOYSA-N 0.000 claims description 2
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 claims description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000009615 deamination Effects 0.000 claims 1
- 238000006481 deamination reaction Methods 0.000 claims 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 102000004190 Enzymes Human genes 0.000 abstract description 10
- 108090000790 Enzymes Proteins 0.000 abstract description 10
- 230000003287 optical effect Effects 0.000 abstract description 7
- 239000000463 material Substances 0.000 abstract description 4
- YSQLGGQUQDTBSL-UHFFFAOYSA-N 2-(2,4,5-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(F)C=C1F YSQLGGQUQDTBSL-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 abstract description 3
- 230000004913 activation Effects 0.000 abstract description 2
- HYHBKLWDTGTBME-UHFFFAOYSA-N pyrazin-1-ium;chloride Chemical compound Cl.C1=CN=CC=N1 HYHBKLWDTGTBME-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229930194542 Keto Natural products 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 4
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
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- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
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- 150000002503 iridium Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- FCHXJFJNDJXENQ-UHFFFAOYSA-N pyridoxal hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(C=O)=C1O FCHXJFJNDJXENQ-UHFFFAOYSA-N 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a sitagliptin intermediate and a preparation method of sitagliptin, 2,4, 5-trifluoro phenylacetic acid and 2-piperazinone are used as starting materials, chiral amine compounds are obtained through aminotransferase, and the chiral amine compounds are subjected to amino protection, amide activation and trifluoro acethydrazide ring closure to obtain a sitagliptin product with high optical purity and high yield; the invention can effectively reduce enzyme residues in the sitagliptin product, improve the product quality, avoid using pyrazine hydrochloride with high price and effectively reduce the cost; the materials used are simple and easy to obtain, the synthesis flow is simple, no special requirement is made on equipment, and the obtained product has high yield, high purity and high ee value, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicine production, and particularly relates to a sitagliptin intermediate and a preparation method of sitagliptin.
Background
Sitagliptin is known as 7- [ 1-oxo- (3R) -3-amino-4- (2, 4, 5-trifluorophenyl) butyl ] -3-trifluoromethyl-5, 6,7, 8-tetrahydro-1, 2, 4-triazole [4,3-a ] pyrazine, an oral antihyperglycemic agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class.
The chiral carbon atom with R configuration exists in the molecular formula of sitagliptin, and the chiral purity of the medicine directly influences the absorption and curative effect of the medicine, so that the method for preparing the pure single configuration has an important effect on the chiral medicine.
Currently, the synthesis of sitagliptin in the R configuration mainly comprises the following methods:
first, after synthesizing racemic sitagliptin, R-configuration sitagliptin is obtained by chiral resolution, as disclosed in CN200910148240.5, resolution of the racemate with camphorsulfonic acid or tartaric acid to obtain R-configuration sitagliptin. The resolution method is complex in process, a large amount of organic solvents are needed, and S-configuration sitagliptin cannot be reused, so that raw materials are wasted, the cost is high, and industrial production is not facilitated.
Second, the sitagliptin with R configuration can be directly obtained through asymmetric hydrogenation reduction of enamine intermediate (1). As disclosed in Chinese patent CN200580010669.8, a process for the asymmetric synthesis of sitagliptin from enamine intermediate (1) is disclosed, the metal precursor used being rhodium or iridium complexes, such as [ Rh (COD) Cl ]] 2 The ligand is chiral ferrocenyl biphosphine ligand. However, the price of the rhodium or iridium and ferrocenyl biphosphine ligand is very expensive, and the hydrogenation reaction time is long, so that the ligand is not suitable for large-scale production. The synthetic route is as follows:
thirdly, directly converting the keto ester substrate intermediate (2) by utilizing polypeptide biocatalysis in the presence of an amino donor to obtain the sitagliptin with the R configuration. The production of sitagliptin in the R configuration by contacting a ketoester substrate intermediate (2) with a transaminase polypeptide in the presence of an amino donor is disclosed in CN 201080017312.3. The synthesis process directly obtains the R-sitagliptin by using an enzyme catalytic reaction in the last reaction, so that the residual risk of the bioactive enzyme in the product is increased, and certain difficulty is brought to the purification of the raw material medicine. The synthetic route is as follows:
according to the synthetic process of the R-sitagliptin, most of the current synthetic methods of the R-sitagliptin are to firstly synthesize a key intermediate keto ester substrate intermediate (2) by taking triazolopyrazine hydrochloride (3) as a raw material, and then asymmetrically synthesize the key intermediate keto ester substrate intermediate to obtain the R-sitagliptin. The synthesis process needs to access the pyrazine fragment with higher price to obtain the keto ester substrate intermediate (2), and has higher production cost. Therefore, there is an urgent need to develop a new method for synthesizing R-sitagliptin.
Disclosure of Invention
The invention relates to a sitagliptin intermediate and a preparation method of sitagliptin.
In order to achieve the purpose, the invention adopts the following technical scheme:
a process for the preparation of a compound of formula (V) comprising the steps of:
s1: reacting a compound of formula (II) with an amino protecting agent in a reaction solvent under alkaline conditions to obtain a compound of formula (III),
s2: reacting the compound of formula (III) with an activating reagent in a reaction solvent to obtain a compound of formula (IV),
s3: the compound of the formula (IV) is cyclized with trifluoroacetyl hydrazine in a reaction solvent, and then the amino protecting group is removed, finally the compound of the formula (V) is obtained,
wherein PG is an amino protecting group, and LG is an amide activating group.
In some embodiments, the PG is selected from formyl, acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthalimido, or p-toluenesulfonyl.
In some embodiments, the LG is selected from Cl, br, C 1 -C 6 Alkoxy, -SH, C 1 -C 6 Alkylthio or-O-P (=o) R 1 R 2 At least one or more of (a), wherein R is 1 、R 2 Each independently selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 6 -C 10 Aryloxy or C 6 -C 10 An arylamino group.
In other embodiments, the LG is selected from Cl, br, methoxy, ethoxy, -SH, methylthio, ethylthio, -O-P (=o) (OCH) 3 ) 2 、-O-P(=O)O(OCH 2 CH 3 ) 2 、-O-P(=O)(NHCH 3 ) 2 、-O-P(=O)(NHCH 2 CH 3 ) 2 、-O-P(=O)(OC 6 H 5 ) 2 or-O-P (=o) (NHC 6 H 5 ) 2 。
In some embodiments, the amino protecting agent is selected from Boc 2 At least one or more of O acetic anhydride, benzyl chloroformate, benzyloxycarbonyl chloride, 9-fluorenylmethyl chloroformate, acetic anhydride, trifluoroacetic anhydride, phthalic anhydride, p-toluenesulfonyl chloride and methanesulfonyl chloride.
In some embodiments, the activating reagent is at least one or more of lawson reagent, phosphorus pentasulfide, diethyl chlorophosphate, dimethyl chlorophosphate, diphenyl chlorophosphate, dimethyl sulfate, methyl triflate, trimethyloxonium tetrafluoroborate.
In some embodiments, in the reaction step S1, the base is selected from at least one or more of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
In some embodiments, in the reaction step S1, the reaction solvent is selected from at least one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate.
In some embodiments, in reaction step S1, the reaction temperature is from-10℃to 60 ℃.
In some embodiments, in reaction step S1, the molar ratio of the compound of formula (II) to the amino protecting agent is from 0.9 to 2.5.
In some embodiments, in the reaction step S2, the reaction solvent is selected from at least one or more of acetonitrile, toluene, tetrahydrofuran, dichloromethane, 1, 4-dioxane, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate.
In some embodiments, in reaction step S2, the reaction temperature is 20℃to 110 ℃.
In some embodiments, in reaction step S2, the molar ratio of the compound of formula (III) to the activating reagent is between 0.4 and 2.
In some embodiments, in reaction step S2, the molar ratio of the compound of formula (III) to the activating reagent is between 0.5 and 2.
In some embodiments, in reaction step S2, the molar ratio of the compound of formula (III) to the activating reagent is from 0.4 to 0.5.
In some embodiments, in the step S3, the reaction solvent is selected from at least one or more of methanol, ethanol, isopropanol, N-butanol, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, toluene, acetonitrile, 1, 4-dioxane, acetone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide.
In some embodiments, in reaction step S3, the cyclization reaction temperature is 20 ℃ to 130 ℃.
In some embodiments, in reaction step S2, the cyclization reaction temperature is 20 to 110 ℃.
In some embodiments, in reaction step S2, the cyclization reaction temperature is 110 to 130 ℃.
The invention also relates to a preparation method of the intermediate shown in the formula (II), which comprises the following steps: reacting a compound of formula (I) with an organic amine in the presence of a transaminase and a coenzyme to obtain a compound of formula (II),
in some embodiments, the intermediate of formula (II) is prepared by a process wherein the organic amine is selected from at least one or more of isopropylamine, ethylamine, phenethylamine, and L-alanine.
In some embodiments, the molar ratio of the compound of formula (I) to the organic amine in the process for the preparation of the intermediate of formula (II) is from 0.5 to 3.
In some embodiments, the molar ratio of the compound of formula (I) to the organic amine in the process for the preparation of the intermediate of formula (II) is from 3 to 5. In some embodiments, the transaminase is a ω -transaminase in a process for preparing an intermediate of formula (II).
In some embodiments, in the method for preparing the intermediate shown in formula (II), the coenzyme is at least one or more of pyridoxal phosphate and pyridoxal hydrochloride.
In some embodiments, the reaction temperature in the process for preparing the intermediate of formula (II) is 20℃to 60 ℃.
In some embodiments, the pH of the reaction system in the process for preparing the intermediate of formula (II) is from 6.5 to 12.
The invention also relates to a preparation method of the intermediate shown in the formula (I), which comprises the following steps: reacting a compound of formula (A) and a compound of formula (B) in a reaction solvent in the presence of alkali to obtain a compound of formula (C); the compound of the formula (C) reacts with the compound (D) to obtain the compound of the formula (I),
in some embodiments, in the preparation of the intermediate of formula (I), the compound of formula (C) may be isolated from the reaction system or may be directly involved in subsequent reactions without isolation.
In some embodiments, the molar ratio of the compound of formula (C) to the compound of formula (D) in the process for the preparation of the intermediate of formula (I) is from 0.8 to 2.0.
In some embodiments, the reaction solvent is selected from at least one or more of 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone, dichloromethane, ethyl acetate, toluene in the preparation method of the intermediate shown in the formula (I).
In some embodiments, the molar ratio of the compound of formula (a) to the compound of formula (B) in the process for the preparation of the intermediate of formula (I) is from 0.8 to 1.5.
In some embodiments, in the preparation method of the intermediate shown in the formula (I), an activating reagent is further added into the reaction system, wherein the activating reagent is at least one or more selected from N, N-diisopropylcarbodiimide, N-dicyclohexylcarbodiimide, N-carbonyldiimidazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, pivaloyl chloride and p-toluenesulfonyl chloride.
In some embodiments, the molar ratio of the compound of formula (a) to the activating agent in the process for the preparation of the intermediate of formula (I) is from 0.5 to 2.
In some embodiments, the reaction temperature for synthesizing the compound of formula (C) in the preparation of the intermediate of formula (I) is from 0℃to 60 ℃.
In some embodiments, the reaction temperature for synthesizing the compound of formula (D) is 20 ℃ to 100 ℃ in the preparation of the intermediate of formula (I).
In some embodiments, the base is selected from at least one or more of diisopropylethylamine, isopropyldiethylamine, diiso Ding Yian, triethylamine, N-dimethylaniline, 4-dimethylaminopyridine, pyridine, and a process for preparing the intermediate of formula (I). A preparation method of an intermediate shown in a formula (III) comprises the steps of taking a compound shown in a formula (A) and a compound shown in a formula (B) as raw materials, and reacting in a reaction solvent in the presence of alkali to obtain a compound shown in a formula (C); the compound of the formula (C) is reacted with a compound (D) to obtain a compound of the formula (I), the compound of the formula (I) is reacted with organic amine in the presence of transaminase and coenzyme to obtain a compound of the formula (II), and amino protection is carried out to obtain a compound of the formula (III).
In some embodiments, the molar ratio of the compound of formula (C) to the compound of formula (D) is from 0.8 to 2.0.
In some embodiments, the compound of formula (I) synthesizes a compound of formula (II) the transaminase is a ω -transaminase.
The invention also relates to a compound shown in the general formula (a), or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate or pharmaceutically acceptable salt thereof:
wherein R is 3 And R is 4 Each independently selected from H, NH 2 Or NHPG, wherein PG is an amino protecting group; or R is 3 And R is 4 Together, form = O or = S;
R 5 selected from-OH, -SH, cl, br, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio or-O-P (=o) R 6 R 7 Wherein said R is 6 、R 7 Each independently selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 6 -C 10 Aryloxy or C 6 -C 10 An arylamino group.
In some embodiments, wherein the PG is selected from formyl, acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthalimido, or p-toluenesulfonyl.
In some embodiments, wherein the R 5 Selected from-OH, -SH, cl, br, methoxy, ethoxy, methylthio, ethylthio, -O-P (=O) (OCH) 3 ) 2 、-O-P(=O)(OCH 2 CH 3 ) 2 、-O-P(=O)(NHCH 3 ) 2 、-O-P(=O)(NHCH 2 CH 3 ) 2 、-O-P(=O)(OC 6 H 5 ) 2 or-O-P (=o) (NHC 6 H 5 ) 2 。
In some embodiments, the invention relates to a compound comprising the structure, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:
the invention has the beneficial effects that:
the application provides a novel method for preparing sitagliptin, which uses 2,4, 5-trifluoro phenylacetic acid and 2-piperazinone as starting materials, obtains chiral amine compounds through transaminase, and obtains a sitagliptin product with high optical purity and high yield through amino protection, amide activation and trifluoroacetyl hydrazine ring closure; according to the scheme, the enzyme catalysis step is advanced, and the enzyme residue in the sitagliptin product can be effectively reduced through multi-step synthesis and purification, so that the product quality is improved, and meanwhile, the use of pyrazine hydrochloride with high price is avoided, so that the cost is effectively reduced; the materials used in the scheme are simple and easy to obtain, the synthesis flow is simple, no special requirements are imposed on equipment, and the obtained product has high yield, high purity and high ee value, and is suitable for industrial production.
Description of the terms
g represents gram, mg represents milligrams, DEG C represents degrees Celsius, h represents hours, mL represents milliliters, min represents minutes, HPLC represents high performance liquid chromatography, pH represents pH value, ESI-MS represents electrospray mass spectrometry, Q-TOF represents ultra-high speed liquid chromatography-four-rod time-of-flight tandem mass spectrometry, 1 H-NMR means nuclear magnetic resonance hydrogen spectrum, MHz means megahertz, CDCl 3 Represents deuterated chloroform, DMAP represents 4-dimethylaminopyridine, DMSO represents dimethyl sulfoxide, and CO 2 Represents carbon dioxide, boc 2 O-acetic anhydride represents di-tert-butyl dicarbonate, lawson's reagent represents 2, 4-bis (p-methoxyphenyl) -1, 3-dithio-two-phospho-cyclobutane-2, 4-sulfide, PLP represents pyridoxal phosphate, THF represents tetrahydrofuran, and DMF represents N, N-dimethylformamide.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound I" and "compound represented by formula I" mean the same compound.
In the present invention, the term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be converted to each other by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include tautomerism by proton shift, such as keto-enol and imine-enamine isomerisation. Valency (valence) tautomers include tautomers that reorganize into bond electrons. For example, in the present invention,and->Tautomers of each other, ->And->Are tautomers of each other.
Drawings
FIG. 11 mass spectrum of- (3-oxopiperazin-1-yl) -4- (2, 4, 5-trifluorophenyl) butane-1, 3-dione (compound I);
FIG. 2 1 nuclear magnetic resonance hydrogen spectrum of- (3-oxopiperazin-1-yl) -4- (2, 4, 5-trifluorophenyl) butane-1, 3-dione (compound I);
FIG. 3 (R) -mass spectrum of 4- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) piperazin-2-one (Compound II);
FIG. 4 (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamic acid tert-butyl ester (Compound III) nuclear magnetic resonance hydrogen spectrum;
FIG. 5 (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamic acid tert-butyl ester (Compound III);
FIG. 6 (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamic acid tert-butyl ester (Compound IV-1) nuclear magnetic resonance hydrogen spectrum;
FIG. 7 (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamic acid tert-butyl ester (compound IV-1) mass spectrum.
The specific embodiment is as follows:
the invention will be further illustrated with reference to specific examples. The present invention will be described in further detail with reference to examples, but is not limited to these examples.
Example 11 Synthesis of- (3-Oxopiperazin-1-yl) -4- (2, 4, 5-trifluorophenyl) butane-1, 3-dione (Compound I)
To a reaction flask containing 1, 4-dioxane (100 ml) was successively added 2,4, 5-trifluorophenylacetic acid (12 g), mevalonic acid (10 g,1.1 eq) and DMAP (8.48 g,1.1 eq) at room temperature, and after stirring until the solid was dissolved, the temperature was lowered to 0℃and N, N-diisopropylcarbodiimide (9.56 g,1.2 eq) was continuously added dropwise. After the completion of the dropwise addition, the reaction was continued at 0℃overnight. After the reaction of the raw materials, 2-piperazinone (6.3 g,1 eq) was added, the system was heated to 100 ℃ for 2 hours, cooled, the solvent was distilled off under reduced pressure, the residue was recrystallized with ethanol/water, filtered, and dried under vacuum to give the objective compound 1- (3-oxopiperazin-1-yl) -4- (2, 4, 5-trifluorophenyl) butane-1, 3-dione (I) (18.5 g) as a white solid in 93% yield.
Q-TOF(m/z):315.0960([M+H] + ).
1 H NMR(599MHz,CDCl 3 )δ14.55(s,1H),7.44(s,1H),7.21(s,1H),7.10–7.02(m,1H),6.94(tt,J=12.0,6.0Hz,1H),4.23(s,1H),4.06(s,1H),3.87(d,J=11.3Hz,2H),3.85–3.77(m,1H),3.69(d,J=17.5Hz,2H),3.65–3.57(m,1H),3.40(dt,J=10.8,7.6Hz,2H).
Example 2 Synthesis of (R) -4- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) piperazin-2-one (Compound II)
Isopropylamine (10 g) was dissolved in water (100 mL), pH 7.5-8.0 was adjusted with aqueous hydrochloric acid, DMSO (25 mL) was added, then 0.1M Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-hydrochloric acid) buffer was used to dilute to 100mL, and heated to 40 ℃, omega-aminotransferase lyophilized powder (1 g) and pyridoxal phosphate (0.8 g) were added, then 1- (3-oxopiperazin-1-yl) -4- (2, 4, 5-trifluorophenyl) butane-1, 3-dione (1 g) in DMSO (25 mL) was added dropwise, pH 7.5-8.0 was controlled with 20% aqueous isopropylamine solution during the reaction, and the temperature was maintained at 40-45 ℃ for more than 24 hours. The solid was removed by filtration, the mother liquor was extracted 3 times with ethyl acetate, the combined organic phases were concentrated under reduced pressure and evaporated to dryness to give the title compound (R) -4- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) piperazin-2-one (II) (0.93 g) as a pale yellow solid with a yield of 93%, ee >99%. The resulting product was used in the next reaction without purification.
ESI-MS(m/z):316.1270([M+H] + ).
Example 3 Synthesis of tert-butyl (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (Compound III)
(R) -4- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) piperazin-2-one (II) (3.15 g) was dissolved in methylene chloride (20 ml) at room temperature, triethylamine (2.02 g,2.0 eq) was added, the reaction system was cooled to 0℃and Boc was added dropwise via a constant pressure dropping funnel 2 O anhydride (2.3 g,1.1 eq), after the completion of the dropwise addition, the reaction system was warmed to room temperature to continue the reaction for 4 timesHours. After the completion of the reaction, a saturated sodium bisulfate solution (20 ml) was added, the solution was separated, the organic phase was washed with saturated brine to neutrality, and the organic phase was concentrated under reduced pressure to give tert-butyl (III-1) (4.0 g) carbamate, which was the target compound (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl), as a white solid in 96% yield.
Q-TOF(m/z):438.1606([M+Na] + ).
1 H NMR(400MHz,DMSO)δ8.10(d,J=20.4Hz,1H),7.44(dd,J=17.1,10.0Hz,1H),7.31(dd,J=17.7,9.4Hz,1H),6.81–6.66(m,1H),4.13–3.96(m,2H),3.89(t,J=18.7Hz,1H),3.59(ddd,J=29.0,18.3,11.5Hz,3H),3.24(s,2H),3.13(s,1H),2.83(dd,J=38.6,25.0Hz,1H),2.69–2.53(m,2H),1.27(s,9H).
Example 4 Synthesis of tert-butyl (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (Compound IV-1)
Tert-butyl (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (III-1) (10 g) was dissolved in dry acetonitrile (100 ml) at room temperature, and the Lawson reagent (7.0 g,0.8 eq) was added in three portions with a slight exotherm, and after addition the reaction was allowed to react at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure at a temperature of not more than 35℃and the crude product was purified by column chromatography to give tert-butyl (IV-1) (9.8 g) carbamate (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) as a target compound (R) - (4-oxo-4- (3-thiopiperazin-1-yl) as a white solid powder in a yield of 94%.
ESI-MS(m/z):432.3([M+H] + ).
1 H NMR(400MHz,DMSO)δ10.63(d,J=23.6Hz,1H),7.44(dd,J=17.2,10.0Hz,1H),7.31(dd,J=17.6,9.4Hz,1H),6.81–6.65(m,1H),4.54–4.24(m,2H),4.04(s,1H),3.77–3.55(m,2H),3.25(s,1H),2.84(d,J=13.8Hz,1H),2.70–2.53(m,3H),1.27(s,9H).
Example 5 Synthesis of tert-butyl (IV-1) carbamate (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl)
Tert-butyl (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (III-1) (4 g) was dissolved in toluene (30 ml) at room temperature, and phosphorus pentasulfide (0.9 g,0.5 eq) was added, and after the addition, the reaction system was warmed to reflux overnight. The crude product was purified by column chromatography after concentrating the reaction solution under reduced pressure to give tert-butyl (IV-1) (3.94 g) carbamate (3.94 g) as a white solid powder in 95% yield, which was the target compound (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl).
Example 6 Synthesis of tert-butyl (IV-1) carbamate (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl)
Tert-butyl (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (III-1) (30 g) was dissolved in tetrahydrofuran (300 ml) at room temperature, and phosphorus pentasulfide (6.42 g,0.4 eq) was added thereto, and after the addition, the reaction system was warmed to 60℃for reaction overnight. After the reaction, the solvent was dried under reduced pressure, water was added, the pH was adjusted to 6 to 8 with saturated sodium carbonate, and the mixture was filtered and dried to give t-butyl (IV-1) (29.9 g) of the objective compound (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate as a white solid powder in 96% yield.
EXAMPLE 7 Synthesis of R-sitagliptin (V)
Tert-butyl (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (IV-1) (3.0 g) was dissolved in methanol (20 ml) at room temperature, and trifluoroacethydrazide (1.33 g,1.5 eq) was added, and after the solid was dissolved, the reaction system was warmed to reflux for 16 hours. After the reaction of the raw materials is completed, the temperature is reduced to room temperature, a hydrogen chloride methanol solution (10 ml) is added, the reaction is continued for 4 hours, the methanol is distilled off under reduced pressure to obtain the target compound R-sitagliptin (2.50 g), the yield is 88.3%, the purity reaches 99.9%, the optical purity is 100%, and the enzyme residue is not detected.
EXAMPLE 8 Synthesis of R-sitagliptin (V)
Tert-butyl (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (IV-1) (5.0 g) was dissolved in toluene (100 ml) at room temperature, and trifluoroacethydrazide (2.97 g,2.0 eq) was added thereto, and after the solid was dissolved, the reaction system was warmed to 100℃for 10 hours. Cooling to room temperature after the raw materials react, adding an ethanol solution of hydrogen chloride (20 ml), continuing to react for 4 hours, and evaporating the solvent under reduced pressure to obtain the target compound R-sitagliptin (4.22 g), wherein the yield is 89.4%, the purity reaches 99.8%, the optical purity is 100%, and the enzyme residue is not detected.
EXAMPLE 9 Synthesis of R-sitagliptin (V)
Tert-butyl (R) - (4-oxo-4- (3-thiopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (IV-1) (6.0 g) was dissolved in n-butanol (30 ml) at room temperature, and added trifluoroacetyl hydrazine (2.67 g,1.5 eq) was reacted at 120℃for 6 hours. Cooling to room temperature after the raw materials are reacted, adding an ethanol solution of hydrogen chloride (20 ml), continuing to react for 4 hours, and evaporating the solvent under reduced pressure to obtain the target compound R-sitagliptin (5.2 g), wherein the yield is 92%, the purity reaches 99.9%, the optical purity is 100%, and the enzyme residue is not detected.
Example 10 (R) - (4-oxo-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazol [4,3-a ] piperazine-7 (8H))
Synthesis of (E) amino-tert-butyl-1- (2, 4, 5-trifluorophenyl) butan-2-yl)
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Tert-butyl (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (III-1) (3 g) was dissolved in acetonitrile (30 ml) at room temperature, diethyl chlorophosphate (1.9 g,1.5 eq) was added, N-tert-butyl-1, 1-tris (pyrrolidinyl-1-yl) -15-phosphoramidamine (3.4 g,1.5 eq) was added dropwise, and the reaction system was stirred at room temperature for 4 hours after the addition. Trifluoro acethydrazide (1.4 g,1.5 eq) was added at a time, and the reaction system was warmed to 60 ℃ and reacted overnight. After the reaction, the crude product is concentrated under reduced pressure and purified by column chromatography to obtain the target compound (R) - (4-oxo-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazol [4,3-a ] piperazin-7 (8H) -yl)) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) amino tert-butyl ester (E) (3.14 g) which is a white solid with a yield of 85.8%, a purity of 99.9%, an optical purity of 100% and undetected enzyme residues.
ESI-MS(m/z):530.2(M+Na).
Example 11 (R) - (4-oxo-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] piperazin-7 (8H))
Synthesis of (E) amino-tert-butyl-1- (2, 4, 5-trifluorophenyl) butan-2-yl)
Tert-butyl (R) - (4-oxo-4- (3-oxopiperazin-1-yl) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) carbamate (III-1) (10 g) was dissolved in methylene chloride (100 ml) at room temperature, cooled to 0 ℃, and methyl triflate (7.1 g,1.8 eq) was added dropwise, and after the addition, the reaction system was stirred at room temperature for 8 hours. After the completion of the reaction, trifluoroacetyl hydrazine (4.6 g,1.5 eq) was added, and the reaction system was heated to reflux for 16 hours. The crude product was purified by column chromatography to give the objective compound (R) - (4-oxo-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazol [4,3-a ] piperazin-7 (8H) -yl)) -1- (2, 4, 5-trifluorophenyl) butan-2-yl) amino tert-butyl ester (E) (10.35 g) as a white solid with a yield of 84.7% and purity of 99.9% and an optical purity of 100% and undetectable enzyme residue.
The above embodiments are merely preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the embodiments and features in the embodiments in the present application may be arbitrarily combined with each other without collision. The protection scope of the present invention is defined by the claims, and the protection scope includes equivalent alternatives to the technical features of the claims. I.e., equivalent replacement modifications within the scope of this invention are also within the scope of the invention.
Claims (19)
1. A process for the preparation of a compound of formula (V), comprising the steps of:
s1: reacting a compound of formula (II) with an amino protecting agent in a reaction solvent under alkaline conditions to obtain a compound of formula (III),
s2: reacting the compound of formula (III) with an activating reagent in a reaction solvent to obtain a compound of formula (IV),
s3: the compound of the formula (IV) reacts with trifluoroacetyl hydrazine in a reaction solvent to carry out cyclization, and then deamination protecting group is carried out to obtain the compound of the formula (V),
wherein PG is an amino protecting group, and LG is an amide activating group; the PG is selected from formyl, acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyleneoxycarbonyl, phthalimido or p-tolueneA sulfonyl group; the LG is selected from Cl, br, C 1 -C 6 Alkoxy, -SH, C 1 -C 6 Alkylthio or-O-P (=o) R 1 R 2 Wherein said R is 1 、R 2 Each independently selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 6 -C 10 Aryloxy or C 6 -C 10 An arylamino group.
2. The preparation method according to claim 1, wherein LG is selected from Cl, br, methoxy, ethoxy, -SH, methylthio, ethylthio, -O-P (=o) (OCH 3 ) 2 、-O-P(=O)O(OCH 2 CH 3 ) 2 、-O-P(=O)(NHCH 3 ) 2 、-O-P(=O)(NHCH 2 CH 3 ) 2 、-O-P(=O)(OC 6 H 5 ) 2 or-O-P (=o) (NHC 6 H 5 ) 2 Is a kind of medium.
3. The method of claim 1, wherein the amino protecting agent is selected from the group consisting of Boc 2 At least one or more of O acetic anhydride, benzyl chloroformate, benzyloxycarbonyl chloride, 9-fluorenylmethyl chloroformate, acetic anhydride, trifluoroacetic anhydride, phthalic anhydride, p-toluenesulfonyl chloride, and methanesulfonyl chloride
In the reaction step S1, the alkali is selected from at least one or more of triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
in the reaction step S1, the reaction solvent is selected from at least one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, toluene, methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate;
in the reaction step S2, the reaction solvent is at least one or more selected from acetonitrile, toluene, tetrahydrofuran, dichloromethane, 1, 4-dioxane, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate.
4. The method according to claim 1, wherein the activating reagent is at least one or more of lawson reagent, phosphorus pentasulfide, diethyl chlorophosphate, dimethyl chlorophosphate, diphenyl chlorophosphate, dimethyl sulfate, methyl triflate and trimethyloxonium tetrafluoroborate.
5. The process according to claim 1, wherein the molar ratio of the compound of formula (III) to the activating reagent is from 0.5 to 2.
6. The process according to claim 1, wherein the molar ratio of the compound of formula (III) to the activating reagent is from 0.4 to 0.5.
7. The method according to claim 1, wherein in the reaction step S3, the reaction solvent is at least one or more selected from the group consisting of methanol, ethanol, isopropanol, N-butanol, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, methylene chloride, toluene, acetonitrile, 1, 4-dioxane, acetone, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.
8. The process according to claim 1, wherein in the reaction step S3, the cyclization reaction temperature is 20℃to 110 ℃.
9. The process according to claim 1, wherein in the reaction step S3, the cyclization reaction temperature is 110℃to 130 ℃.
10. A process for the preparation of an intermediate of formula (II), comprising the steps of: reacting a compound of formula (I) with an organic amine in the presence of a transaminase and a coenzyme to obtain a compound of formula (II),
11. the process according to claim 10, wherein the molar ratio of the compound of formula (I) to the organic amine is from 0.5 to 3.
12. The process according to claim 10, wherein the molar ratio of the compound of formula (I) to the organic amine is from 3 to 5.
13. A process for the preparation of an intermediate of formula (I), comprising the steps of:
reacting a compound of formula (A) and a compound of formula (B) in a reaction solvent in the presence of alkali to obtain a compound of formula (C); the compound of the formula (C) reacts with the compound (D) to obtain the compound of the formula (I),
wherein the compound of formula (C) may be isolated from the reaction system or may be directly involved in a subsequent reaction without isolation.
14. A preparation method of an intermediate shown in a formula (III) is characterized in that a compound shown in the formula (A) and a compound shown in the formula (B) are used as raw materials, and react in a reaction solvent in the presence of alkali to obtain a compound shown in the formula (C); the compound of the formula (C) is reacted with a compound (D) to obtain a compound of the formula (I), the compound of the formula (I) is reacted with organic amine in the presence of transaminase and coenzyme to obtain a compound of the formula (II), and amino protection is carried out to obtain a compound of the formula (III).
Wherein the compound of formula (C) may be isolated from the reaction system or may be directly involved in a subsequent reaction without isolation.
15. The process according to claim 10 or 14, wherein the compound of formula (I) is synthesized to a compound of formula (II) wherein the transaminase is ω -transaminase.
16. The process according to claim 13 or 14, wherein the molar ratio of the compound of formula (C) to the compound of formula (D) is from 0.8 to 2.0.
17. A compound of formula (a), or a stereoisomer, geometric isomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof:
wherein R is 3 And R is 4 Each independently selected from H, NH 2 Or NHPG, wherein PG is an amino protecting group; or (b)
R 3 And R is 4 Together, form = O or = S;
R 5 selected from-OH, -SH, cl, br, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio or-O-P (=o) R 6 R 7 Wherein said R is 6 、R 7 Each independently selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 6 -C 10 Aryloxy or C 6 -C 10 An arylamino group.
18. The compound of claim 17, wherein PG is selected from formyl, acetyl, trifluoroacetyl, t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthalimido, or p-toluenesulfonyl;
R 5 selected from-OH, -SH, cl, br, methoxy, ethoxy, methylthio, ethylthio, -O-P (=O) (OCH) 3 ) 2 、-O-P(=O)(OCH 2 CH 3 ) 2 、-O-P(=O)(NHCH 3 ) 2 、-O-P(=O)(NHCH 2 CH 3 ) 2 、-O-P(=O)(OC 6 H 5 ) 2 or-O-P (=o) (NHC 6 H 5 ) 2 。
19. The compound of claim 17, comprising a compound of the structure or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof:
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