- Sitagliptin derivative or pharmaceutically acceptable salt, as well as preparation method and application thereof
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The invention relates to a sitagliptin derivative or pharmaceutically acceptable salt, as well as a preparation method and application thereof, and belongs to the technical field of synthesis of a medicine intermediate. In order to solve the problem that the conventional chain easily generates low-energy conformation, the invention provides the sitagliptin derivative or pharmaceutically acceptablesalt, and the preparation method thereof. The method comprises the following steps: under the existence of a coupling agent, performing coupling reaction on an enamine intermediate and a triazol[4,3-a]pyrazine compound to obtain an intermediate; performing deprotection reaction on the intermediate to remove a Boc group, and performing cyclization reaction on the hydroxylamine hydrochloride to obtain the corresponding sitagliptin derivative or pharmaceutically acceptable salt. Amino and carbonyl in flexible chain alkyl in the molecular structure are cyclized to form a five-membered ring structure, so that low-energy isomerism phenomena are effectively reduced, medicine stability is improved, and selectivity and medicine use safety are improved. The synthesis method is simple, and use of anexpensive chiral reagent can be avoided.
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Paragraph 0119
(2018/04/01)
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- PROCESS FOR PREPARATION OF (2R)-4-OXO-4-[3- (TRIFLUOROMETHYL)-5,6-DIHYDRO [1,2,4]-TRIAZOLO[4,3-A]PYRAZIN- 7(8H)-YL]-L-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE and NEW IMPURITIES IN PREPARATION THEREOF
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The present invention relates to synthesis of β-amino acid derivatives of formula (I) and its salts of formula (Ia) by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4-oxo-4-[3-Ctrifluoromethyl)-5,6-dihydrol[1,2,4]triazolo[4,3-alpyrazin-7(8H)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine. In an embodiment the invention disclosed polymorphic forms of formula (I), phosphate salt of formula (I) and also a Dibenzoyl-L-tartaric acid salt of formula (I).
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- PROCESS FOR THE PREPARATION OF R-SITAGLIPTIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides processes for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof.
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Page/Page column 11
(2010/12/29)
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- IMPROVED PROCESS FOR PREPARATION OF (2R)-4-OXO-4-[3- (TRIFLUOROMETHYL)-5,6-DIHYDRO [1,2,4]-TRIAZOLO[4,3-A]PYRAZIN- 7(8H)-YL]-L-(2,4,5-TRIFLUOROPHENYL)BUTAN-2-AMINE and NEW IMPURITIES IN PREPARATION THEREOF
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The present invention relates to synthesis of β-amino acid derivatives of formula (I) and its salts of formula (Ia) by a novel process. The process comprises the reduction of a protected or unprotected prochiral β-amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure. The resulting racemic β-amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4-oxo-4- [3-Ctrifluoromethyl)-5, 6-dihydrol [1,2,4]triazolo [4,3-alpyrazin-7(8H)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine. In an embodiment the invention disclosed polymorphic forms of formula (I), phosphate salt of formula (I) and also a Dibenzoyl-L-tartaric acid salt of formula (I).
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Page/Page column 32
(2010/04/25)
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- PROCESSES FOR THE PREPARATION OF SITAGLIPTIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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There is provided salts and polymorphs of sitagliptin, processes for the preparation thereof, and pharmaceutical compositions comprising the same.
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Page/Page column 28
(2009/08/14)
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- Direct asymmetric reductive amination
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(Chemical Equation Presented) Asymmetric reductive amination of β-keto amides catalyzed by the chiral catalyst Ru(OAc)2 ((R)-dm-segphos) produces unprotected β-amino amides with high yields and high enantioselectivities (94.7-99.5% ee). This "one-pot" methodology is general in substrate scope and has been successfully employed to produce sitagliptin with 99.5% ee and 91% assay yield. The excellent reaction efficiency is attributed to the remarkable tolerance to high concentrations of ammonium ion, the high chemoselectivity, and the high enantioselectivity (99.5% ee) of the Ru catalyst system.
- Steinhuebel, Dietrich,Sun, Yongkui,Matsumura, Kazuhiko,Sayo, Noboru,Saito, Takao
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scheme or table
p. 11316 - 11317
(2011/03/19)
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- A PROCESS FOR THE PREPARATION OF R-SIT AGLIPTIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides processes for the preparation of R-sitagliptin and its pharmaceutically acceptable salts thereof.
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Page/Page column 23-24
(2009/08/14)
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