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(1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-phenyl formate novel crystal form and preparation method thereof

A technology of phenyl formate and tetrahydroisoquinoline, which is applied in the field of medicine and chemical industry, and achieves the effects of mild conditions, easy reaction and low toxicity

Active Publication Date: 2014-03-26
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the good stability of crystal form A, it is beneficial to the removal of impurities and the preservation of intermediates in the production process, which greatly improves the shortcomings of the existing oily intermediates used in the production process of solifenacin succinate

Method used

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  • (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-phenyl formate novel crystal form and preparation method thereof
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  • (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-phenyl formate novel crystal form and preparation method thereof

Examples

Experimental program
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Effect test

preparation example 1

[0051] Preparation Example 1: Preparation of crude (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenyl ester:

[0052] This preparation example is obtained with reference to the document US20090203915A1;

[0053] Dissolve 35g (167mmol) of (S)-1-phenyl-1,2,3,4-tetrahydro-isoquinoline in 175ml of toluene, add 35.8g (167mmol) of diphenyl carbonate and a catalytic amount of dimethyl Aminopyridine was then refluxed. After the reaction was complete, the reactant was cooled, and the resulting reaction solution was washed with 5% NaOH, 1M hydrochloric acid and saturated brine, respectively, and the solvent was distilled off under reduced pressure to obtain compound I as a yellow oil.

Embodiment 1

[0054] Example 1: Preparation of (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenyl ester crystal form A

[0055] Add 10 g of the crude compound I obtained in Preparation Example 1 into 50 ml of n-heptane, stir and heat to reflux to dissolve, cool down to crystallize, filter with suction, and dry to obtain 9.8 g of a white solid with a yield of 98% and a purity of 100%. After measurement, the X-ray powder diffraction pattern of gained product is as follows figure 1 As shown, its differential scanning analysis (DSC) pattern is as follows figure 2 shown.

Embodiment 2

[0056] Example 2: Preparation of (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenyl ester crystal form A

[0057] Add 10 g of the crude compound I obtained in Preparation Example 1 into 20 ml of petroleum ether, stir and heat to reflux to dissolve, cool down to crystallize, filter with suction, and dry to obtain 9.7 g of a white solid with a yield of 97% and a purity of 99.9%; The X-ray powder diffraction pattern of gained product and figure 1 Basically the same, its DSC spectrum and figure 2 Basically the same.

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and in provides to a crystal form of (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-phenyl formate and a preparation method thereof. The obtained crystal form A has the advantages of easy dissolution, mild reaction conditions and good stability in the preparation process of solifenacin, and does not need long-term high temperature reflow conditions, so as to increase industrial maneuverability and reduce energy consumption and production cost. The good stability of the crystal form A is conducive to impurity removal and intermediate preservation in the preparation process, thereby greatly improving the disadvantages caused by usage of an oil intermediate in the existing production process of solifenacin.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to a new crystal form of solifenacin intermediate (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid phenyl ester, A method for preparing the crystalline form is also disclosed. Background technique [0002] Solifenacin succinate is a selective M3 receptor antagonist developed and marketed by Japan Astellas Pharmaceutical Company for the treatment of overactive bladder (OAB). It was launched for the first time in August 2004 It was launched simultaneously in the Netherlands, Germany, the United Kingdom, France and Denmark, and was approved by the US FDA in November 2004. It has the following structural formula: [0003] [0004] A variety of methods for preparing solifenacin are disclosed in the existing literature, such as patent documents EP0801067, WO2005105795, WO2007147374, WO2009142522 and WO2011086003, which report the preparatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/06
CPCC07D217/06
Inventor 高源张贵岭田振平周晓东潘雷范传文
Owner QILU PHARMA HAINAN
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