CN108912032A - It is a kind of（3S, 4R）The chemical synthesis process of -4- methylpyrrolidin- 3- base amino methanol t-butyl ester hydrochloride - Google Patents

Abstract

The present invention relates to a kind of chemical synthesis method of (3S, 4R)-4-methylpyrrolidin-3-ylcarbamate tert-butyl ester hydrochloride, comprising adding (E)-but-2-dienic acid ethyl ester into two In the methyl chloride solvent, add N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine again, cool down, add the dichloromethane solution of trifluoroacetic acid dropwise, Reaction at room temperature, after the reaction is complete, (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-ethyl formate is obtained; (3S, 4S)-1-benzyl-4-methylpyrrolidine Add ‑3‑ethyl formate to the hydrogenation bottle, add ethanol to dissolve, add concentrated hydrochloric acid and catalyst, hydrogenation reaction at room temperature, and obtain (3S, 4S‑4‑methylpyrrolidine‑3‑carboxylate ethyl ester salt Acid salt etc. totally seven steps. The present invention uses (E)-buta-2-dilute ethyl ester and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl ) methylamine as a raw material provides an efficient method for the synthesis of this compound.

Description

A kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride chemical synthesis method

technical field

The invention relates to (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride and a chemical synthesis method thereof.

Background technique

Pyrrolidine derivatives are an important class of nitrogen heterocyclic compounds, which widely exist in the whole nature and often have important physiological and pharmacological activities. For example, pyrrolidine derivatives are important pharmaceutical intermediates and can be used in the synthesis of many drugs. In addition, as an intermediate of fine chemical products, pyrrolidine is widely used in the fields of catalysts, medicines, pesticides, etc. Therefore, the synthesis of pyrrolidine derivatives is of great significance.

(3S,4R)-4-Methylpyrrolidin-3-ylaminomethanol tert-butyl hydrochloride is an important pharmaceutical intermediate, so the synthesis of this compound has important practical significance.

Contents of the invention

The object of the present invention is to provide a highly efficient chemical synthesis method of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride.

Technical scheme of the present invention is as follows:

2. A chemical synthesis method of (3S, 4R)-4-methylpyrrolidin-3-ylaminocarbinol tert-butyl ester hydrochloride, characterized in that, from (E)-butan-2-enzylic acid ethyl ester Starting from N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine as raw material, (3S,4R)-4-methylpyrrole is obtained through seven-step reaction Alkyl-3-ylaminomethanol tert-butyl ester hydrochloride, its synthetic route is as follows:

Described chemical synthesis method is:

(A) Dissolve (E)-butan-2-enzylic acid ethyl ester in dichloromethane solvent, then add N-(methoxymethyl)(phenyl)-N-((trimethylsilyl) Methyl) methylamine, lower the temperature to below 10°C, add trifluoroacetic acid dichloromethane solution dropwise, prevent material flushing during the dropwise addition, rise to room temperature after the dropwise addition, react at room temperature, and get (3S, 4S) after the reaction is completed - ethyl 1-benzyl-4-methylpyrrolidine-3-carboxylate;

(B) Add ethyl (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylate into the hydrogenation bottle, add ethanol to dissolve, add hydrochloric acid, and add palladium hydroxide carbon catalyst under nitrogen protection , hydrogenation reaction at room temperature, the reaction ends to obtain (3S, 4S-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride;

(C) Dissolve (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester) hydrochloride in water, control the temperature at 10°C, add potassium carbonate, methyl tert-butyl ether and chloroformic acid Benzyl ester, the temperature is raised to room temperature, and the reaction ends to obtain ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate;

(D) Dissolve ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate in potassium dihydrogen phosphate, add enzyme and methyl tert-butyl ester, control the temperature, and get (3S, 4S)- 1-Benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester;

(E) Dissolve ethyl (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate in tetrahydrofuran solution, add lithium hydroxide aqueous solution, control the temperature, and obtain (3S, 4S) at the end of the reaction -1-Benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid;

(F) Dissolve (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid in tert-butanol solution, add triethylamine, drop diphenylphosphoryl azide, drop After the addition, stir at room temperature for 0.5 h, raise the temperature, and control the reaction temperature. After the reaction is completed, (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester is obtained;

(G) Add (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester into a hydrogenation bottle, dissolve it with methanol, add a catalyst under nitrogen protection, and hydrogenate, The reaction temperature is controlled, and after the reaction is completed, (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride is obtained.

Further, the reaction temperature in the step (A) is 10-30°C.

Further, the concentration of hydrochloric acid used in the step (B) is 37% by volume.

Further, the reaction in the step (C) is controlled in a reflux state.

Further, the pH of the reaction in the step (D) is controlled at about 7.

Further, the reaction in the step (E) is controlled in a reflux state.

Further, when diphenyl phosphoric azide is added dropwise in the step (F), the reaction temperature is below 20°C, and the reaction temperature is 95°C.

Further, the reaction in the step (G) is controlled in a reflux state.

The beneficial effect of the present invention is: chemical synthesis method of the present invention, with (E)-butan-2-enenoic acid ethyl ester and N-(methoxymethyl)(phenyl)-N-((trimethylsilane (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride was synthesized through seven steps of reaction. Compared with the prior art, the synthesis method of the invention improves the yield and provides an efficient synthesis method for the synthesis of the compound.

Detailed ways

The specific implementation mode below will describe in detail the specific implementation of the present invention. These specific implementation methods are only for description and are not used to limit the scope or implementation principle of the present invention. The protection scope of the present invention shall be determined by the claims, including obvious changes or changes made on this basis.

Example 1

(A) Synthesis of (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester:

In a 5L four-necked flask, 425g (E)-butan-2-enzylic acid ethyl ester was dissolved in 1.5L of dichloromethane, and under mechanical stirring, 209.7g N-(methoxymethyl)(phenyl) was added -N-((trimethylsilyl)methyl)methylamine, after cooling down to below 10°C with an ice-salt bath, slowly add trifluoroacetic acid in dichloromethane solution dropwise, and prevent material flushing during the dropwise addition. After the dropwise addition, it was naturally raised to room temperature. Liquid chromatographic analysis of raw material reaction is complete, add 1L dichloromethane to the system, wash with saturated sodium bicarbonate, dry and concentrate, and distill under reduced pressure to obtain (3S, 4S)-1-benzyl-4-methylpyrrolidine - 910 g of ethyl 3-carboxylate, a colorless liquid, with a yield of 93%.

(B) Synthesis of (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride:

Add 130g (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester into 1L hydrogenation bottle and dissolve in 500mL ethanol, under magnetic stirring, add concentrated hydrochloric acid 44mL, under nitrogen protection , magnetic stirring, adding palladium hydroxide carbon catalyst 10g, hydrogenation at room temperature. Thin-layer chromatography analyzed that the reaction of raw materials was complete, the added catalyst was filtered, and the filtrate was spin-dried to obtain 714 g of oily (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride, with a yield of 100%.

(C) Synthesis of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate:

Add 714g (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride to a 5L reaction flask and dissolve it in 3L of water. Under mechanical stirring, use an ice-salt bath to cool down to 10°C, add 1001g potassium carbonate, add methyl tert-butyl ether, after controlling the temperature below 10°C, add benzyl chloroformate dropwise, after the dropwise addition, rise to room temperature to react overnight. According to thin-layer chromatography, the reaction of the raw materials was complete, and the liquid was separated to obtain the aqueous phase. The aqueous phase was extracted with methyl tert-butyl ether (2×2L), the organic phase was washed with dilute hydrochloric acid, and then washed with saturated brine, and dried over anhydrous sodium sulfate. , suction filtration under reduced pressure, rotary evaporation, petroleum ether: ethyl acetate = 6:1 as eluent column chromatography, to obtain 822g of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate, yield 76.5 %.

(D) Synthesis of (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester:

Add 822g of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate into 5L of 0.5mol/L potassium dihydrogen phosphate (PH=7) in a 10L four-necked bottle, and add the enzyme under mechanical stirring React with methyl tert-butyl ether for 15D at room temperature, and the measured content of the target product is 85%. Filter to remove the enzyme, adjust the reaction solution to PH=9-10 with potassium carbonate, separate the layers, extract the aqueous phase with methyl tert-butyl ether (2×3L), dry the organic phase, filter under reduced pressure, and spin dry to obtain 499 g of ethyl (3S,4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate, yield 60.7%.

(E) Synthesis of (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid:

Add 499g (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester into 5L four-neck flask and dissolve in 2L tetrahydrofuran, under mechanical stirring, add lithium hydroxide aqueous solution, room temperature Leave to react overnight. Thin-layer chromatography analysis of raw material reaction is complete, concentrated to remove tetrahydrofuran, add 1L of water, the aqueous phase was washed with ethyl acetate (2 × 1.5L), the pH of the aqueous phase was adjusted to 1-2 with hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (2×1.5 L), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and rotary evaporated to obtain 239g (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine- 3-Carboxylic acid, the yield was 53%, and the content of the target product was 83%.

(F) Synthesis of (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester:

In a 5L DE four-necked bottle, add 239g (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid and dissolve in 2.5L tert-butanol, under mechanical stirring, add triethylamine, and The temperature of the reaction system was controlled below 20°C, and diphenylphosphoryl azide was added dropwise. After the dropwise addition, it was stirred at room temperature for 0.5h, and the temperature was raised to 95°C for overnight reaction. According to thin-layer chromatography, the reaction of the raw materials was complete, concentrated tert-butanol, added 2L of ethyl acetate, washed once with water, washed once with saturated aqueous sodium bicarbonate solution, concentrated, petroleum ether: ethyl acetate = 3:1 column chromatography, obtained The product was beaten with 2L petroleum ether:ethyl acetate=3:1 to obtain 144g crude product, which was recrystallized twice with 1.25L petroleum ether to obtain 88g (3S,4R)-3-tert-butoxycarbonyl-4 -Benzyl methylpyrrolidine-1-carboxylate, yield 29%.

(G) Synthesis of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride:

Add 88g (3S,4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylate benzyl ester in 1L hydrogenation bottle, dissolve in 500ml methanol solution, stir magnetically, under nitrogen protection, add 5% wet palladium on carbon, hydrogenation at room temperature overnight after addition. Thin-layer chromatography analyzed that the reaction was complete, filtered, the filtrate was spin-dried, added 1.5 L of methyl tert-butyl ether, and the temperature was lowered to 0°C using an ice-salt bath, and diethyl ether hydrochloride was added dropwise to control pH = 7, stirred for 1 h, filtered, The filter cake was dried to obtain 46 g of (3S,4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride with a yield of 73.8%.

Example 2

(A) Synthesis of (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester:

In a 5L four-necked flask, 425g (E)-butan-2-enzylic acid ethyl ester was dissolved in 1.5L of dichloromethane, and under mechanical stirring, 209.7g N-(methoxymethyl)(phenyl) was added -N-((trimethylsilyl)methyl)methylamine, after cooling down to below 10°C with an ice-salt bath, slowly add trifluoroacetic acid in dichloromethane solution dropwise, and prevent material flushing during the dropwise addition. After the dropwise addition, it was naturally raised to room temperature. Liquid chromatographic analysis of raw material reaction is complete, add 1L dichloromethane to the system, wash with saturated sodium bicarbonate, dry and concentrate, and distill under reduced pressure to obtain (3S, 4S)-1-benzyl-4-methylpyrrolidine - 910 g of ethyl 3-carboxylate, a colorless liquid, with a yield of 93%.

(B) Synthesis of (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride:

Add 130g (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester into 1L hydrogenation bottle and dissolve in 500mL ethanol, under magnetic stirring, add concentrated hydrochloric acid 44mL, under nitrogen protection , magnetic stirring, adding palladium hydroxide carbon catalyst 10g, hydrogenation at room temperature. Thin-layer chromatography analyzed that the reaction of raw materials was complete, the added catalyst was filtered, and the filtrate was spin-dried to obtain 714 g of oily (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride, with a yield of 100%.

(C) Synthesis of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate:

Add 714g (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride to a 5L reaction flask and dissolve it in 3L of water. Under mechanical stirring, use an ice-salt bath to cool down to 10°C, add 1001g potassium carbonate, add methyl tert-butyl ether, after controlling the temperature below 10°C, add benzyl chloroformate dropwise, after the dropwise addition, rise to room temperature to react overnight. According to thin-layer chromatography, the reaction of the raw materials was complete, and the liquid was separated to obtain the aqueous phase. The aqueous phase was extracted with methyl tert-butyl ether (2×2L), the organic phase was washed with dilute hydrochloric acid, and then washed with saturated brine, and dried over anhydrous sodium sulfate. , suction filtration under reduced pressure, rotary evaporation, petroleum ether: ethyl acetate = 6:1 as eluent column chromatography, to obtain 822g of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate, yield 76.5 %.

(D) Synthesis of (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester:

Add 822g of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate into 5L of 0.5mol/L potassium dihydrogen phosphate (PH=7) in a 10L four-necked bottle, and add the enzyme under mechanical stirring React with methyl tert-butyl ether for 15D at room temperature, and the measured content of the target product is 85%. Filter to remove the enzyme, adjust the reaction solution to PH=9-10 with potassium carbonate, separate the layers, extract the aqueous phase with methyl tert-butyl ether (2×3L), dry the organic phase, filter under reduced pressure, and spin dry to obtain 499 g of ethyl (3S,4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate, yield 60.7%.

(E) Synthesis of (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid:

Add 499g (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester into 5L four-neck flask and dissolve in 2L tetrahydrofuran, under mechanical stirring, add lithium hydroxide aqueous solution, room temperature Leave to react overnight. Thin-layer chromatography analysis of raw material reaction is complete, concentrated to remove tetrahydrofuran, add 1L of water, the aqueous phase was washed with ethyl acetate (2 × 1.5L), the pH of the aqueous phase was adjusted to 1-2 with hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (2×1.5 L), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and rotary evaporated to obtain 239g (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine- 3-Carboxylic acid, the yield was 53%, and the content of the target product was 83%.

(F) Synthesis of (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester:

In a 5L DE four-necked bottle, add 239g (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid and dissolve in 2.5L tert-butanol, under mechanical stirring, add triethylamine, and The temperature of the reaction system was controlled below 20°C, and diphenylphosphoryl azide was added dropwise. After the dropwise addition, it was stirred at room temperature for 0.5h, and the temperature was raised to 95°C for overnight reaction. According to thin-layer chromatography, the reaction of the raw materials was complete, concentrated tert-butanol, added 2L of ethyl acetate, washed once with water, washed once with saturated aqueous sodium bicarbonate solution, concentrated, petroleum ether: ethyl acetate = 3:1 column chromatography, obtained The product was beaten with 2L petroleum ether:ethyl acetate=3:1 to obtain 144g crude product, which was recrystallized twice with 1.25L petroleum ether to obtain 88g (3S,4R)-3-tert-butoxycarbonyl-4 -Benzyl methylpyrrolidine-1-carboxylate, yield 29%.

(G) Synthesis of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride:

Add 88g (3S,4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylate benzyl ester in 1L hydrogenation bottle, dissolve in 500ml methanol solution, stir magnetically, under nitrogen protection, add 5% wet palladium on carbon, hydrogenation at room temperature overnight after addition. Thin-layer chromatography analyzed that the reaction was complete, filtered, the filtrate was spin-dried, added 1.5L of methyl tert-butyl ether, and the temperature was lowered to 0°C using an ice-salt bath, then diethyl ether hydrochloride was added dropwise, and the pH was controlled to be 8, stirred for 1 h, and filtered. The filter cake was dried to obtain 42 g of (3S,4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride with a yield of 67.4%.

Example 3

(A) Synthesis of (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester:

In a 5L four-necked flask, 425g (E)-butan-2-enzylic acid ethyl ester was dissolved in 1.5L of dichloromethane, and under mechanical stirring, 209.7g N-(methoxymethyl)(phenyl) was added -N-((trimethylsilyl)methyl)methylamine, after cooling down to below 10°C with an ice-salt bath, slowly add trifluoroacetic acid in dichloromethane solution dropwise, and prevent material flushing during the dropwise addition. After the dropwise addition, it was naturally raised to room temperature. Liquid chromatographic analysis of raw material reaction is complete, add 1L dichloromethane to the system, wash with saturated sodium bicarbonate, dry and concentrate, and distill under reduced pressure to obtain (3S, 4S)-1-benzyl-4-methylpyrrolidine - 910 g of ethyl 3-carboxylate, a colorless liquid, with a yield of 93%.

(B) Synthesis of (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride:

Add 130g (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylic acid ethyl ester into 1L hydrogenation bottle and dissolve in 500mL ethanol, under magnetic stirring, add concentrated hydrochloric acid 44mL, under nitrogen protection , magnetic stirring, adding palladium hydroxide carbon catalyst 10g, hydrogenation at room temperature. Thin-layer chromatography analyzed that the reaction of raw materials was complete, the added catalyst was filtered, and the filtrate was spin-dried to obtain 714 g of oily (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride, with a yield of 100%.

(C) Synthesis of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate:

Add 714g (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride to a 5L reaction flask and dissolve it in 3L of water. Under mechanical stirring, use an ice-salt bath to cool down to 10°C, add 1001g potassium carbonate, add methyl tert-butyl ether, after controlling the temperature below 10°C, add benzyl chloroformate dropwise, after the dropwise addition, rise to room temperature to react overnight. According to thin-layer chromatography, the reaction of the raw materials was complete, and the liquid was separated to obtain the aqueous phase. The aqueous phase was extracted with methyl tert-butyl ether (2×2L), the organic phase was washed with dilute hydrochloric acid, and then washed with saturated brine, and dried over anhydrous sodium sulfate. , suction filtration under reduced pressure, rotary evaporation, petroleum ether: ethyl acetate = 6:1 as eluent column chromatography, to obtain 822g of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate, yield 76.5 %.

(D) Synthesis of (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester:

Add 822g of ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate into 5L of 0.5mol/L potassium dihydrogen phosphate (PH=7) in a 10L four-necked bottle, and add the enzyme under mechanical stirring React with methyl tert-butyl ether for 15D at room temperature, and the measured content of the target product is 85%. Filter to remove the enzyme, adjust the reaction solution to PH=9-10 with potassium carbonate, separate the layers, extract the aqueous phase with methyl tert-butyl ether (2×3L), dry the organic phase, filter under reduced pressure, and spin dry to obtain 499 g of ethyl (3S,4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate, yield 60.7%.

(E) Synthesis of (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid:

Add 499g (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester into 5L four-neck flask and dissolve in 2L tetrahydrofuran, under mechanical stirring, add lithium hydroxide aqueous solution, room temperature Leave to react overnight. Thin-layer chromatography analysis of raw material reaction is complete, concentrated to remove tetrahydrofuran, add 1L of water, the aqueous phase was washed with ethyl acetate (2 × 1.5L), the pH of the aqueous phase was adjusted to 1-2 with hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (2×1.5 L), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and rotary evaporated to obtain 239g (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine- 3-Carboxylic acid, the yield was 53%, and the content of the target product was 83%.

(F) Synthesis of (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester:

In a 5L DE four-necked bottle, add 239g (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid and dissolve in 2.5L tert-butanol, under mechanical stirring, add triethylamine, and The temperature of the reaction system was controlled below 20°C, and diphenylphosphoryl azide was added dropwise. After the dropwise addition, it was stirred at room temperature for 0.5h, and the temperature was raised to 95°C for overnight reaction. According to thin-layer chromatography, the reaction of the raw materials was complete, concentrated tert-butanol, added 2L of ethyl acetate, washed once with water, washed once with saturated aqueous sodium bicarbonate solution, concentrated, petroleum ether: ethyl acetate = 3:1 column chromatography, obtained The product was beaten with 2L petroleum ether:ethyl acetate=3:1 to obtain 144g crude product, which was recrystallized twice with 1.25L petroleum ether to obtain 88g (3S,4R)-3-tert-butoxycarbonyl-4 -Benzyl methylpyrrolidine-1-carboxylate, yield 29%.

(G) Synthesis of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride:

Add 88g (3S,4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylate benzyl ester in 1L hydrogenation bottle, dissolve in 500ml methanol solution, stir magnetically, under nitrogen protection, add 5% wet palladium on carbon, hydrogenation at room temperature overnight after addition. Thin-layer chromatography analyzed that the reaction was complete, filtered, the filtrate was spin-dried, added 1.5 L of methyl tert-butyl ether, and the temperature was lowered to 0°C using an ice-salt bath, and diethyl ether hydrochloride was added dropwise to control the pH = 9, stirred for 1 h, and filtered. The filter cake was dried to obtain 39 g of (3S,4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride with a yield of 62.6%.

Claims (8)

1. A chemical synthesis method of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride, characterized in that, from (E)-butan-2-enzylic acid ethyl ester And N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine as starting material, get (3S,4R)-4-methylpyrrole through seven-step reaction Alkane-3-ylaminomethanol tert-butyl ester hydrochloride, its synthetic route is as follows: Described chemical synthesis method is: (A) Dissolve (E)-butan-2-enzylic acid ethyl ester in dichloromethane solvent, then add N-(methoxymethyl)(phenyl)-N-((trimethylsilyl) Methyl) methylamine, lower the temperature to below 10°C, add trifluoroacetic acid dichloromethane solution dropwise, prevent material flushing during the dropwise addition, rise to room temperature after the dropwise addition, react at room temperature, and get (3S, 4S) after the reaction is completed - ethyl 1-benzyl-4-methylpyrrolidine-3-carboxylate; (B) Add ethyl (3S, 4S)-1-benzyl-4-methylpyrrolidine-3-carboxylate into the hydrogenation bottle, add ethanol to dissolve, add hydrochloric acid, and add palladium hydroxide carbon catalyst under nitrogen protection , hydrogenation reaction at room temperature, the reaction ends to obtain (3S, 4S-4-methylpyrrolidine-3-carboxylic acid ethyl ester hydrochloride; (C) Dissolve (3S, 4S)-4-methylpyrrolidine-3-carboxylic acid ethyl ester) hydrochloride in water, control the temperature at 10°C, add potassium carbonate, methyl tert-butyl ether and chloroformic acid Benzyl ester, the temperature is raised to room temperature, and the reaction ends to obtain ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate; (D) Dissolve ethyl 1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate in potassium dihydrogen phosphate, add enzyme and methyl tert-butyl ester, control the temperature, and get (3S, 4S)- 1-Benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylic acid ethyl ester; (E) Dissolve ethyl (3S, 4S)-1-benzyloxycarbonyl-4-methyl-3-pyrrolecarboxylate in tetrahydrofuran solution, add lithium hydroxide aqueous solution, control the temperature, and obtain (3S, 4S) at the end of the reaction -1-Benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid; (F) Dissolve (3S, 4S)-1-benzyloxycarbonyl-4-methylpyrrolidine-3-carboxylic acid in tert-butanol solution, add triethylamine, drop diphenylphosphoryl azide, drop After the addition, stir at room temperature for 0.5 h, raise the temperature, and control the reaction temperature. After the reaction is completed, (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester is obtained; (G) Add (3S, 4R)-3-tert-butoxycarbonyl-4-methylpyrrolidine-1-carboxylic acid benzyl ester into a hydrogenation bottle, dissolve it with methanol, add a catalyst under nitrogen protection, and hydrogenate, The reaction temperature is controlled, and the reaction is completed to obtain (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride. 2. the chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step A, The reaction temperature is 10-30°C. 3. The chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step B, The concentration of hydrochloric acid used is 37% by volume. 4. The chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step C, The reaction was controlled at reflux. 5. The chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step D, The pH of the reaction was 7. 6. The chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step E, The reaction was controlled at reflux. 7. The chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step F, When diphenyl phosphoric azide is added dropwise, the reaction temperature is below 20°C, and the reaction temperature is 95°C. 8. The chemical synthesis method of a kind of (3S, 4R)-4-methylpyrrolidin-3-ylaminomethanol tert-butyl ester hydrochloride according to claim 1, characterized in that: in the step G, The reaction was controlled at reflux.