CN111087400A - Synthetic method of sitagliptin - Google Patents
Synthetic method of sitagliptin Download PDFInfo
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- CN111087400A CN111087400A CN202010029573.2A CN202010029573A CN111087400A CN 111087400 A CN111087400 A CN 111087400A CN 202010029573 A CN202010029573 A CN 202010029573A CN 111087400 A CN111087400 A CN 111087400A
- Authority
- CN
- China
- Prior art keywords
- sitagliptin
- hydroxy
- piperazine hydrochloride
- dioxane
- dimethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960004034 sitagliptin Drugs 0.000 title claims abstract 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 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 2, 4, 5-trifluorophenyl Chemical group 0.000 claims abstract description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 5
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims 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 claims abstract description 4
- 230000006324 decarbonylation Effects 0.000 claims abstract description 4
- 238000006606 decarbonylation reaction Methods 0.000 claims abstract description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000010992 reflux Methods 0.000 claims abstract description 4
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 claims abstract 3
- 230000007062 hydrolysis Effects 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 238000009833 condensation Methods 0.000 claims description 9
- 230000005494 condensation Effects 0.000 claims description 9
- 150000001277 beta hydroxy acids Chemical class 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 239000007795 chemical reaction product Substances 0.000 claims 2
- QUMRLXXCRQWODL-UHFFFAOYSA-N 1-methylpiperazin-1-ium;chloride Chemical compound [Cl-].C[NH+]1CCNCC1 QUMRLXXCRQWODL-UHFFFAOYSA-N 0.000 claims 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims 1
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical compound C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 claims 1
- 229940050176 methyl chloride Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 229930194542 Keto Natural products 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 abstract 1
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- OFZKQVDROYOFSU-UHFFFAOYSA-N 1-ethyl-2,2-dimethyl-1-propylhydrazine Chemical compound CCCN(CC)N(C)C OFZKQVDROYOFSU-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- BCALRHVPKFQYMU-UHFFFAOYSA-N [Na].[Ru] Chemical compound [Na].[Ru] BCALRHVPKFQYMU-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 229960004115 sitagliptin phosphate Drugs 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
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of sitagliptin, which comprises the following steps: reacting 2,4, 5-trifluoro-phenylacetic acid serving as a raw material with pivaloyl chloride to convert the trichloroacetic acid into acyl chloride, condensing the acyl chloride with 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone under the combined action of N, N-diisopropylethylamine and 4-dimethylaminopyridine to obtain 5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone, refluxing in a methanol solution for ring opening and decarbonylation to obtain keto ester, and reacting with an intermediate 3-trifluoromethyl- [1, 2, 4] triazolo [4, 3, a ] piperazine hydrochloride at 0 ℃ to obtain amino-protected sitagliptin. The catalyst has less consumption, the reaction conditions in China in the route are mild, the operation of each step of reaction is simple, the feasibility is relatively high, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to the field of sitagliptin preparation, in particular to a synthetic method of sitagliptin.
Background
Sitagliptin is a dipeptidyl peptidase-IV inhibitor drug used for treating type II diabetes, which controls the blood sugar level of a diabetic patient by improving the insulin production capacity of the pancreatic islets β cells of the diabetic patient, increasing the secretion of insulin when the blood sugar is increased, and has good tolerance, no weight gain and no risk of hypoglycemia.The 10M Merck company announces that sitagliptin phosphate (sitagliptin phosphate) is approved by the U.S. food and drug administration in 2006.
At present, most methods for synthesizing sitagliptin at home and abroad relate to chiral induction and asymmetric hydrogenation: the steps are different in length, four or five steps are less, and ten steps are more. The optical purity ee% of the chiral induction and asymmetric hydrogenation is lower, and the ee% needs to be improved by further purification, so that the resource waste exists. And half of isomers in the chemical resolution method cannot be utilized, so that the yield is low and the cost is high.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a sitagliptin synthesis method, which is low in catalyst consumption, mild in reaction conditions in the route, simple in reaction operation in each step, relatively high in feasibility and suitable for industrial production.
In order to achieve the aim of the invention, the invention adopts the specific scheme that:
a process for synthesizing sitagliptin includes such steps as using 2,4, 5-trifluoro-phenylacetic acid as raw material, reacting with pivaloyl chloride to convert it to acyl chloride, condensing with 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone under the action of N, N-diisopropyl ethylamine and 4-dimethylamino pyridine to obtain 5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone, reflux ring-opening decarbonylation in methanol solution to obtain keto ester, catalytic asymmetric hydrogenation of keto ester at 80 deg.C in methanol solution with (S) -dinaphthalene diphenyl phosphate and anhydrous ruthenium sodium, hydrolysis with hydroxide to obtain β -hydroxy acid, condensation of β -hydroxy acid with N-ethyl-N-dimethylamino-propylamine carbodiimide, condensation with O-benzyl amine, dehydration of condensation compound in triphenyl phosphine and diisopropyl azodicarboxylate to obtain β -lactam compound, hydrolysis of its amide in N-ethyl-N-dimethylamino-propylamine under the condition of reaction with morpholine hydrochloride, hydrolysis of L-methyl ester at 3-hydroxy acid to obtain morpholine hydrochloride, hydrolysis of 3-methyl ester at 0-hydroxy amide compound and hydrolysis of morpholine-3-amino-methyl ester.
Further, the amount of the (S) -binaphthyl diphenyl phosphate and anhydrous ruthenium trichloride catalyst was 0.2m 01% of the reactants.
The invention has the beneficial effects that:
the catalyst has less consumption, the reaction conditions in China in the route are mild, the operation of each step of reaction is simple, the feasibility is relatively high, and the method is suitable for industrial production.
Detailed Description
The present invention is further described below by way of specific examples, but the present invention is not limited to only the following examples. Variations, combinations, or substitutions of the invention, which are within the scope of the invention or the spirit, scope of the invention, will be apparent to those of skill in the art and are within the scope of the invention.
A process for synthesizing sitagliptin includes such steps as using 2,4, 5-trifluoro-phenylacetic acid as raw material, reacting with pivaloyl chloride to convert it to acyl chloride, condensing with 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone under the action of N, N-diisopropyl ethylamine and 4-dimethylamino pyridine to obtain 5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone, reflux ring-opening decarbonylation in methanol solution to obtain keto ester, catalytic asymmetric hydrogenation of keto ester at 80 deg.C in methanol solution with (S) -dinaphthalene diphenyl phosphate and anhydrous ruthenium sodium, hydrolysis with hydroxide to obtain β -hydroxy acid, condensation of β -hydroxy acid with N-ethyl-N-dimethylamino-propylamine carbodiimide, condensation with O-benzyl amine, dehydration of condensation compound in triphenyl phosphine and diisopropyl azodicarboxylate to obtain β -lactam compound, hydrolysis of its amide in N-ethyl-N-dimethylamino-propylamine under the condition of reaction with morpholine hydrochloride, hydrolysis of L-methyl ester at 3-hydroxy acid to obtain morpholine hydrochloride, hydrolysis of 3-methyl ester at 0-hydroxy amide compound and hydrolysis of morpholine-3-amino-methyl ester.
The dosage of the (S) -binaphthyl diphenyl phosphate and the anhydrous ruthenium trichloride catalyst is 0.2m 01% of the reactants.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (2)
1. A synthetic method of sitagliptin is characterized in that 2,4, 5-trifluoro phenylacetic acid is used as a raw material, reacts with pivaloyl chloride to be converted into acyl chloride, then is condensed with 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone under the combined action of N, N-diisopropyl ethylamine and 4-dimethylamino pyridine to obtain 5- [ 1-hydroxy-2- (2, 4, 5-trifluoro phenyl) ethylidene ] -2, 2-dimethyl-1, 3-dioxane-4, 6-diketone in a methanol solution, then reflux ring opening and decarbonylation are carried out in the methanol solution to obtain ketone ester, asymmetric hydrogenation is catalyzed by (S) -binaphthyl diphenyl phosphate and anhydrous ruthenium trichloride in the methanol solution at the temperature of 80 ℃, then sodium hydroxide is used for hydrolysis to obtain β -hydroxy acid, β -hydroxy acid is condensed with O-benzyl in the presence of N-ethyl-N-dimethylamino carbodiimide, condensation compound is dehydrated and cyclized in triphenyl phosphine and diisopropyl azodicarboxylate to obtain a condensation compound, then the condensation compound is hydrolyzed with N-ethyl-N-dimethylamino-carbodiimide to obtain a ring opening reaction methyl piperazine hydrochloride, and a reaction product of piperazine hydrochloride under the temperature of 0-hydroxy amide type (S-methyl chloride) and the reaction product of EDC type piperazine hydrochloride to obtain the intermediate of L-methyl piperazine hydrochloride.
2. The method for synthesizing sitagliptin according to claim 1, characterized in that the amount of the (S) -binaphthyl diphenyl phosphate and anhydrous ruthenium trichloride catalyst is 0.2m 01% of the reactants.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010029573.2A CN111087400A (en) | 2020-01-13 | 2020-01-13 | Synthetic method of sitagliptin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010029573.2A CN111087400A (en) | 2020-01-13 | 2020-01-13 | Synthetic method of sitagliptin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111087400A true CN111087400A (en) | 2020-05-01 |
Family
ID=70399034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010029573.2A Pending CN111087400A (en) | 2020-01-13 | 2020-01-13 | Synthetic method of sitagliptin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111087400A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087650A2 (en) * | 2003-03-27 | 2004-10-14 | Merck & Co. Inc. | Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors |
-
2020
- 2020-01-13 CN CN202010029573.2A patent/CN111087400A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087650A2 (en) * | 2003-03-27 | 2004-10-14 | Merck & Co. Inc. | Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| KARL B. HANSEN等: "First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin" * |
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Application publication date: 20200501 |