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Preparation method of dipeptide valine boron proline salt

A technology of valine boroproline salt and valine, which is applied in the field of compound synthesis, can solve the problems of complex steps, low total yield of routes, and large losses, so as to simplify the post-reaction processing steps and increase the total yield , The effect of increasing the yield

Active Publication Date: 2019-11-15
SHANGHAI BALMXY PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Dipeptide valine boroproline salt is an important intermediate of anticancer drugs. The existing synthetic routes all start from valine protected by tert-butoxycarbonyl or trifluoroacetyl, resulting in deprotection Because the target product is very soluble in water, it is difficult to purify and separate it from water. The current method is generally to dechlorinate through ion exchange resin and then form salt. The steps are complicated, and the losses in the reaction process and post-treatment process are large, resulting The final yield of the target product is very low
[0003] Gibson et al. (Organic Process Research & Development 2002, 6, 814-816) reported the synthesis of [(2R)-1-[(2S) from N-Boc-2-pyrrolidine boronic acid and trifluoroacetyl-protected valine as starting materials. - A route to 2-amino-3-methylbutyryl]pyrrolidin-2-yl]boronic acid mesylate using the diastereomeric hydrochloride form of N-Boc-2-pyrrolidineboronic acid The solubility in the solvent is different to resolve, and the yield of the target configuration product is only 18%. In addition, the final product is obtained by dechlorinating the ion exchange resin and then becoming a mesylate. The synthetic route is complicated and the target product The loss is large, and the total yield of the route is very low

Method used

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  • Preparation method of dipeptide valine boron proline salt
  • Preparation method of dipeptide valine boron proline salt
  • Preparation method of dipeptide valine boron proline salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] This example prepares a kind of [(2R)-1-[(2S)-2-amino-3-methylbutyryl]pyrrolidin-2-yl]boronic acid methanesulfonate

[0089] The synthetic route is

[0090]

[0091] (1) N-Boc-2-pyrrolidine boronic acid (215g, 1mol) was dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) was added under stirring, and then (1S, 2S, 3R, 5S) - 2,3-pinanediol (170g, 1mol), after reacting for two hours, filtered, washed, and the organic phase was concentrated and dried, and intermediate A1 was obtained in 331g.

[0092] (2) Intermediate A1 (250 g) was dissolved in 1000 mL of ether, and hydrogen chloride gas was introduced at 0° C. for 30 min. Then the mixture was slowly warmed to room temperature and stirring was continued for 3 h. Cool to 0°C, and then direct rotary evaporation to obtain 204 g of white powder. The white powder was dissolved in water (1000 mL), and saturated aqueous sodium bicarbonate solution was added dropwise to pH=8.5. Then extract with d...

Embodiment 2

[0101]

[0102] Steps (1), (2), (3), (4) and (5) are the same as the preparation method of Example 1, except that the raw material acid HX in step (6) is hydrochloric acid.

[0103] (6) Dissolve 18g of intermediate E1 in 180mL of acetone, add hydrochloric acid (3.176g, 0.087mol) dropwise, stir at room temperature for 2h, filter, wash with acetone, ether, and dry to obtain (2R)-1- [(2S)-2-Amino-3-methylbutyryl]pyrrolidin-2-yl]borate hydrochloride (19.4 g, yield 92%).

[0104] 1 H NMR (MeOH-d 4 ,400MHz):δ4.03(d,1H),3.78-3.74(m,1H),3.49-3.42(m,1H),3.38-3.34(m,1H),3.34-3.19(m,1H),2.25 (ddd,1H), 2.16-2.05(m,2H), 2.04-1.92(m,1H), 1.80-1.67(m,1H), 1.13(s,3H), 1.08(s,3H).

Embodiment 3

[0106] This example prepares a kind of [(2R)-1-[(2S)-2-amino-3-methylbutyryl]pyrrolidin-2-yl]boronic acid methanesulfonate

[0107] The synthetic route is

[0108]

[0109] (1) N-Boc-2-pyrrolidine boronic acid (215g, 1mol) was dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) was added under stirring, and then pinacol (118g, 1mol) was added, After reacting for two hours, it was filtered, washed, and the organic phase was concentrated and dried to obtain intermediate A2 in 276 g.

[0110] (2) Intermediate A2 (270 g) was dissolved in 1000 mL of ether, and hydrogen chloride gas was passed through at 0° C. for 30 min. Then the mixture was slowly warmed to room temperature and stirring was continued for 3 h. Cool to 0°C, and then direct rotary evaporation to obtain 201 g of white powder. The white powder was dissolved in water (1000 mL), and saturated aqueous sodium bicarbonate solution was added dropwise to pH=9. Then dichloromethane was extracte...

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Abstract

The invention provides a preparation method of dipeptide valine boron proline salt. According to the preparation method, pyrrolidine boric acid with protected R<1> groups and valine with protected R<4> groups are used as initial raw materials, and the problem of product loss caused by complex post-treatment during deprotection is avoided, so that the yield of a target product is greatly improved,and mass production is facilitated. Through a resolution method by adopting a resolution agent, the problem of excessive loss of a product with a target configuration due to use of resolution methodswith different solubilities is avoided, so that the yield of the product with the target configuration is greatly improved.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and relates to a preparation method of dipeptide valine boroproline salt. Background technique [0002] Dipeptide valine boroproline salt is an important intermediate of anticancer drugs. The existing synthetic routes all start from valine protected by tert-butoxycarbonyl or trifluoroacetyl, resulting in deprotection Because the target product is very soluble in water, it is difficult to purify and separate it from water. The current method is generally to dechlorinate through ion exchange resin and then form salt. The steps are complicated, and the losses in the reaction process and post-treatment process are large, resulting The final yield of the target product is very low. [0003] Gibson et al. (Organic Process Research & Development 2002, 6, 814-816) reported the synthesis of [(2R)-1-[(2S) from N-Boc-2-pyrrolidine boronic acid and trifluoroacetyl-protected valine as starting mat...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07C309/04C07C303/32
CPCC07C303/32C07C309/04C07F5/025
Inventor 赖桢林增明
Owner SHANGHAI BALMXY PHARMA CO LTD
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