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Preparation method of halofuginone intermediate trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone

A benzyloxycarbonyl and intermediate technology, which is applied in the field of pharmaceutical synthesis, can solve the problems of high cost, high price of Grubbs reagent, high price, etc., and achieves the effects of stable quality, reduced labor protection intensity and high yield

Pending Publication Date: 2022-02-01
CHENGDA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0030] Route 8 uses intermediate 3 to synthesize compound III, which we focus on, but the Grubbs reagent is expensive and expensive, and the source of intermediate 3 is also rare and expensive

Method used

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  • Preparation method of halofuginone intermediate trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone
  • Preparation method of halofuginone intermediate trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone
  • Preparation method of halofuginone intermediate trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of compound IV:

[0072] Compound VIII:DIBAL-H:tetrahydrofuran=1:1.2:56.3.

[0073] (1) In a 20 mL three-necked flask, compound VIII (300 mg, 1.3 mmol) was dissolved in dry tetrahydrofuran (6 mL), the temperature was controlled to -78°C, and DIBAL-H (1 M, 1.54 mL, 1.54 mmol) was slowly added dropwise, and the temperature was kept warm. The reaction was carried out for 1 hour, and the reaction was monitored by TLC until the end of the reaction. Saturated ammonium chloride solution (10 g) was added and stirred to form a white solid layer. The white solid layer was diluted with ethyl acetate, filtered through a pad of celite, the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and used directly for the next reaction.

[0074] Preparation of Intermediate V:

[0075] Compound VI: bromoacetone: potassium carbonate: N,N-dimethylformamide=1:1.2:1.2:23.0.

[0076] (2) In a 2L three-necked flask...

Embodiment 2

[0095] Preparation of compound IV:

[0096] Compound VIII:DIBAL-H:tetrahydrofuran=1:1.2:56.3.

[0097] (1) In a 20 mL three-necked flask, compound VIII (310 mg, 1.3 mmol) was dissolved in dry tetrahydrofuran (6 mL), the temperature was controlled to -40°C, and DIBAL-H (1 M, 1.54 mL, 1.54 mmol) was slowly added dropwise, and the temperature was kept warm. The reaction was carried out for 1.5 hours, and the reaction was monitored by TLC until the end of the reaction. Saturated ammonium chloride solution (10 g) was added and stirred to form a white solid layer. The white solid layer was diluted with ethyl acetate, filtered through a pad of celite, the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and used directly for the next reaction.

[0098] Preparation of Intermediate V:

[0099] Compound VI: bromoacetone: potassium carbonate: tetrahydrofuran=1:1.2:1.2:22.8.

[0100] (2) In a 2L three-necked flask, c...

Embodiment 3

[0111] Preparation of compound IV:

[0112] Compound VIII:DIBAL-H:tetrahydrofuran=1:1.2:56.3.

[0113] (1) In a 20mL three-necked flask, compound VIII (310mg, 1.3mmol) was dissolved in dry tetrahydrofuran (6mL), the temperature was controlled to -30°C, and DIBAL-H (1M, 1.54mL, 1.54mmol) was slowly added dropwise, and the temperature was kept warm. The reaction was carried out for 1.5 hours, and the reaction was monitored by TLC until the end of the reaction. Saturated ammonium chloride solution (10 g) was added and stirred to form a white solid layer. The white solid layer was diluted with ethyl acetate, filtered through a pad of celite, the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, spin-dried, and used directly for the next reaction.

[0114] Preparation of Intermediate V:

[0115] Compound VI: bromoacetone: potassium tert-butoxide: N,N-dimethylformamide=1:1.2:1.2:25.0.

[0116] (2) In a 2L three-necked flask...

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Abstract

The invention relates to the field of drug synthesis, and discloses a preparation method of a halofuginone intermediate trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone. In the preparation method, amino substituted valeraldehyde and a thiazole sulfoxide compound are used as raw materials for the first time, and are subjected to a Misflow-Evans rearrangement reaction; and then the trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone as shown in a formula I is prepared in the specification under the catalysis of lewis acid. According to the preparation method of the halofuginone intermediate trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone, provided by the invention, the yield is relatively high, and the quality is stable. According to the technical scheme, a new route reference is provided for the synthesis of the trans-N-carbobenzoxy-(3-hydroxy-2-piperidyl)-2-acetone, and the reduction of pyridine is avoided, so that the defect that an expensive Rh / Al2O3 metal catalyst needs to be used is overcome.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of halofuginone intermediate trans-N-benzyloxycarbonyl-(3-hydroxy-2-piperidinyl)-2-propanone. Background technique [0002] Halofuginone, also known as halofuginone, is mainly found in plants such as Changshan Mountain and Umbelliferae. Clinical research results show that it has high antimalarial activity. Currently, it is mainly used for coccidiosis and cryptosporidium. Due to its low residue, good insecticidal effect and strong drug resistance, it has become the preferred drug for the treatment of avian coccidiosis. The structure is shown below. [0003] [0004] Through a large number of literature research, the total synthesis of halofuginone needs to complete the construction of a quinazoline fragment and a piperidine ring, and then splicing the two parts to synthesize halofuginone. [0005] Among the many synthetic routes, among the routes of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/42C07C269/06C07C271/18
CPCC07D211/42C07C269/06C07B2200/07C07C271/18Y02A50/30Y02P20/55C07D211/02
Inventor 冯宇许宏吴嘉宣宋丹慧钟为慧凌飞徐超
Owner CHENGDA PHARM CO LTD
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