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Preparation method of dihydropyrimidine derivatives and their acid adducts

An acid addition and compound technology, which is applied in the preparation of acid adducts, optically pure dihydropyrimidine derivatives or the preparation of tautomers thereof, can solve the problem of inability to use large-scale production and high requirements for experimental instruments. question

Active Publication Date: 2018-02-09
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In industrial production, the racemic product is directly resolved by preparative chromatography, which requires high experimental equipment and cannot be used for large-scale production.

Method used

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  • Preparation method of dihydropyrimidine derivatives and their acid adducts
  • Preparation method of dihydropyrimidine derivatives and their acid adducts
  • Preparation method of dihydropyrimidine derivatives and their acid adducts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Example 1: (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3, Preparation of 6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid

[0200]

[0201] Add (3S)-4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6 -Dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (1g) and ethanol (5mL). The mixture was stirred at room temperature for 4 hours and filtered. The filtrate was concentrated under reduced pressure and the solvent was removed to obtain (S)- 4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidine-4- ((Yl)methyl)morpholine-3-carboxylic acid is a yellow foamy solid (0.46 g, 92%) with a chiral purity of 95%.

[0202] MS(ESI,pos.ion)m / z:494.9[M+H] + ;

[0203] 1 H NMR(400MHz, DMSO-d 6 ): δ12.52(br,1H), 9.86(s,1H), 8.03(d,1H), 7.94(d,1H), 7.43-7.38(m,2H), 7.16(td,1H), 6.04( s, 1H), 4.24 (d, 1H), 4.06-3.97 (m, 2H), 3.84 (dd, 1H), 3.73-3.66 (m, 2H), 3.64-3.59 (m, 1H), 3.51 ...

Embodiment 2

[0209] Example 2: (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-1, Preparation of L-tartaric acid complex (c) of 6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (method one)

[0210]

[0211] Add (3S)-4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6 to a 100mL three-necked flask in sequence -Dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (7g, 14.14mmol), ethanol (45mL) and L-tartaric acid (1.2g, 8mmol), the resulting mixture was heated to 55°C, kept and stirred for 30min . Then the heating was turned off, and after the temperature was lowered to 25°C, the temperature was kept and stirred for 16 hours. After the reaction, filter, wash the filter cake with ethanol (10 mL), and then vacuum dry at 65°C for 8 hours to obtain (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)- The L-tartaric acid complex of 5-(methoxycarbonyl)-2-(thiazol-2-yl)-1,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid is a yellow ...

Embodiment 3

[0229] Example 3: (S)-4-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-1, Preparation of L-tartaric acid complex (c) of 6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (method 2)

[0230]

[0231] Add (3S)-4-((6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6 to a 100mL three-necked flask in sequence -Dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (7g, 14.14mmol) and ethanol (45mL), the mixture was stirred at room temperature for 4 hours and filtered. The obtained filtrate was transferred to a single-neck flask (100 mL), and then the temperature was raised to 55° C., and L-tartaric acid (1.2 g, 8 mmol) was added, and the resulting mixture was kept warm and stirred for 30 minutes. Subsequently, the heating was turned off and the temperature was lowered (7°C / hour). After the temperature was lowered to 25°C, the temperature was kept and stirred for 16 hours. Filter, wash with ethanol (10 mL), and then vacuum dry at ...

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Abstract

The invention relates to a preparation method of optically pure dihydropyrimidine derivatives shown in the general formula (I) or a tautomer formula (Ia) and also relates to a preparation method of aL-tartaric acid complex of the dihydropyrimidine derivatives shown in the general formula (I) or a tautomer formula (Ia), wherein variables are defined in the specification. The preparation method iseasy to operate. The product has high optical purity, a high yield and simple post-treatment processes and is suitable for industrial production.

Description

Technical field [0001] The invention belongs to the field of medicine, and specifically relates to a preparation method of an optically pure dihydropyrimidine derivative or its tautomer or a preparation method of an acid adduct thereof. Background technique [0002] WO 2014029193 discloses a series of dihydropyrimidine compounds and their applications in medicines, especially their use as medicines for the treatment and prevention of hepatitis B. Among them, the active compound described is a racemate compound. In the follow-up study, the applicant resolved this type of active compound and obtained four stereoisomers. The pharmacological activities were measured respectively. The experimental results showed that the pharmacokinetic parameters and the stability of liver microsomes also differ significantly between the isomers. . Patent WO2015144093 records the activity difference between different isomers, therefore, it is of great value to prepare active compounds with high opt...

Claims

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Application Information

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IPC IPC(8): C07D417/14C07D413/14
CPCC07B2200/13C07D413/14C07D417/14
Inventor 刘辛昌任青云张英俊S·戈尔德曼
Owner SUNSHINE LAKE PHARM CO LTD
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