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Preparation method and application of chiral amine compound

A technology of imine compounds and compounds, applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as waste

Active Publication Date: 2014-07-16
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chiral resolution typically involves multiple steps and results in a large amount of waste

Method used

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  • Preparation method and application of chiral amine compound
  • Preparation method and application of chiral amine compound
  • Preparation method and application of chiral amine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The imine 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline (1) (1.22mmol) was dissolved in methanol (14.0mL), and trifluoroacetic acid (93.42 μL, 1.22 mmol), and the mixture was stirred for 5 minutes. Catalyst [RuCl(η 6 -p-isopropyltoluene)(S,S)-(N-tosyl-1,2-diphenyl and -1,2-diamine)](A)(0.0122mol) was added to the above mixture ( The molar ratio of substrate to catalyst S / C=100). The reaction system was sealed as a pressure reactor, replaced with hydrogen three times (3×5 bar), and then filled with 15 bar of hydrogen. After reacting for 6 hours, saturated Na 2 CO 3 The solutions were mixed (2 mL). The resulting solution was extracted twice with ether (3×2 mL), and the combined organic phase was washed with anhydrous Na 2 SO 4 Let dry for 1 hour. The resulting ether solution was evaporated to dryness in air vapor. GC analysis showed 1100% conversion of compound 1 to 6,7-dimethyl-1-methyl-1,2,3,4-tetrahydroisoquinoline, ee value 96%.

[0047] Analysis conditions...

Embodiment 2～23

[0050] The operating modes of Examples 2-23 are basically the same as those of Example 1, except that the catalysts and raw materials are different. The catalysts and raw materials used, as well as the conversion ratio and ee value are listed in Table 1.

[0051] The reaction condition and reaction result of table 1 embodiment 2~23

[0052] Example

raw material

catalyst

Conversion rates[%]

ee[%]

2

2

A

100

87

3

3

A

100

92

4

4

A

100

93

5

1

B

100

96

6

2

B

100

85

7

3

B

100

92

8

4

B

100

92

9

1

C

100

96

10

2

C

100

81

11

3

C

100

89

12

4

C

100

90

13

1

D

100

78

14

2

D

100

59

15

3

D

100

68

16

4

D

100

74

17

2

E...

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PUM

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Abstract

The invention discloses a preparation method of a chiral amine compound. In presence of a semi-sandwich type complex and an acid additive, an asymmetrization reaction is carried out on a prochiral amine compound in a hydrogen atmosphere, and postprocessing is carried out after the reaction is completely finished, so that the chiral amine compound is obtained. According to the preparation method of the chiral amine compound, a certain amount of appropriate acid is added in a certain sequence, so that activation of a C=N bond in a reduction reaction can be promoted; the prepared chiral amine compound can be taken as an intermediate and used for synthesizing the following medicines (including but not limited to the medicines) or precursors of the medicines: gantacurium, mivacurium chloride, atracurium besylate, sertraline, sezolamide, almorexant or solifenacin.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and in particular relates to a preparation method and application of chiral amine compounds. Background technique [0002] The pharmacokinetics (such as bioavailability, volume of distribution, or clearance) and / or pharmacodynamic properties of a drug are often very different between a pair of enantiomers of a drug due to biological The corresponding receptors in vivo are enantiospecific. Therefore, the modern pharmaceutical industry inevitably requires the use of optically pure chemical reagents. [0003] In many drugs, there are amino groups attached to chiral carbons, and such structures can be obtained by hydrogenation of imines. If the hydrogenation reaction is non-stereospecific, racemized products are obtained which must be separated by chiral resolution techniques. Chiral resolutions generally involve multiple steps and result in a large amount of waste. [000...

Claims

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Application Information

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IPC IPC(8): C07D217/02B01J31/22
CPCB01J31/1805B01J31/2295B01J2531/0225B01J2531/0238B01J2531/821B01J2531/822B01J2531/827C07D217/02
Inventor 贝娅塔·比尔哈诺娃伊里·瓦茨拉维克彼得·索特马雷克·库马兹亚罗米尔·托曼彼得·卡采尔姚成志陈为人
Owner ZHEJIANG MENOVO PHARMA
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