Synthetic method of sitagliptin phosphate impurities

A technology of sitagliptin phosphate and a synthesis method, which is applied in the field of organic synthesis and achieves the effects of high content, low requirements for reaction equipment and mild reaction conditions

Inactive Publication Date: 2018-11-23
SULI PHARMA TECH JIANGYIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In order to ensure the safety of the API and control its quality, there are clear requirements for the impurity in the registration and declaration process of the API. The current international counterpart method is to carry out the analys...

Method used

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  • Synthetic method of sitagliptin phosphate impurities
  • Synthetic method of sitagliptin phosphate impurities
  • Synthetic method of sitagliptin phosphate impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Step 1. Schiff base reaction

[0036] Add β-ketoester (3.5g), S-benzylglycineamide (2.14g), and glacial acetic acid (4.5g) into isopropanol (50ml), under nitrogen protection, heat to 40°C and keep it warm for 16h. Solids began to precipitate after cooling down to 5-10°C. After 30 minutes, suction filtered and washed the filter cake with an appropriate amount of isopropanol. The filter cake was dried under reduced pressure at 40°C to obtain solid compound 3: (S,Z)-methyl 3-( 2-Amino-2-oxo-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester 4.5g, purity 90%, yield 76% . The NMR structure identification results are as follows:

[0037] 1HNMR (400MHz, DMSO, D2O),

[0038] δ: 3.32(d, J=16.4Hz, 1H), 3.47(d, J=16.7Hz, 1H), 4.20(s, 1H), 5.16(d.J=7.9Hz, 1H), 7.15(dd, J=17.5 , 9.2Hz, 1H), 7.37-7.22 (m, 6H), 7.50-7.39 (m, 1H), 7.73 (s, 1H), 9.53 (d, J = 7.7Hz, 1H).

[0039] Step 2, hydrogenation reaction

[0040] Then compound 3 (4.0g), PtO2 (0.4g), gl...

Embodiment 2

[0046] Step 1. Schiff base reaction

[0047] Add β-ketoester (35g), S-benzylglycine amide (21.4g) and glacial acetic acid (45g) into ethanol (500ml), under nitrogen protection, heat to 40°C for 16h and then cool down for 5-10 After 30 minutes, it was filtered with suction, and the filter cake was washed with an appropriate amount of ethanol. The filter cake was dried under reduced pressure at 40°C to obtain the solid compound 3 ((S, Z)-methyl 3-(2-amino-2- Oxo-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester) 47g, purity 92%, yield 79%. The NMR structure identification results are as follows:

[0048] 1HNMR (400MHz, DMSO, D2O),

[0049] δ: 3.32(d, J=16.4Hz, 1H), 3.47(d, J=16.7Hz, 1H), 4.20(s, 1H), 5.16(d.J=7.9Hz, 1H), 7.15(dd, J=17.5 , 9.2Hz, 1H), 7.37-7.22 (m, 6H), 7.50-7.39 (m, 1H), 7.73 (s, 1H), 9.53 (d, J = 7.7Hz, 1H).

[0050] Step 2, hydrogenation reaction

[0051] Then compound 3 (40g), PtO2 (4g), glacial acetic acid (45ml) and ethanol (12...

Embodiment 3

[0057] Step 1. Schiff base reaction

[0058] Add β-ketoester (350g), S-benzylglycineamide (214g) and glacial acetic acid (450g) into ethanol (5000ml), under nitrogen protection, heat to 40°C for 16 hours, then cool down by 5-10°C After 30 minutes, a solid was precipitated, and after 30 minutes, it was suction filtered, and the filter cake was washed with an appropriate amount of ethanol, and the filter cake was dried under reduced pressure at 40°C to obtain a solid compound 3 ((S, Z)-methyl 3-(2-amino-2-oxo Substituent-1-phenethylamino)-4-(2,4,5-trifluorophenyl)but-2-enoic acid methyl ester) 480g, purity 92%, yield 80%. The NMR structure identification results are as follows:

[0059] 1HNMR (400MHz, DMSO, D2O),

[0060] δ: 3.32(d, J=16.4Hz, 1H), 3.47(d, J=16.7Hz, 1H), 4.20(s, 1H), 5.16(d.J=7.9Hz, 1H), 7.15(dd, J=17.5 , 9.2Hz, 1H), 7.37-7.22 (m, 6H), 7.50-7.39 (m, 1H), 7.73 (s, 1H), 9.53 (d, J = 7.7Hz, 1H).

[0061] Step 2, hydrogenation reaction

[0062] Then compound 3 (...

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Abstract

The invention discloses a synthetic method of sitagliptin phosphate impurities. The synthetic method is characterized in that the sitagliptin phosphate impurities are (R)-3-(S)-2-amino-2-oxo-1-phenethyl ammonia-4-(2,4,5-fluorophenyl) butanoic acid and are obtained by taking beta-keto ester, S-phenylglycine amide and glacial acetic acid as starting materials through a three-step technology of Schiff base reaction, hydrogenation reaction and hydrolysis reaction. The synthetic method provided by the invention is relatively available in reaction raw materials, simple to operate in reaction process, low in requirement for reaction equipment, relatively moderate in reaction condition and high in yield and content, saves the cost and can have very great promotion effect to deeper and wider studyon the drug use safety, the reliability and the stability relative to sitagliptin phosphate and quality control in the production process.

Description

technical field [0001] The invention relates to a sitagliptin phosphate impurity ((R)-3-(S)-2-amino-2-oxo-1-phenethylamine-4-(2,4,5-trifluorobenzene The synthetic method of base) butyric acid) provides a reliable impurity source for the research and quality control of sitagliptin phosphate crude drug, and belongs to the technical field of organic synthesis. Background technique [0002] A specific impurity (R)-3-(S)-2-amino-2-oxo-1-phenylethylamino-4-(2,4,5 -trifluorophenyl)butanoic acid, molecular structure: [0003] [0004] Molecular formula: C 18 h 17 f 3 N 2 o 2 , molecular weight: 350.12 [0005] It is synthetic Sitagliptin phosphate (Sitagliptin) chemical name 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6 , 7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolone[4,3-a]pyrazine is an impurity produced in the raw material drug process, sitagliptin phosphate is the first A DPP-4 inhibitor approved for the treatment of type 2 diabetes can inhibit β-cel...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12
CPCC07B2200/07C07C231/12C07C237/20
Inventor 梁朝阳高桂祥汪静莉
Owner SULI PHARMA TECH JIANGYIN
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