CN115960007A - Preparation method of sitagliptin intermediate by using nitrogen-containing formyl catalyst - Google Patents
Preparation method of sitagliptin intermediate by using nitrogen-containing formyl catalyst Download PDFInfo
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- CN115960007A CN115960007A CN202211603152.1A CN202211603152A CN115960007A CN 115960007 A CN115960007 A CN 115960007A CN 202211603152 A CN202211603152 A CN 202211603152A CN 115960007 A CN115960007 A CN 115960007A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 239000003054 catalyst Substances 0.000 title claims abstract description 25
- 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 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 239000002879 Lewis base Substances 0.000 claims abstract description 17
- 150000007527 lewis bases Chemical class 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000005046 Chlorosilane Substances 0.000 claims abstract description 11
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000000852 hydrogen donor Substances 0.000 claims abstract description 7
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- -1 aromatic aldehyde group compound Chemical class 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 238000006722 reduction reaction Methods 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 claims description 8
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 6
- XALHICXNSREUAV-UHFFFAOYSA-N 2-oxopyrrolidine-1-carbaldehyde Chemical compound O=CN1CCCC1=O XALHICXNSREUAV-UHFFFAOYSA-N 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 5
- 239000005052 trichlorosilane Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 229960001270 d- tartaric acid Drugs 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- SOYVLBDERBHIME-UHFFFAOYSA-N chloro(diethyl)silicon Chemical compound CC[Si](Cl)CC SOYVLBDERBHIME-UHFFFAOYSA-N 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 claims description 2
- YCITZMJNBYYMJO-UHFFFAOYSA-N chloro(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](Cl)C1=CC=CC=C1 YCITZMJNBYYMJO-UHFFFAOYSA-N 0.000 claims description 2
- KTQYJQFGNYHXMB-UHFFFAOYSA-N dichloro(methyl)silicon Chemical compound C[Si](Cl)Cl KTQYJQFGNYHXMB-UHFFFAOYSA-N 0.000 claims description 2
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000005048 methyldichlorosilane Substances 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000010531 catalytic reduction reaction Methods 0.000 abstract description 6
- 238000009987 spinning Methods 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- SLLGVCUQYRMELA-UHFFFAOYSA-N chlorosilicon Chemical compound Cl[Si] SLLGVCUQYRMELA-UHFFFAOYSA-N 0.000 description 13
- 229960004034 sitagliptin Drugs 0.000 description 13
- 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 description 13
- 239000000706 filtrate Substances 0.000 description 10
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000000746 purification Methods 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000010948 rhodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000002081 enamines Chemical class 0.000 description 4
- 229910000510 noble metal Inorganic materials 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
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- 230000000052 comparative effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229960004115 sitagliptin phosphate Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 1
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- VUTUHLLWFPRWMT-QMDOQEJBSA-M (1z,5z)-cycloocta-1,5-diene;rhodium;trifluoromethanesulfonate Chemical compound [Rh].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1.[O-]S(=O)(=O)C(F)(F)F VUTUHLLWFPRWMT-QMDOQEJBSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 229930007927 cymene Natural products 0.000 description 1
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- 238000010511 deprotection reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XKJLQAJESSUVAA-UHFFFAOYSA-N methyl 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoate Chemical compound COC(=O)C=C(N)CC1=CC(F)=C(F)C=C1F XKJLQAJESSUVAA-UHFFFAOYSA-N 0.000 description 1
- XDQLWVSUKUDAEO-UHFFFAOYSA-N methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound COC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F XDQLWVSUKUDAEO-UHFFFAOYSA-N 0.000 description 1
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- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention provides a preparation method of a sitagliptin intermediate by using a nitrogen-containing formyl catalyst, which comprises the following steps: dissolving a compound shown in a formula I in an organic solvent, carrying out catalytic reduction by taking chlorosilane as a hydrogen donor under the catalysis of Lewis base containing nitrogen formyl to obtain a mixed spinning product shown in a formula II, further splitting the mixed spinning product by adopting an organic acid splitting agent with a D configuration, and alkalifying to prepare an intermediate shown in a formula III, wherein R is hydrogen or alkyl of C1-C5. The preparation method provided by the invention has the characteristics of high yield, relatively mild conditions, simplicity in operation and relatively low cost, and has a good application value in industry.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a sitagliptin intermediate by using a nitrogen-containing formyl catalyst.
Background
Sitagliptin phosphate (Sitagliptin) is an important drug for treating type II diabetes, belongs to dipeptidyl peptidase 4 (DPP-4) inhibitors, and can be used for treating diabetes by being taken alone or combined with hypoglycemic drugs to form a compound drug.
The sitagliptin phosphate has the following structural formula:
at present, most of documents or patents reporting chemical synthesis methods of sitagliptin mainly relate to the construction of chiral carbon atoms in R configuration, and at present, three preparation methods for constructing chiral carbon in R configuration in a sitagliptin structure by a chemical method mainly exist:
firstly, after racemic sitagliptin or an intermediate thereof is synthesized, chiral sitagliptin or a key intermediate thereof is obtained through chiral resolution, for example, in CN101928289A, chiral drug molecule sitagliptin is obtained by resolving racemate with camphorsulfonic acid or tartaric acid; CN101824037A discloses that a D-configuration organic acid resolving agent is adopted to resolve racemic sitagliptin free base, and then chiral sitagliptin is obtained.
And secondly, the enamine intermediate is subjected to asymmetric hydrogenation reduction to obtain the product. The preparation method mainly uses metal catalyst mainly containing noble metal such as ruthenium, rhodium, etc., such as [ Rh (cod) 2 ]OTf、[Rh(NBD) 2 ]BF 4 、[Rh(cod)Cl] 2 、[Ru(cymene)Cl] 2 、Ru(OAc) 2 In combination with different chiral phosphine ligands, e.g., (S) -Cy2-p-Tol-Biphemp, (R, S) -p-CF 3 Josiphos, R, S-t-butyl Josiphos, etc., in H 2 Under the action of (3), the enamine precursor is subjected to asymmetric hydrogenation to obtain chiral amino.
As in WO2009064476, this route performs reductive amination of the intermediate β -enamine ester during sitagliptin synthesis, also using an expensive chiral noble metal ruthenium catalyst and a chiral phosphine ligand, and in the reaction in which a chiral amino group is introduced, the chiral selectivity is low (32% ee), the route is long, the reaction is five steps in total, and the yield is low, about 13% in total. The route is as follows:
and thirdly, introducing a chiral amino structure through other chemical synthesis routes of non-asymmetric hydrogenation reduction, such as CN105061434A, obtaining N-arylmethyl-2R-hydroxy-3-cyanopropylamine through multi-step reaction by using S-epichlorohydrin or R-epichlorohydrin, and preparing N-arylmethyl-2S-cyanomethylacridine through intramolecular dehydration reaction, thereby constructing the chiral center of sitagliptin.
Disclosure of Invention
Aiming at the bottleneck problem existing in the prior art, the preparation route of the chiral amino-containing key intermediate provided by the invention is that the compound shown in the formula I is subjected to catalytic reduction to obtain a racemic product, and the racemic product is further resolved to prepare the common chiral amino-containing sitagliptin intermediate compound shown in the formula III. The preparation route of the key intermediate containing chiral amino provided by the invention is shown in figure 1.
Aiming at the defect of lacking a high-efficiency green catalytic reduction method for the compound shown in the formula I in the preparation route in the prior art, the invention provides a preparation method for a sitagliptin intermediate by utilizing a Lewis base catalyst containing a nitrogen formyl group, and the preparation method creatively provides a catalytic system which takes the Lewis base containing the nitrogen formyl group as the catalyst and takes chlorosilane as a hydrogen donor, and the high-efficiency selective reduction of the compound shown in the formula I is realized under the catalytic system. Meanwhile, the invention further discloses a resolution method of the racemic compound shown in the formula II obtained after catalytic reduction, and the target product can be separated simply and efficiently. The preparation method of the sitagliptin intermediate provided by the invention has the characteristics of high yield, relatively mild conditions, simplicity in operation and relatively low cost, and has a good application value in industry.
The invention provides a preparation method of a sitagliptin intermediate by using a nitrogen-containing formyl catalyst.
A preparation method of a sitagliptin intermediate by using a nitrogen-containing formyl catalyst, wherein the structural formula of the sitagliptin intermediate is shown as a formula III, and the preparation method comprises the following steps:
(1) Dissolving a compound shown in a formula I in an organic solvent, and carrying out reduction reaction of carbon-carbon double bonds by using trichlorosilane as a hydrogen donor under the catalysis of a Lewis base containing nitrogen formyl to obtain a sitagliptin intermediate, wherein the chemical reaction equation is as follows:
in the formula, R is C1-C5 alkyl;
the Lewis base catalyst containing the nitrogen formyl is one of N, N-dimethylformamide, N-diethylformamide, N-di-N-propylformamide, N-formylpiperidine and 1-formylpyrrolidone;
the temperature of the reduction reaction is-78-35 ℃;
(2) Adopting an organic acid resolving agent with a D configuration to resolve and alkalize the racemic sitagliptin intermediate obtained in the step (1) to obtain a chiral sitagliptin intermediate shown in a formula III, wherein a chemical reaction equation is as follows:
the D-configuration organic acid resolving agent is D-tartaric acid or D-camphorsulfonic acid.
The preparation method provided by the invention comprises the steps of (1) catalytic reduction of the compound shown in the formula I and (2) resolution of the racemic compound shown in the formula II, so that efficient preparation of the chiral amino-containing key intermediate of sitagliptin shown in the formula III is realized. In the step (1) of the preparation method, the invention creatively adopts a catalytic system which takes Lewis base containing nitrogen formyl group as a catalyst and takes chlorosilane as a hydrogen donor to carry out high-efficiency selective reduction on carbon-carbon double bonds in enamine, thereby realizing the high-efficiency reduction of the compound shown in the formula I, achieving the beneficial technical effect of obtaining a target product with high yield (> 95 percent), and being obviously superior to the general catalytic system which takes chlorosilane as a hydrogen donor. This study found that specific nitrogen formyl group-containing lewis bases including N, N-dimethylformamide, N-diethylformamide, N-di-N-propylformamide, N-formylpiperidine, and 1-formylpyrrolidone and chlorinated silanes can achieve efficient reduction of the carbon-carbon double bond in the enamine.
Preferably, in step (1), the lewis base catalyst containing a carbamoyl group is N, N-dimethylformamide.
Preferably, in step (1), the chlorosilane is trichlorosilane (SiHCl) 3 ) Methyl dichlorosilane (MeSiHCl) 2 ) Dichlorosilane (SiH) 2 Cl 2 ) Or dimethylchlorosilane (Me) 2 SiHCl 2 ) Diethyl chlorosilane (Et) 2 SiHCl 2 ) Diphenylchlorosilane (Ph) 2 SiHCl 2 ) (ii) a More preferably, the chlorosilane is trichlorosilane.
Preferably, in the step (1), the molar ratio of the chlorosilane to the compound shown in the formula I is 1.
Preferably, the Lewis base containing a nitrogen formyl group is N, N-dimethylformamide, N-diethylformamide, N-di-N-propylformamide, N-formylpiperidine, 1-formylpyrrolidone, preferably N, N-dimethylformamide.
Preferably, the molar ratio of the lewis base catalyst containing a carbamoyl group to the compound represented by formula I is 1; further preferably, the molar ratio of the chlorosilane to the compound represented by the formula I is 3.
Preferably, in step (1), the molar ratio of the lewis base catalyst containing a carbamoyl group to the compound represented by formula I is 1; further preferably, the molar ratio of the lewis base catalyst containing a carbamoyl group to the compound represented by the formula I is 1.
Preferably, in step (1), the organic solvent is one or more of toluene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, acetonitrile and dichloromethane; more preferably, the organic solvent is dichloromethane.
Preferably, in the step (1), the volume-to-mass ratio of the organic solvent to the compound shown in the formula I is 1-10 mL/g.
Preferably, in the step (1), the temperature of the reduction reaction is-10 ℃ to 35 ℃; more preferably, the temperature of the reduction reaction is 30 to 35 ℃.
Preferably, in the step (2), the D-configuration organic acid resolving agent is D-tartaric acid.
Preferably, in step (2), the specific method for splitting is as follows: a dynamic kinetic resolution method is adopted, and the resolution is carried out in the presence of an aromatic aldehyde compound catalyst and a ketone solvent at the pH value of 1-3 and the temperature of 0-25 ℃.
In a preferred embodiment, the resolution is carried out at a pH of 2 to 3 and a temperature of 0 to 10 ℃.
Preferably, in the step (2), the aromatic aldehyde-based compound is p-hydroxybenzaldehyde or benzaldehyde; the ketone solvent is acetone or methyl isobutyl ketone.
The preparation method of the sitagliptin intermediate by using the catalyst containing the nitrogen formyl avoids noble metal ruthenium and rhodium catalysts in asymmetric reduction, meets the requirement of green chemical development, and reduces the cost. The preparation method realizes the catalysis of HSiCl by the Lewis base containing the nitrogen formyl group with simple structure and low price 3 The beta-enamine ester which is the important intermediate of sitagliptin and has unprotected amino is efficiently and selectively reduced, and the yield is high (>95 percent), short reaction time and simple operation. And provides a resolution method of the racemic compound shown in the formula II, which can simply and efficiently separate out a target product.
Compared with the prior art, the invention at least has the following advantages:
1. the preparation route of the invention avoids noble metal ruthenium and rhodium catalyst in asymmetric reduction, meets the requirement of green chemical development, reduces the cost and is suitable for industrial production.
2. The preparation method provided by the invention has the advantages of relatively mild conditions, simple operation, no need of adding protection and deprotection steps and simple post-treatment process.
3. The invention provides a catalytic system which takes Lewis base containing nitrogen formyl group as a catalyst and takes chlorosilane as a hydrogen donor, realizes high-efficiency catalytic reduction of beta-enamine, and has short reaction time, simple operation and high yield (> 95%); and further provides a resolution method of the racemic compound shown in the formula II, and the obtained target chiral molecule has high chemical purity and optical purity.
Drawings
FIG. 1 is a preparation route diagram of a key intermediate of sitagliptin containing chiral amino provided by the invention.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
Example 1
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butenoate (formula I)
Methyl 4- (2, 4, 5-trifluorophenyl) acetoacetate (2.50g, 10.2mmol) and ammonium acetate (3.85g, 50mmol) were added to methanol (25 mL), and after stirring at 60 ℃ for 12 hours, the reaction mixture was concentrated under vacuum, and dissolved in 20mL of dichloromethane to precipitate a large amount of white solid, and the filtrate was collected by filtration and concentrated under vacuum. Dissolving the concentrated solution in 3mL of EDCM, dripping the solution into 20mL of n-hexane to precipitate a light yellow solid, filtering and collecting the solid, and drying to obtain 2.04g of 3-amino-4- (2, 4, 5-trifluorophenyl) butyl-2-methyl enoate. The yield thereof was found to be 81%.
1H NMR(400MHz,CDCl3)，δ7.85(s,1H),7.09(dd,J＝17.9,7.9Hz,1H),6.95(dd,J＝16.1,9.5Hz,1H),4.57(s,1H),3.65(s,3H),3.41(s,2H).
Example 2
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To dichloromethane (2 mL) was added, in order, 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 3uL (0.04 mmol) of DMF, HSiCl 3 120uL (0.6 mmol), after stirring the reaction at 0 ℃ for 36h, 2mL of saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by column chromatography (petroleum ether: ethyl acetate: triethylamine = 5%) gave 43mg of a colorless oily liquid in a yield of 87%.
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
Example 3
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To methylene chloride (2 mL) were added, in order, 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 3uL (0.04 mmol) of DMF, and HSiCl 3 120uL (0.6 mmol), stirred at 10 ℃ for 24h, then 2mL saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5%) gave 45mg of a colorless oily liquid in a yield of 91%.
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
Example 4
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To methylene chloride (2 mL) were added, in order, 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 3uL (0.04 mmol) of DMF, and HSiCl 3 120uL (0.6 mmol), after stirring the reaction at 30 ℃ for 12h, 2mL of saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purifying by column chromatography (petroleum ether: ethyl acetate: triethylamine)5% = 5).
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
Example 5
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To acetonitrile (2 mL) were added, in order, 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 3uL (0.04 mmol) of DMF, and HSiCl 3 120uL (0.6 mmol), stirred at 30 ℃ for 12h, then 2mL saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Column purification (petroleum ether: ethyl acetate: triethylamine = 5%) gave 40mg of a colorless oily liquid in a yield of 81%.
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
Example 6
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To toluene (2 mL) were added, in order, 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 3uL (0.04 mmol) of DMF, HSiCl 3 120uL (0.6 mmol), stirred at 30 ℃ for 12h, then 2mL saturated NaHCO was added 3 The reaction was quenched, filtered and the filtrate collected, extracted with 10mL ethyl acetateCollecting organic phase for 3 times, drying with anhydrous sodium sulfate, filtering, and concentrating. Purification by column chromatography (petroleum ether: ethyl acetate: triethylamine = 5%) gave 48mg of a colorless oily liquid in 93% yield.
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
Example 7
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To ethyl acetate (2 mL) were added, in order, 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 3uL (0.04 mmol) of DMF, and HSiCl 3 120uL (0.6 mmol), after stirring the reaction at 30 ℃ for 12h, 2mL of saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5%) gave 44mg of a colorless oily liquid in a yield of 89%.
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
Comparative example 1
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To methylene chloride (2 mL) were added 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 4.1mg (0.04 mmol) of 1-formylpyrrolidone in that order，HSiCl 3 120uL (0.6 mmol), stirred at 30 ℃ for 12h, then 2mL saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by column (petroleum ether: ethyl acetate: triethylamine = 5%) gave 38mg of a colorless oily liquid in 78% yield.
The characterization data for the product prepared in this example are as follows:
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
comparative example 2
Preparation of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (formula II)
To methylene chloride (2 mL) were added 49.0mg (0.2 mmol) of methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate, 3.6uL (0.2 mmol) of water, 4.1mg (0.04 mmol) of triethylamine, HSiCl 3 120uL (0.6 mmol), after stirring the reaction at 30 ℃ for 12h, 2mL of saturated NaHCO was added 3 The reaction was quenched, filtered to collect the filtrate, extracted 3 times with 10mL ethyl acetate, the organic phase collected, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by column chromatography (petroleum ether: ethyl acetate: triethylamine = 5%) gave 5mg of a colorless oily liquid in 10% yield.
The characterization data for the product prepared in this example are as follows:
1H NMR(400MHz,CDCl3),δ7.04(ddd,J＝10.3,8.8,6.9Hz,1H),6.94-6.86(m,1H),3.68(s,3H),3.44(ddd,J＝9.0,8.6,7.1Hz,1H),2.73(dd,J＝13.7,5.8Hz,1H),2.66-2.57(m,1H),2.48(dd,J＝16.0,4.1Hz,1H),2.32(dd,J＝16.0,8.7Hz,1H).
example 8
This example provides a method for preparing 3R-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate tartrate, comprising the steps of: racemic methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate was prepared according to the same method as in example 2. D-tartaric acid (1.5g, 10mmol) was completely dissolved in 40ml of acetone with stirring, a catalytic amount of p-hydroxybenzaldehyde (6.1mg, 0.05mmol) was added thereto, and after adjusting the reaction pH =3 by adding glacial acetic acid dropwise with stirring, the reaction solution was cooled to 0 ℃. After the obtained racemic methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate (2.45g, 10 mmol) was dissolved in 20ml of acetone, the prepared racemic methyl 3-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate acetone solution was added dropwise to a tartaric acid solution with stirring at 0 to 5 ℃ and a white solid was precipitated during the dropwise addition. After the dropwise addition, the mixture is kept at 5 ℃ and stirred for crystallization for 10 hours. Filtering, washing the filter cake with acetone, and drying to obtain 1.5g of white solid, namely 3R-amino-4- (2, 4, 5-trifluorophenyl) -2-butyric ester tartrate. Yield 78%, ee% =99%.
Example 9
This example provides a method for preparing 3R-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoic acid ester, comprising the following steps: 1.5g of 3R-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate tartrate, 18mL of diethyl ether, and 12mL of pure water were mixed with stirring for 30min, and then the mixture was cooled to 5 ℃ or lower. Dropwise adding concentrated ammonia water at 0-5 ℃, adjusting the pH of the reaction solution to be =8-9, layering, washing an ether layer twice with water, and drying for 5h by using anhydrous magnesium sulfate. Filtration and concentration of the filtrate to dryness under reduced pressure gave 0.87g of a colorless oily liquid, i.e., methyl 3R-amino-4- (2, 4, 5-trifluorophenyl) -2-butanoate. The yield was 91%, and ee% =99%.
Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the above description of the present invention, and equivalents also fall within the scope of the invention defined by the appended claims.
Claims (9)
1. A preparation method of a sitagliptin intermediate by using a nitrogen formyl group-containing catalyst is characterized in that the structural formula of the sitagliptin intermediate is shown as a formula III, and the preparation method comprises the following steps:
(1) Dissolving a compound shown in a formula I in an organic solvent, and carrying out reduction reaction of carbon-carbon double bonds by taking trichlorosilane as a hydrogen donor under the catalysis of Lewis base containing nitrogen formyl to obtain a sitagliptin intermediate, wherein the chemical reaction equation is as follows:
in the formula, R is C1-C5 alkyl;
the Lewis base catalyst containing the nitrogen formyl is one of N, N-dimethylformamide, N-diethylformamide, N-di-N-propylformamide, N-formylpiperidine and 1-formylpyrrolidone;
the temperature of the reduction reaction is-78-35 ℃;
(2) Adopting an organic acid resolving agent with a D configuration to resolve and alkalize the racemic sitagliptin intermediate obtained in the step (1) to obtain a chiral sitagliptin intermediate shown in a formula III, wherein a chemical reaction equation is as follows:
the D-configuration organic acid resolving agent is D-tartaric acid or D-camphorsulfonic acid.
2. The method according to claim 1, wherein in the step (1), the chlorosilane is trichlorosilane, methyldichlorosilane, dichlorosilane, dimethylchlorosilane, diethylchlorosilane or diphenylchlorosilane.
3. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the chlorosilane to the compound represented by the formula I is 1.
4. The production method according to claim 1, wherein in step (1), the molar ratio of the lewis base catalyst containing a carbamoyl group to the compound represented by the formula I is 1 to 1.
5. The preparation method according to claim I, wherein in the step (1), the organic solvent is one or more of toluene, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, acetonitrile and dichloromethane.
6. The preparation method according to claim 1, wherein the volume-to-mass ratio of the organic solvent to the compound represented by formula I is preferably 1 to 10mL/g.
7. The method according to claim 1, wherein the temperature of the reduction reaction is-10 ℃ to 35 ℃.
8. The preparation method according to claim 1, wherein in step (2), the specific method for the resolution is: a dynamic kinetic resolution method is adopted, and the resolution is carried out in the presence of an aromatic aldehyde group compound catalyst and a ketone solvent at the pH value of 1-3 and the temperature of 0-25 ℃.
9. The preparation method according to claim 8, wherein in the step (2), the aromatic aldehyde-based compound is p-hydroxybenzaldehyde or benzaldehyde; the ketone solvent is acetone or methyl isobutyl ketone.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5359107A (en) * | 1993-11-23 | 1994-10-25 | Dow Corning Corporation | β-cyanoalkylsilane preparation using triorganophosphine compounds as catalyst |
| CN102574856A (en) * | 2009-05-11 | 2012-07-11 | 基因里克斯(英国)有限公司 | Sitagliptin synthesis |
| CN102757431A (en) * | 2011-04-24 | 2012-10-31 | 浙江华海药业股份有限公司 | Novel method for synthesizing sitagliptin |
| CN103172539A (en) * | 2011-12-23 | 2013-06-26 | 上海阳帆医药科技有限公司 | Preparation method of new diabetes drug sitagliptin intermediate aminobenzene butyric acid derivative |
| CN109957586A (en) * | 2017-12-23 | 2019-07-02 | 浙江九洲药业股份有限公司 | The preparation method of beta-aminoacid-derivatives rich in enantiomer |
-
2022
- 2022-12-13 CN CN202211603152.1A patent/CN115960007A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5359107A (en) * | 1993-11-23 | 1994-10-25 | Dow Corning Corporation | β-cyanoalkylsilane preparation using triorganophosphine compounds as catalyst |
| CN102574856A (en) * | 2009-05-11 | 2012-07-11 | 基因里克斯(英国)有限公司 | Sitagliptin synthesis |
| CN102757431A (en) * | 2011-04-24 | 2012-10-31 | 浙江华海药业股份有限公司 | Novel method for synthesizing sitagliptin |
| CN103172539A (en) * | 2011-12-23 | 2013-06-26 | 上海阳帆医药科技有限公司 | Preparation method of new diabetes drug sitagliptin intermediate aminobenzene butyric acid derivative |
| CN109957586A (en) * | 2017-12-23 | 2019-07-02 | 浙江九洲药业股份有限公司 | The preparation method of beta-aminoacid-derivatives rich in enantiomer |
Non-Patent Citations (4)
| Title |
|---|
| MICHELE KUBRYK等: "Application of the asymmetric hydrogenation of enamines to the preparation of a beta-amino acid pharmacophore", 《TETRAHEDRON: ASYMMETRY》, vol. 17, pages 205 - 209 * |
| 弓建红: "1，2-二苯基-2-氨基乙醇及衍生物的合成与手性拆分的研究", 《中国优秀博硕士学位论文全文数据库 (硕士) 工程科技Ⅰ辑》, vol. 04, pages 014 - 124 * |
| 张鹏等: "α-氟-β-氨基酸酯的合成", 《合成化学》, vol. 20, no. 3, pages 389 - 392 * |
| 朱一恒等: "D-(-)-对羟基苯甘氨酸的试制", 《沈阳药学学报》, vol. 15, pages 95 - 100 * |
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