CN1298702C

CN1298702C - Process for preparing (s)-1-allyl-2-amidomethyl tetrahydropyrrole

Info

Publication number: CN1298702C
Application number: CNB2005100384680A
Authority: CN
Inventors: 杨敏; 徐宇平; 潘栋辉; 曹国宪; 项景德
Original assignee: Jiangsu Institute of Nuclear Medicine
Current assignee: Jiangsu Institute of Nuclear Medicine
Priority date: 2005-03-15
Filing date: 2005-03-15
Publication date: 2007-02-07
Anticipated expiration: 2025-03-15
Also published as: CN1683335A

Abstract

A preparation method of (s)-1-allyl-2-aminomethyl tetrahydropyrrole relates to the technical field of organic synthesis of pharmaceutical intermediates. The invention discloses a preparation method of a pharmaceutical intermediate (s)-1-allyl-2-aminomethyltetrahydropyrrole. The structural formula of the pharmaceutical intermediate is: the preparation method comprises allyl Alkylation reaction, reduction reaction of the amide structure in the allylation product. The product prepared by the invention is widely used as an intermediate of dopamine D2 receptor PET imaging agent ¹⁸ F-fallypride and other drugs for treating mental diseases; the invention has simple preparation process, easy operation, little pollution, safe production and high yield.

Description

The preparation method of a kind of (s)-1-allyl group-2-amine methyl Pyrrolidine

Technical field

The present invention relates to a kind of d2 dopamine receptor PET developer ¹⁸The preparation method of the intermediate of F-fallypride and other mental disorder medicines (s)-1-allyl group-2-amine methyl Pyrrolidine.Relate to the pharmaceutical intermediate technical field of organic synthesis.

Background technology

Along with China's economy and social development, industrialization, urbanization, aging population process are accelerated, and spirit and behavioral problem have become important public health problem of China and comparatively outstanding social concern.Known have multiple neural psychotic disorder all relevant with expression with the function of DA acceptor, these diseases mainly contain motion sickness (as Parkinson's disease, Parkinsonism, huntington's chorea, carrying out property coker paralysis, multiple system atrophy and Wilson ' s disease), schizophrenia and emotionally disturbed, and some specific neuroendocrine disorders.Cerebral receptor imaging is the unique inspection method of nuclear medicine, utilizes single photon tomography (SPECT) and positron emission tomography (PET) (PET), understands the quantity and the changing function of these morbid states DA acceptor, will help the diagnosis and differential diagnosis of these diseases.

¹⁸F-fallypride is a kind of well behaved novel d2 dopamine receptor PET developer.Its synthetic route is as follows:

By said synthesis route as seen, (s)-1-allyl group-2-amine methyl Pyrrolidine is the novel d2 dopamine receptor developer of preparation ¹⁸The important intermediate of F-fallypride.Now do not have any producer both at home and abroad this intermediate finished product can be provided.Relevant synthetic this intermediate literature summary is as follows:

It is raw material that US4335045 adopts tetrahydrofurfuryl amine, through with hydrogen chloride gas and thionyl chloride effect open loop after obtain 2,5-dichloropentane base amine hydrochlorate; Again itself and excess acetyl chloride are got N-ethanoyl-2,5-dichloropentane base amine; Make 1-allyl group-2-amine methyl Pyrrolidine through allylation and deacetylated reaction more at last.This technology products therefrom is a racemic modification compound and raw material is perishable, severe reaction conditions, and separating difficulty is big.

It is raw material that EP0253785 adopts the L-proline(Pro), makes (s)-1-allyl group-pyrrolidine 2 carboxylic acid ester with the allyl bromide 98 reaction; Again itself and sodium cyanide are reacted in ammoniacal liquor and make (s)-1-allyl group pyrrole amides; After two (2-methoxy ethoxy) sodium aluminum hydride reduce (s)-1-allyl group-2-amine methyl Pyrrolidine.The still complicated and raw materials used severe toxicity of this reaction scheme easily causes environmental pollution.

Jogeshwar Mukherjee (Acta Chemica Scandinavica, 1989,43:660～664) has simplified reactions steps, and it is a raw material with the L-prolineamide, makes (s)-1-allyl group pyrrole amides with the allyl iodide reaction; Under-78 ℃, promptly get (s)-1-allyl group-2-amine methyl Pyrrolidine-78 ℃ of reduction again through diisobutyl aluminium hydride.This operational path is simple, reaction yield is moderate, but raw materials used as allyl iodide, diisobutyl aluminium hydride cost an arm and a leg and unstable, the very low temperature reaction conditions is very harsh, is unfavorable for suitability for industrialized production.

Summary of the invention

The preparation method who the purpose of this invention is to provide a kind of (s)-1-allyl group-2-amine methyl Pyrrolidine.

Technical scheme of the present invention, reaction formula is:

Comprise the following steps: successively

A) L-prolineamide (1) and allyl bromide 98 are carried out allylation reaction under the condition that soda ash exists, get (s)-1-allyl group pyrrole amides (2);

B) (s)-1-allyl group pyrrole amides (2) and tetra lithium aluminium hydride are carried out the reduction of amide reaction, get (s)-1-allyl group-2-amine methyl Pyrrolidine (3);

Concrete technology is:

A) allylation reaction:

1) the L-prolineamide is dissolved in the tetrahydrofuran (THF), stirs adding allyl bromide 98 and anhydrous sodium carbonate down, charging capacity mol ratio: L-prolineamide: allyl bromide 98: anhydrous sodium carbonate is 1: 1: 0.5;

2) after refluxing 24 hours under 80 ℃, be cooled to room temperature;

3) transfer to pH＞10 with sodium hydroxide solution, use dichloromethane extraction, merge organic phase;

4) drying, solvent recuperation gets white crystal;

B) reduction of amide reaction:

1) tetra lithium aluminium hydride is dissolved in the tetrahydrofuran (THF), ice bath drips the tetrahydrofuran solution that contains (s)-1-allyl group pyrrole amides down, charging capacity mol ratio: tetra lithium aluminium hydride: (s)-and 1-allyl group pyrrole amides is 1: 1;

2) ice bath reacted 0.5 hour down, refluxed 24 hours down in 80 ℃ then, was cooled to room temperature;

3) add an amount of sodium hydroxide solution, filter, filtrate is used extracted with diethyl ether, merges organic phase;

4) drying, solvent recuperation get (s)-1-allyl group-2-amine methyl Pyrrolidine crude product;

5) crude product is got finished product (s)-1-allyl group-2-amine methyl Pyrrolidine through underpressure distillation or column chromatography.

Beneficial effect of the present invention: product (the s)-1-allyl group-2-amine methyl Pyrrolidine of the present invention's preparation is as d2 dopamine receptor PET developer ¹⁸The intermediate of F-fallypride and other mental disorder medicines, of many uses; Preparation technology of the present invention is simple, easy to operate, it is little to pollute, production safety, yield height.

Embodiment

The present invention will be further described below in conjunction with example.

Embodiment 1

(s)-preparation method of 1-allyl group-2-amine methyl Pyrrolidine comprises the following steps: successively

1, allylation reaction

1) 10g (87.7mmol) (1) is dissolved in the 250ml tetrahydrofuran (THF), adds anhydrous sodium carbonate 5g (43.9mmol) and 7.5ml allyl bromide 98 (87.7mmol).

2) 80 ℃ of following backflows were cooled to room temperature after 24 hours.

3) transfer to pH＞10 with sodium hydroxide solution.With dichloromethane extraction (100ml * 4), merge organic phase.

4) the anhydrous sodium sulfate drying solvent recuperation gets white crystal (2) (12.5g, productive rate 92.3%), mp78～80 ℃.

2, reduction of amide reaction

1) 1.2g tetra lithium aluminium hydride (28mmol) is dissolved in the 100ml anhydrous tetrahydro furan, and ice bath drips 25ml down and contains 4.0g (2) tetrahydrofuran solution (26mmol).

2) under ice bath, reacted 0.5 hour.The back is cooled to room temperature after refluxing 24 hours under 80 ℃.

3) add the 50ml10% sodium hydroxide solution, filter.Filtrate merges organic phase with anhydrous diethyl ether extraction (50ml * 4).Anhydrous sodium sulfate drying, concentrated organic phase gets the safran oily liquids.

Purification step

4a) safran oily liquids underpressure distillation (20mmHg, 80 ℃) gets colourless oil liquid (3) (2.32g, productive rate 63.37%).MS(m/z)：141(M ⁺+H)，110。IR(KBr)γ(cm ^-1)：3292，2959，2870，1675，1442，994，914。

4b) (stationary phase: silica gel, moving phase: methylene chloride/ammoniacal liquor=60/40/1), solvent recuperation gets colourless oil liquid (3) (2.00g, productive rate 54.9%) to safran oily liquids column chromatography.

Claims

1, a kind of preparation method of (s)-1-allyl-2-aminomethyl tetrahydropyrrole, it is characterized in that reaction formula is:

Include the following steps in order:

A) carrying out allylation reaction of L-prolinamide (1) and allyl bromide in the presence of soda ash to obtain (s)-1-allylpyrrole amide (2);

B) Carrying out amide reduction reaction of (s)-1-allylpyrrole amide (2) and lithium aluminum tetrahydride to obtain (s)-1-allyl-2-aminomethyltetrahydropyrrole (3);

The specific process is:

A) Allylation reaction:

1) Dissolve L-prolineamide in tetrahydrofuran, add allyl bromide and anhydrous sodium carbonate under stirring, and the molar ratio of the feeding amount: L-prolineamide: allyl bromide: anhydrous sodium carbonate is 1:1 : 0.5;

2) After reflux at 80°C for 24 hours, cool to room temperature;

3) Adjust the pH to >10 with sodium hydroxide solution, extract with dichloromethane, and combine the organic phases;

4) drying, solvent recovery to obtain white crystals;

B) Amide reduction reaction:

1) Dissolve lithium aluminum tetrahydride in tetrahydrofuran, add the tetrahydrofuran solution containing (s)-1-allylpyrrole amide dropwise under ice bath, the molar ratio of the feeding amount: lithium aluminum tetrahydride: (s)-1-ene Propylpyrrolamide is 1:1;

2) React in an ice bath for 0.5 hours, then reflux at 80°C for 24 hours, and cool to room temperature;

3) adding an appropriate amount of sodium hydroxide solution, filtering, extracting the filtrate with ether, and combining the organic phases;

4) drying, solvent recovery to obtain (s)-1-allyl-2-aminomethyl tetrahydropyrrole crude product;

5) Distill the crude product under reduced pressure or column chromatography to obtain the finished product (s)-1-allyl-2-aminomethyltetrahydropyrrole.