CN102863341B - Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative - Google Patents

Abstract

The invention relates to a chemical synthesis method of a (1R, 2S)-2-aryl cyclopropylamine derivative. 3-aryl crylic acid serves as a raw material, the raw material and N,O-dimethyl hydroxy amine hydrochloride are subjected reaction to prepare a corresponding amide intermediate, cyclization reaction is conducted, 2- aryl cyclopropylamine is obtained; and finally D-mandelic acid serves as a resolving agent to obtain the (1R, 2S)-2-aryl cyclopropylamine derivative. The method has the advantages of being high in yield and high in e.e. value.

Description

A kind of chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivative

technical field

The invention relates to a chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives. the

Background technique

(1R,2S)-2-Arylcyclopropylamine derivatives are an important class of chiral pharmaceutical intermediates. Many literatures describe their modification in new anticancer drug molecules. Therefore, the synthesis research of this kind of compounds has important practical significance. the

Although (1R,2S)-2-arylcyclopropylamine derivatives have important functions in drug molecules, there are few reports on their synthesis. It has been reported in the literature that (1R,2S)-phenylcyclopropylamine was synthesized by the following route using styrene as a raw material. In general, although this route directly generates a chiral center, its stereoselectivity is not high. the

Contents of the invention

In order to overcome the defect of low stereoselectivity of the existing synthesis method, the present invention provides a chemical synthesis method of (1R,2S)-2-arylcyclopropylamine series derivatives with high e.e. value. the

The chemical reaction formula of the present invention is as follows:

The steps of the chemical synthesis method of (1R,2S) 2-arylcyclopropylamine series derivatives are as follows:

A. Stir and dissolve 3-aryl acrylic acid, N,O-dimethylhydroxylamine hydrochloride and acid-binding agent in an organic solvent, then add a catalyst and react at room temperature to prepare N-methoxy-N-methyl- 3-aryl acrylamide;

B. Take the N-methoxy-N-methyl-3-aryl-acrylamide obtained in the previous step, dissolve it in a strong polar aprotic solvent, and add a strong base and trimethyl iodide under nitrogen protection Sulfone, reacted at room temperature to prepare N-methoxy-N-methyl-2-arylcyclopropylcarboxamide;

C, get the N-methoxyl group-N-methyl-2-aryl cyclopropanecarboxamide obtained in the previous step, be dissolved in a solvent, and be hydrolyzed to obtain 2-aryl cyclopropanecarboxylic acid;

D. Dissolve 2-arylcyclopropanecarboxylic acid in tert-butanol, and under the action of diphenylphosphoryl azide, N-Boc-2-arylcyclopropylmethylamine is prepared, and Boc is freed under acidic conditions Amino reaction gives 2-arylcyclopropylamine;

E. Dissolve 2-arylcyclopropylmethylamine in an alcohol solvent, add D-mandelic acid, and crystallize the product through ethyl acetate to obtain (1R,2S)-2-arylcyclopropylamine.

The chemical synthesis method, in step A, the organic solvent is one of dichloromethane, chloroform, benzene, toluene; the catalyst used is 1-ethyl (3-dimethylaminopropyl) carbodiimide or dicyclohexylcarbodiimide. In step B, the selected strong polar aprotic solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide; the selected base is sodium hydride or potassium hydride. In the hydrolysis reaction of step C, the solvent used is a mixed solvent of water-methanol or water-ethanol. The acid used in the de-Boc free amino reaction in step D is hydrochloric acid or trifluoroacetic acid. The alcohol described in step E is methanol or ethanol. the

The key point of the chemical synthesis method of the present invention is to obtain (1R,2S)-2-arylcyclopropylamine through final chemical resolution. This synthetic approach not only improves the yield of the reaction, but also avoids the risk of racemization in the subsequent reaction of the chiral precursor in the existing method, thereby improving the e.e. value of the product and providing a method for the efficient synthesis of such compounds new way. the

Detailed ways:

In order to deepen the understanding of the present invention, the present invention will be further described below in conjunction with the examples. The following examples are only used to explain the present invention, and do not constitute a limitation to the protection scope of the present invention.

Example 1:

Synthesis of N-methoxy-N-methyl-3-phenylacrylamide: 50.0 g 3-phenylacrylic acid, 30.0 g triethylamine, 31.0 g N-O-dimethylhydroxylamine hydrochloride, 400 ml dichloro Add methane into a 1L reaction flask, stir mechanically for 30 min, then add 60.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at room temperature overnight, wash the dichloromethane phase with water twice, and use Wash with saturated sodium bicarbonate, ammonium chloride, dilute acid and sodium chloride aqueous solution, dry and concentrate to obtain 52.0 g of light yellow N-methoxy-N-methyl-3-phenylacrylamide liquid, with a yield of 80.6%.

Synthesis of 2-phenyl-cyclopropylcarboxylic acid: Add 10.0 g NaH and 250 ml dimethyl sulfoxide into a three-necked flask under nitrogen protection, and add N-methoxy-N-methyl-3-phenylpropene in batches Amide 27.4 g, stirred and dissolved for 30 min, then added dropwise 42.0 g trimethylsulfoxide iodide, and reacted at room temperature. After adding water to quench and extract with methyl tert-butyl ether, the organic phase was washed with water three times, dried and concentrated to obtain 25.0 g of light yellow liquid with a yield of 85.0%. Transfer the yellow product to a single-necked bottle, add 200 ml of methanol and 100 ml of water, stir to dissolve, then add 10.0 g of sodium hydroxide, and stir to react overnight. After the reaction was completed, water was added to adjust the pH to 3-4, extracted with dichloromethane, and concentrated to obtain 17.8 g of white 2-phenyl-cyclopropyl formic acid solid, with a yield of 90.1%. the

Synthesis of N-Boc-2-phenylcyclopropylamine: Add 15.0g 2-phenylcyclopropanecarboxylic acid, 150 ml tert-butanol, and 11.2 g triethylamine into a 300 ml four-necked flask, heat, stir and reflux. Add 26.0 g diphenylphosphoryl azide dropwise, stir at room temperature for 30 min, and then heat to 85 °C overnight. Add water to quench the reaction, extract with methyl tert-butyl ether, wash the organic phase with water 3 times, dry and concentrate the obtained solid to recrystallize with a mixed solution of methyl tert-butyl ether and petroleum ether to obtain 19.5 g of white solid N-Boc -2-phenylcyclopropylamine, yield 90.4%. the

Synthesis of (1R,2S)-2-phenylcyclopropylamine: Add 15.0 g of N-Boc-2-phenylcyclopropylamine, 100 ml of methyl tert-butyl ether, and 30.0 g of hydrochloric acid into a 250 ml four-neck flask in a warm water bath at 40°C. After the reaction, the liquid was separated, and the pH of the aqueous phase was adjusted to 12, then extracted with dichloromethane, concentrated to obtain 8.2 g of light yellow 2-phenylcyclopropylamine liquid, and the yield was 95.7%. Add the light yellow liquid obtained in the previous step, 30ml ethanol, and 7.0 g D-mandelic acid into a 100 ml four-neck flask, keep the temperature at 90°C, and reflux for 3 hours. After the reaction, recrystallization with ethyl acetate gave 3.5 g of (1R,2S)-2-phenylcyclopropylamine as a solid, with a yield of 85.4% and an ee of 99.0%. ¹ HNMR in CDCl ₃ : δ H = 2.17 (qn, 1H), 2.60 (s, 1H), 2.70 (t, 1H), 2.88 (m, 1H), 7.23 (m, 5H).

Example 2:

Synthesis of N-methoxy-N-methyl-3-(4'-methoxyphenyl)acrylamide: 60.0 g 3-(4'-methoxyphenyl)acrylic acid, 33.5 g triethylamine , 32.7 g of N-O-dimethylhydroxylamine hydrochloride, 400 ml of dichloromethane were added to a 1L reaction flask, mechanically stirred for 30 min, and then 62.0 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodisulfide was added Amine hydrochloride at room temperature overnight, washed with dichloromethane phase twice, washed with saturated sodium bicarbonate, ammonium chloride, dilute acid, sodium chloride aqueous solution, dried and concentrated to obtain yellow N-methoxy-N methyl-3 -(4'-methoxyphenyl)acrylamide liquid 55.3 g, the yield is 74.3%.

Synthesis of 2-(4'-methoxyphenyl)-cyclopropanecarboxylic acid: Add 10.0 g NaH and 300 ml dimethyl sulfoxide into a three-necked flask under nitrogen protection, and add N-methoxy-N 31.7 g of methyl-3-(4'-methoxyphenyl)acrylamide was stirred and dissolved for 30 min, then 42.0 g of trimethylsulfoxide iodide was added dropwise, and reacted at room temperature. After adding water to quench, extract with methyl tert-butyl ether, wash with water three times, dry and concentrate to obtain 30.0 g of yellow liquid, yield 89.0%. Transfer the yellow product to a single-necked bottle, add 250 ml of methanol and 125 ml of water, stir to dissolve, then add 10.0 g of sodium hydroxide, and stir to react overnight. After the reaction was completed, water was added to adjust the pH to 3-4, extracted with dichloromethane, and concentrated to obtain 22.3 g of light yellow 2-(4'-methoxyphenyl)cyclopropanecarboxylic acid solid, with a yield of 91.0%. the

Synthesis of N-Boc-2-(4'-methoxyphenyl)cyclopropylamine: 17.8 g 2-(4'-methoxyphenyl)cyclopropanecarboxylic acid, 200 ml tert-butanol, 11.2 g triethyl Amine was added in the 300ml four-neck flask, heated and stirred and refluxed. Add 26.0 g diphenylphosphoryl azide dropwise, stir at room temperature for 30 min, and then heat to 85 °C overnight. Add water to quench the reaction, extract with methyl tert-butyl ether, wash with water three times, dry and concentrate the obtained solid to recrystallize to obtain 21.4 g light yellow solid N-Boc-2-(4'-methoxyphenyl) ring Propylamine, yield 87.8%. the

Synthesis of (1R,2S)-2-(4'-methoxyphenyl)cyclopropylamine: 17.0 g of N-Boc-2-(4'-methoxyphenyl)cyclopropylamine, 125 ml of methyl Tert-butyl ether and 30.0 g of hydrochloric acid were added into a 250 ml four-necked flask, and reacted in a warm water bath at 40 °C. After the reaction, liquid separation was added, and the pH of the aqueous phase was adjusted to 12, then extracted with dichloromethane, concentrated to obtain 9.9 g of light yellow 4'-methoxyphenylcyclopropylamine liquid, and the yield was 94.0%. Add the light yellow liquid obtained in the previous step, 50 ml of ethanol, and 7.5 g of D-mandelic acid into a 100 ml four-necked flask, keep the temperature at 90°C, and reflux for 3 hours. After the reaction, recrystallization with ethyl acetate gave 4.0 g of (1R,2S)-2-(4'-methoxyphenyl)cyclopropylamine as a solid, with a yield of 80.8% and an ee of 98.5%. ¹ HNMR in CDCl ₃ : δ H = 1.18–1.31 (m,1H), 1.32–1.43 (m, 1H), 2.28–2.41 (m, 1H), 2.76 (dt, 1H), 3.75 (s, 3H), 6.82–6.91 (m, 2H), 7.04–7.16 (m, 2H).

Example 3:

Synthesis of N-methoxy-N-methyl-3-(4'-bromophenyl)acrylamide: 75.0 g 3-(4'-bromophenyl)acrylic acid, 33.0 g triethylamine, 32.7 g N-O - Add dimethylhydroxylamine hydrochloride and 400 ml of dichloromethane into a 1L reaction flask, mechanically stir for 30 min, then add 64.0 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride Overnight at room temperature, the dichloromethane phase was washed twice with water, washed with saturated sodium bicarbonate, ammonium chloride, dilute acid, and aqueous sodium chloride solution, dried and concentrated to obtain yellow N-methoxy-N methyl-3-(4' -Bromophenyl) acrylamide liquid 75.4 g, yield is 84.5%.

Synthesis of 2-(4'-bromophenyl)-cyclopropanecarboxylic acid: Add 10.0 g NaH and 350 ml dimethyl sulfoxide into a three-necked flask under nitrogen protection, and add N-methoxy-N methyl - 38.7 g of 3-(4'-bromophenyl)acrylamide, stirred and dissolved for 30 min, then added dropwise 42.0 g of trimethylsulfoxide iodide, and reacted at room temperature. After quenching with water, it was extracted with methyl tert-butyl ether, washed with water three times, dried and concentrated to obtain 32.3 g of yellow liquid with a yield of 79.3%. Transfer the yellow product to a single-necked bottle, add 300 ml of methanol and 150 ml of water, stir to dissolve, then add 10.0 g of sodium hydroxide, and stir to react overnight. After the reaction was completed, adjust the pH to 3-4, extract with dichloromethane, and concentrate to obtain 24.3 g of light yellow 2-(4'-bromophenyl)cyclopropanecarboxylic acid solid, with a yield of 88.6%. the

Synthesis of N-Boc-2-(4'-bromophenyl)cyclopropylamine: 22.3 g 2-(4'-bromophenyl)cyclopropanecarboxylic acid, 250 ml tert-butanol, 11.2 g triethylamine were added to 300 ml four-neck flask, heated and stirred and refluxed. Add 26.0 g diphenylphosphoryl azide dropwise, stir at room temperature for 30 min, and then heat to 85 °C overnight. Add water to quench the reaction, extract with methyl tert-butyl ether, wash with water 3 times, dry and concentrate the obtained solid to recrystallize with a mixed solution of methyl tert-butyl ether and petroleum ether to obtain 26.7 g of white solid N-Boc-2 -(4'-bromophenyl)cyclopropylamine, yield 92.5%. the

Synthesis of (1R,2S)-2-(4'-bromophenyl)cyclopropylamine: 20.0 g of N-Boc-2-(4'-bromophenyl)cyclopropylamine, 200 ml of methyl tert-butyl ether 1. Add 30.0 g of hydrochloric acid into a 500 ml four-neck flask, and react in a warm water bath at 40 °C. After the reaction, MTBE was added to separate the liquid, and the pH of the aqueous phase was adjusted to 12, then extracted with dichloromethane, and concentrated to obtain 12.7 g of light yellow 2-(4'-bromophenyl)cyclopropylamine with a yield of 93.5%. Add the light yellow liquid obtained in the previous step, 70 ml of ethanol, and 7.5 g of D-mandelic acid into a 100 ml four-neck flask, keep the temperature at 90°C, and reflux for 3 hours. After the reaction, recrystallization with EA gave 5.6 g of (1R,2S)-2-(4'-bromophenyl)cyclopropylamine as a solid, with a yield of 88.2% and an ee of 98.5%. ¹ HNMR in CDCl ₃ : δ H = 1.39 (m, 1H), 1.49 (ddd, 1H), 2.42 (ddd, 1H), 2.90 (dt, 1H), 7.16 (d, 2H), 7.51 (d, 2H) .

The key point of the chemical synthesis method of the present invention is to obtain (1R,2S)-2-arylcyclopropylamine through final chemical resolution. This synthetic approach not only improves the yield of the reaction, but also avoids the risk of racemization in the subsequent reaction of the chiral precursor in the existing method, thereby improving the e.e. value of the product and providing a method for the efficient synthesis of such compounds new way. the

Claims (8)

1. A chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives, characterized in that: the chemical reaction formula is as follows:

, the resulting (1R,2S)-2-arylcyclopropylamine series derivatives

, wherein R is independently selected from: hydrogen, C _1-6 alkyl, C _1-6 alkoxy, X is independently selected from: F, Cl, Br, I; The chemical synthesis method of the (1R,2S)-2-arylcyclopropylamine series derivatives is as follows: A. Stir and dissolve 3-aryl acrylic acid, N,O-dimethylhydroxylamine hydrochloride and acid-binding agent in an organic solvent, then add a catalyst and react at room temperature to prepare N-methoxy-N-methyl- 3-aryl acrylamide; B. Take the N-methoxy-N-methyl-3-aryl-acrylamide obtained in the previous step, dissolve it in a strong polar aprotic solvent, and add a strong base and trimethyl iodide under nitrogen protection Sulfone, reacted at room temperature to prepare N-methoxy-N-methyl-2-arylcyclopropylcarboxamide; C, get the N-methoxyl group-N-methyl-2-aryl cyclopropanecarboxamide obtained in the previous step, be dissolved in a solvent, and be hydrolyzed to obtain 2-aryl cyclopropanecarboxylic acid; D. Dissolve 2-arylcyclopropanecarboxylic acid in tert-butanol, and under the action of diphenylphosphoryl azide, N-Boc-2-arylcyclopropylmethylamine is prepared, and Boc is freed under acidic conditions Amino reaction gives 2-arylcyclopropylamine; E. Dissolve 2-arylcyclopropylmethylamine in an alcohol solvent, add D-mandelic acid, and crystallize the product through ethyl acetate to obtain (1R,2S)-2-arylcyclopropylamine. 2. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives according to claim 1, characterized in that: in step A, the organic solvent is dichloromethane, chloroform, One of benzene and toluene. 3. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives described in claim 1, characterized in that: in step A, the catalyst used is 1-ethyl (3-dimethyl aminopropyl) carbodiimide or dicyclohexylcarbodiimide. 4. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives described in claim 1, characterized in that: in step B, the selected strong polar aprotic solvent is N,N- One of dimethylformamide, N,N-dimethylacetamide, and dimethylsulfoxide. 5. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives as claimed in claim 1, characterized in that: the base selected in the reaction of step B is sodium hydride or potassium hydride. 6. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives described in claim 1, characterized in that: in the hydrolysis reaction of step C, the solvent used is water-methanol or water- mixed solvents of ethanol. 7. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives described in claim 1, characterized in that: the acid used in the de-Boc free amino reaction in step D is hydrochloric acid or tris Fluoroacetic acid. 8. The chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives described in claim 1, characterized in that: the alcohol described in step E is methanol or ethanol.