Synthesis process of chiral pyrrolidine and intermediates

A synthesis process and pyrrolidine technology, which is applied in the synthesis process and intermediate field of chiral pyrrolidine, can solve the problems of large demand, high production cost and high price of lithium triethyl borohydride, and achieve easy control and industrialization , Reduction of reaction steps, high product yield

Active Publication Date: 2018-06-01
上海鑫凯化学科技有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Above-mentioned method adopts chiral agent (S)-2-tert-butyl-sulfonamide to induce the synthesis of chiral intermediate, yet above-mentioned technique adopts lithium triethyl borohydride (LiBEt 3 ) to reduce tert-butylsulfinimide, it needs to be carried out under the supercooled condition of -78°C, and when the above-mentioned reduction step and the synthesis of the final product chiral pyrrolidine, the yield of these two steps is only 36%; in addition, in In this process method, due to the large demand and high price of lithium triethylborohydride, and the relatively harsh temperature conditions, the production cost is relatively high

Method used

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  • Synthesis process of chiral pyrrolidine and intermediates
  • Synthesis process of chiral pyrrolidine and intermediates
  • Synthesis process of chiral pyrrolidine and intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] This example is used to illustrate the synthesis process of Route 1.

[0067] Step 1: Synthesis of the compound of formula (A) (4-chloro-1-(2,5-difluorophenyl)-1-butanone)

[0068]

[0069] Add isopropylmagnesium chloride (2M THF solution, 60ml, 120mmol) in a 500ml three-necked flask, cool to 0 degrees, start to add dropwise a tetrahydrofuran (150ml) solution of 2,5-difluorobromobenzene (19.3g, 100mmol), After the dropwise addition, react at room temperature for 2h; then, control the temperature below 20°C, add dropwise a solution of N-methoxy-N-methyl-4-chlorobutanamide (16.5g, 100mmol) in tetrahydrofuran (50ml), drop After the addition, react at room temperature for 16 hours; add 50ml of hydrochloric acid with an equivalent concentration of 2N to the reaction mixture dropwise, stir for 30min, separate the liquids, extract the aqueous phase twice with 100ml of ethyl acetate (EA), combine the organic phases, and use It was washed with 50 ml of saturated brine, dried...

Embodiment 2

[0084] This example is used to illustrate the synthesis process of Route 1.

[0085] Step 1: the synthesis of formula (E) compound

[0086]

[0087] Add isopropylmagnesium chloride (2M THF solution, 60ml, 120mmol) in a 500ml three-necked flask, cool to 0°C, start to drop a solution of 5-fluoro-3-bromopyridine (17.5g, 100mmol) in tetrahydrofuran (150ml), After the dropwise addition, react at room temperature for 2h; then, control the temperature below 20°C, add dropwise a solution of N-methoxy-N-methyl-4-chlorobutanamide (16.5g, 100mmol) in tetrahydrofuran (50ml), drop After the addition, react at room temperature for 16 h; then, add 50 ml of hydrochloric acid with an equivalent concentration of 2N dropwise to the reaction mixture, stir for 30 min, separate the liquids, extract the aqueous phase twice with 100 ml of ethyl acetate (EA), combine the organic phases, It was washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was re...

Embodiment 3

[0100] This example is used to illustrate the synthesis process of Route 1.

[0101] The difference from Example 1 is that in step 3, methanesulfonyl chloride was replaced by p-toluenesulfonyl chloride, that is, a dichloromethane solution (50 ml) of p-toluenesulfonyl chloride (19.0 g, 99.6 mmol) was added dropwise to the raw material.

[0102] In this embodiment, the yield of the product is 76%, and the ee% is 90%.

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Abstract

The invention discloses a synthesis process of chiral pyrrolidine and intermediates. The synthesis process adopts 2, 5-difluorohalobenze or 5-fluoro-3 halogenated pyridine as the raw material substrate, and employs a chiral catalyst to induce chiral reaction so as to reduce a ketone compound into a corresponding chiral alcohol compound, and then carries out substitution reaction to introduce an easily leavable group to an alcoholic hydroxyl group so as to facilitate ring formation reaction (or carry out ring formation reaction directly). The process provided by the invention has the advantagesof significant increase of product yield and reduction of cost, also the reaction temperature is mild, and the process is easy to control and industrialize.

Description

technical field [0001] The invention relates to the technical field of synthesis of anti-tumor pharmaceutical intermediates, in particular to a synthesis process and intermediates of chiral pyrrolidine. Background technique [0002] As an advanced pharmaceutical intermediate, chiral pyrrolidine can be used in the synthesis of various anticancer drugs. Among the currently disclosed Trk inhibitors, the structure of the new anticancer drug larotrectinib announced by the American Society of Clinical Oncology in 2017 contains (R )-2-(2,5-difluorophenyl)pyrrolidine structure [0003] In the synthesis method of chiral pyrrolidine, the method of chiral induction is one of the commonly used methods. Very low temperature is often required in this type of reaction. As the temperature increases, the result of chiral induction becomes worse. For example, the US patent application publication number US2015 / 005280A1 discloses a preparation method of chiral pyrrolidine, which is carried ou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08C07D401/04C07D213/61C07C271/16
CPCC07B2200/07C07C271/16C07D207/08C07D213/61C07D401/04
Inventor 张奕超董金鹏李侠顾学新
Owner 上海鑫凯化学科技有限公司
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