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Synthetic method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyrylamide with high optical purity

A technology of tetrahydroisoquinoline tert-butyramide and optical purity, applied in the direction of organic chemistry and the like, can solve the problems of low total yield, long reaction steps and high production cost, and achieve the effects of low raw material cost and mild reaction conditions

Active Publication Date: 2010-06-23
苏州正济药业有限公司
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Problems solved by technology

[0006] Among the above three methods, the route of method (1) is relatively simple, but phosgene is used in it, which is a highly dangerous chemical and has great limitations in use.
Method (2) has many reaction steps and is comparatively complicated, and the overall yield is relatively low
Method (3) has two-step hydrogenation, high production cost, and relatively long reaction steps

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  • Synthetic method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyrylamide with high optical purity
  • Synthetic method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyrylamide with high optical purity

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[0021] Such as figure 1 Shown, the synthetic method of high optical purity (S)-1,2,3,4-tetrahydroisoquinoline tert-butyramide, with (S)-1,2,3,4-tetrahydroisoquinoline carboxylic acid As a raw material, dimethyl carbonate is used to synthesize (S)-N-methyl formate-1,2,3,4-tetrahydroisoquinoline carboxylate methyl ester, and to obtain ureide by aminolysis, removal of ureido group, alkalization, Obtain (S)--1,2,3,4-tetrahydroisoquinoline tert-butyramide, specifically comprising the following steps:

[0022] ①Quinoline carboxylic acid compound (2) is reacted with dimethyl carbonate to prepare compound (3) of N-methyl formate; the catalyst is a halogenated salt, the solvent is dimethyl carbonate, and the reaction temperature is 0°C to 95°C;

[0023] ② Compound (3) is subjected to aminolysis with tert-butylamine to prepare compound (4); the solvent is an inert solvent of aromatic hydrocarbon or halogenated alkanes, and the reaction temperature is 20°C to 160°C;

[0024] ③The compo...

Embodiment 1

[0030] Step 1 Put 38.4 g of S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 2), 200 ml of dimethyl carbonate, and 23 g of anhydrous CaCl into a reaction flask. The reaction was stirred at room temperature for 30 minutes, and the temperature was raised to reflux for 2 hours. After the reaction was completed, dimethyl carbonate was concentrated under reduced pressure, and about 50ml remained, and 50ml of water was slowly added dropwise, cooled to 0°C, stirred for 30 minutes, filtered with suction to obtain a light yellow solid, and dried to obtain about S-N-methyl formate-1,2, 45 g of methyl 3,4-tetrahydroisoquinoline-3-carboxylate (compound 3). HPLC purity: 99.0%, yield: 85%.

[0031] Step 2 Add 26.4g of S-N-methyl formate-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (compound 3), 300ml of toluene, and 20g of tert-butylamine into a 1000ml autoclave, and replace with nitrogen Air in the kettle. Stir and heat up to 100°C, and react for 18 hours. Cool to room temp...

Embodiment 2

[0035] Step 1 Put 38.4 g of S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 2), 200 ml of dimethyl carbonate, and 3.2 g of MgCl2 into a reaction flask. The reaction was stirred at room temperature for 30 minutes, and the temperature was raised to reflux for 10 hours. After the reaction was completed, dimethyl carbonate was concentrated under reduced pressure, and about 50ml remained, and 50ml of water was slowly added dropwise, cooled to 0°C, stirred for 30 minutes, filtered with suction to obtain a light yellow solid, and dried to obtain about S-N-methyl formate-1,2, 48 g of methyl 3,4-tetrahydroisoquinoline-3-carboxylate (compound 3). HPLC purity: 98.7%, yield: 90%.

[0036] Step 2 Add 26.4g of S-N-methyl formate-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (compound 3), 200ml of dichloroethane, and 20g of tert-butylamine into a 1000ml autoclave , Nitrogen replaced the air in the kettle. Stir and heat up to 80°C, and react for 10 hours. Cool to room temperat...

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Abstract

The invention relates to a synthetic method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyrylamide with high optical purity, comprising the following steps: 1. allowing a quinoline carboxylic acid compound (2) to react with dimethyl carbonate at the temperature of 0-95 DEG C to prepare a N-methyl formate compound (3), wherein, halogeno salt is taken as a catalyst and dimethyl carbonate is taken as solvent; 2. performing aminolysis to the compound (3) by tert-butylamine at the temperature of 20-160 DEG C to prepare a compound (4), wherein, arene or halogenated hydrocarbon inert solvent is adopted; 3. carrying out decarboxylation reaction to the compound (4) by halogenated acid at the temperature of -50-80 DEG C to prepare an amide compound (5), wherein, the mixed solvent of arene or halogenated hydrocarbon and water is adopted; and 4. mixing alkali with sodium hydroxide, extracting, concentrating and crystallizing to obtain a target product. An environmental-friendly and clean raw material of dimethyl carbonate is adopted, highly toxic raw materials such as phosgene and the like are not used so as to avoid reaction with certain danger in case of low temperature, ultralow temperature, hydrogenation and the like. The synthetic method has low raw material cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of (S)-1,2,3,4-tetrahydroisoquinoline tert-butyramide with high optical purity. Background technique [0002] (S)-1,2,3,4-Tetrahydroisoquinoline tert-butyramide is a key intermediate in the synthesis of anti-AIDS drug nelfinavir. Currently reported synthesis methods mainly include the following three categories: [0003] (1) Using (S)-1,2,3,4-tetrahydroisoquinolinecarboxylic acid as raw material, adopting phosgene or diphosgene to prepare internal acid anhydride, and then acylation with tert-butylamine to obtain the target compound (see patent us6433177, 6340760, 5587481). [0004] (2) Using phenylalanine as a raw material, using benzyl chloroformate to protect the amino group to obtain a compound, and then using tert-butyl chloroformate to make an active ester, and performing amination to obtain a compound, which is cyclized to form N-benzyloxycarbonyl 1 , 2,3,4-Tetrahydroisoquinoline tert-butyramide (com...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/08
Inventor 吴朝阳蒋勇
Owner 苏州正济药业有限公司
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