CN110372559A - One kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method - Google Patents

One kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method Download PDF

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CN110372559A
CN110372559A CN201910830617.9A CN201910830617A CN110372559A CN 110372559 A CN110372559 A CN 110372559A CN 201910830617 A CN201910830617 A CN 201910830617A CN 110372559 A CN110372559 A CN 110372559A
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boc
deg
proline
4s
methoxy
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CN201910830617.9A
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林文清
刘小波
朱剑平
郑宏杰
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重庆博腾制药科技股份有限公司
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Priority to CN201410836352.0A priority Critical patent/CN105801462A/en
Priority to CN201910830617.9A priority patent/CN110372559A/en
Publication of CN110372559A publication Critical patent/CN110372559A/en

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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of products other than chlorine, adipic acid, caprolactam, or chlorodifluoromethane, e.g. bulk or fine chemicals or pharmaceuticals
    • Y02P20/55Synthetic design, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses one kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic methods, including using L- hydroxy-proline as starting material, protect the step of obtaining N-Boc-L- hydroxy-proline by Boc;N-Boc-L- hydroxy-proline is dissolved in solvent the step of obtaining (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid with TEMPO (tetramethyl piperidine nitrogen oxides) oxidation reaction;(2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid and methoxymethyl triphenylphosphonium phosphonium chloride are dissolved in solvent and carry out the step of wittig reacts obtained (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid;(4S)-N-Boc-4-- methoxy-L-PROLINE is made in (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid and tert-butylamine hydrogenated react soluble in water;The reaction shortens reaction step;The use for avoiding hypertoxic cyanide increases safety and reduces environmental protection pressure;It has done Atom economy high, has reduced the discharge of waste;Cost of material declines to a great extent.

Description

One kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method

It is " a kind of that the application, which is application number 201410836352.0,29 days December 2014 applying date, invention and created name, The divisional application of (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method ".

Technical field

The present invention relates to pharmaceutical technology fields, in particular to one kind (4S)-N-Boc-4-- methoxy-L-PROLINE Synthetic method.

Background technique

(4S)-N-Boc-4-- methoxy-L-PROLINE is the anti-hepatitis drug that Ji Leadd B.V, the U.S. is being studied Important intermediate, which is currently in clinical 2 phases.Synthetic method reported in the literature has to pass through by raw material of L- hydroxy-proline It crosses multistep reaction and obtains product, this method is long in the presence of reaction route, the deficiency of cost of material and high production cost;Also because using Extremely toxic substance Cymag and the high iodomethane of toxicity and there is safety problems and environmental issue.In document US20130115194 In, disclosing (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylate methyl ester and 1- diazo -2- oxopropyl) dimethyl phosphonate is anti- The method that should obtain (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid, this method are deposited because having used diazonium compound In some potential safety problems problem.

Therefore, in view of the above problems, should be designed a kind of completely new from Atom economy and cost and the angle of environmental protection (4S)-N-Boc-4- methoxy-L-PROLINE synthetic route, it is poly- to reduce reaction step, cost of material is effectively reduced, into And production cost is reduced, while avoiding using Poisons, it is highly-safe, while the discharge of the three wastes is reduced, mitigate environmental protection pressure.

Summary of the invention

In view of this, the purpose of the present invention is to provide one kind (4S)-N-Boc-4-- methoxy-L-PROLINEs Synthetic method, it is poly- by reducing reaction step from Atom economy and cost and the angle of environmental protection, be effectively reduced raw material at This, and then production cost is reduced, while avoiding using Poisons, it is highly-safe, while the discharge of the three wastes is reduced, mitigate environmental protection Pressure.

A kind of compound of the invention, shown in structural formula such as general formula (1):

Wherein, R is amido protecting group.

Invention additionally discloses one kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method, including it is following Step:

B. N-Boc-L- hydroxy-proline is dissolved in solvent and reacts to obtain (2S)-with tetramethyl piperidine nitrogen oxides The step of N-Boc-4- oxo-pyrrolidine -2- carboxylic acid;

Its synthetic route are as follows:

Further, further comprising the steps of:

A. using L- hydroxy-proline as starting material, the step of obtaining N-Boc-L- hydroxy-proline is protected by Boc;

C. (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid and methoxymethyl triphenylphosphonium phosphonium chloride are dissolved in solvent It carries out wittig and reacts the step of (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is made;

D. the hydrogenated reaction soluble in water of (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid and tert-butylamine is made Obtain (4S)-N-Boc-4- methoxy-L-PROLINE;

Its synthetic route are as follows:

Further, in step a, L- hydroxy-proline is dissolved in after water adjusts PH=8~9 and is heated to 20~25 DEG C, is added dropwise (Boc)2The THF solution of O extracts after the THF in 20~25 DEG C of insulation reaction 16-19h, removing system, it is subsequently cooled to 0~ 5℃;

Further, 23 DEG C are heated to after adjusting pH value, is added dropwise (Boc)2The THF solution of O subtracts in 23 DEG C of insulation reaction 18h Extracted after pressing the THF that is distilled off in system with methyl tertiary butyl ether(MTBE), be subsequently cooled to 3 DEG C, with 4N HCl be adjusted to PH=2~ Solid NaCl is added after 3, then is extracted with ethyl acetate 3 times, merges organic phase, with saturated common salt water washing, liquid separation, organic phase is used Anhydrous sodium sulfate is dry;

Further, it in step b, N-Boc-L- hydroxy-proline is dissolved in methylene chloride and is added after TCCA is added in batches Tetramethyl piperidine nitrogen oxides;

Further, in step c, by (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid, methoxymethyl triphenylphosphonium chlorination It is cooled to -5~0 DEG C after Phosphonium, THF mixing, potassium tert-butoxide is added in batches, is warming up to 10~20 DEG C to cooling down after salmon pink solution To -5~0 DEG C, 10~20 DEG C of reaction 10-14h are warming up to after THF solution then is added dropwise;

Further, it is cooled to -3 DEG C after mixing, potassium tert-butoxide is added in batches, is warming up to 15 DEG C to dropping after salmon pink solution Temperature is warming up to 15 DEG C of reaction 12h after THF solution is then added dropwise to -3 DEG C, and saturated sodium bicarbonate solution quenching reaction, decompression is added dropwise It adds water and stirs and filters after solvent is evaporated off, 40% citric acid is added after being extracted with methyl tertiary butyl ether(MTBE) in water phase, adjust PH=3 ~4, it is then extracted with ethyl acetate three times, merges organic phase and dried, filtered with anhydrous sodium sulfate, filtrate concentration;

Further, in step d, (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is dissolved in water and tertiary fourth is added 10-15h is reacted at being respectively 20~25 DEG C in temperature after nitrogen, hydrogen displacement after amine;

Further, with air in nitrogen displacement bottle three times afterwards with nitrogen in hydrogen displacement bottle three times, be 23 DEG C anti-in temperature Answering filtering after 12h, simultaneously part filtrate citric acid adjusting PH=3~4, ethyl acetate extraction, combining extraction liquid simultaneously use anhydrous sodium sulfate It dries, filters, obtains white solid after filtrate concentration, recrystallized with ethyl acetate/n-hexane.

Beneficial effects of the present invention: one kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthesis of the invention Method directly shortens only 4 step synthetic routes from existing multistep synthetic route, avoids the use of hypertoxic cyanide, increases Safety and reduce environmental protection pressure, improve Atom economy, while reducing the discharge of waste liquid, cost of material substantially under Drop saves economic cost.

Specific embodiment

A kind of compound of the present embodiment, shown in structural formula such as general formula (1):

Wherein, R is amido protecting group, such as-Boc ,-Bz ,-Cbz etc.

One kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method of the present embodiment, including following step It is rapid:

A. using L- hydroxy-proline as starting material, the step of obtaining N-Boc-L- hydroxy-proline is protected by Boc;

B. N-Boc-L- hydroxy-proline is dissolved in solvent and is obtained with TEMPO (tetramethyl piperidine nitrogen oxides) oxidation reaction The step of to (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid;

C. (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid and methoxymethyl triphenylphosphonium phosphonium chloride are dissolved in solvent It carries out wittig and reacts the step of (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is made;

D. the hydrogenated reaction soluble in water of (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid and tert-butylamine is made Obtain (4S)-N-Boc-4-- methoxy-L-PROLINE;Its synthetic route are as follows:

In the present embodiment, in step a, L- hydroxy-proline is dissolved in after water adjusts PH=8~9 and is heated to 20~25 DEG C, It is added dropwise (Boc)2The THF solution of O is extracted after the THF in 20~25 DEG C of insulation reaction 16-19h, removing system, is then cooled down To 0~5 DEG C.

In the present embodiment, 23 DEG C are heated to after adjusting pH value, is added dropwise (Boc)2The THF solution of O, in 23 DEG C of insulation reactions It is extracted after 18h, the THF being evaporated under reduced pressure in removing system with methyl tertiary butyl ether(MTBE), is subsequently cooled to 3 DEG C, is adjusted to 4N HCl Solid NaCl is added behind PH=2~3, then is extracted with ethyl acetate 3 times, merges organic phase, with saturated common salt water washing, liquid separation, Organic phase is dry with anhydrous sodium sulfate.

In the present embodiment, in step b, N-Boc-L- hydroxy-proline is dissolved in methylene chloride and is added after TCCA in batches It is added tetramethyl piperidine nitrogen oxides (TEMPO).

In the present embodiment, in step c, by (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid, methoxymethyl triphenylphosphonium It is cooled to -5~0 DEG C after phosphonium chloride, THF mixing, potassium tert-butoxide is added in batches, is warming up to 10~20 DEG C to after salmon pink solution It is cooled to -5~0 DEG C, is warming up to 10~20 DEG C of reaction 10-14h after THF solution then is added dropwise.

In the present embodiment, it is cooled to -3 DEG C after mixing, potassium tert-butoxide is added in batches, is warming up to 15 DEG C to salmon pink solution After be cooled to -3 DEG C, be warming up to 15 DEG C of reaction 12h after THF solution then is added dropwise, dropwise addition saturated sodium bicarbonate solution quenching reaction, It adds water and stirs and filters after evaporating solvent under reduced pressure, 40% citric acid is added after being extracted with methyl tertiary butyl ether(MTBE) in water phase, adjust Then PH=3~4 are extracted with ethyl acetate three times, merge organic phase and dried, filtered with anhydrous sodium sulfate, filtrate concentration.

In the present embodiment, in step d, (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is dissolved in water and is added 10-15h is reacted at being respectively 20~25 DEG C in temperature after nitrogen, hydrogen displacement after tert-butylamine.

In the present embodiment, with air in nitrogen displacement bottle three times afterwards with nitrogen in hydrogen displacement bottle three times, temperature be 23 Filtering and part filtrate adjust PH=3~4 with citric acid after DEG C reaction 12h, ethyl acetate extraction, combining extraction liquid and with anhydrous sulphur Sour sodium dries, filters, and obtains white solid after filtrate concentration, is recrystallized with ethyl acetate/n-hexane.

Below by specific embodiment, the present invention is further elaborated.

CompoundIn R be Boc group.

The synthesis of 1.N-Boc-L- hydroxy-proline (IM1):

Embodiment one

In 2L reaction flask, 131.13g (1mol) L- hydroxy-proline and 500mL water is added, stirs to dissolve;Again plus Enter about 240g unsaturated carbonate potassium solution and adjusts PH=8~9.Reaction solution is heated to 23 DEG C, is added dropwise 218.25g (1mol) (Boc)2The 500mL THF solution of O.After being added dropwise, in 23 DEG C of insulation reaction 18h.After the reaction was completed, it is evaporated under reduced pressure, boils off in system THF, water phase with 2 × 250mL methyl tertiary butyl ether(MTBE) extract, be subsequently cooled to 3 DEG C, after being adjusted to PH=2~3 with 4N HCl plus Enter solid NaCl, is extracted 3 times with 1.1L ethyl acetate.Merge organic phase, with 300mL saturated common salt water washing, liquid separation, organic phase With the dry 2h of anhydrous sodium sulfate, filtering, after filtrate concentration grease, at white solid, weight 230.0g, yield after standing 99%.

Embodiment two

In 2L reaction flask, 131.24g (1mol) L- hydroxy-proline and 500mL water is added, stirs to dissolve;Again plus Enter about 240g unsaturated carbonate potassium solution and adjusts PH=8~9.Reaction solution is heated to 20 DEG C, is added dropwise 218.18g (1mol) (Boc)2The 500mL THF solution of O, after being added dropwise, in 20 DEG C of insulation reaction 16h.After the reaction was completed, it is evaporated under reduced pressure, boils off in system THF.Water phase is extracted with 2 × 250mL methyl tertiary butyl ether(MTBE), is subsequently cooled to 0 DEG C, is added after being adjusted to PH=2~3 with 4N HCl Enter solid NaCl, is extracted 3 times with 1.1L ethyl acetate.Merge organic phase, with 300mL saturated common salt water washing, liquid separation, organic phase With the dry 2h of anhydrous sodium sulfate, filtering, after filtrate concentration grease, at white solid, weight 223.1g, yield after standing 96%.

Embodiment three

In 2L reaction flask, 130.89g (1mol) L- hydroxy-proline and 500mL water is added, stirs to dissolve;Again plus Enter about 240g unsaturated carbonate potassium solution and adjusts PH=8~9.Reaction solution is heated to 25 DEG C, is added dropwise 218.15g (1mol) (Boc)2The 500mL THF solution of O.After being added dropwise, in 25 DEG C of insulation reaction 19h.After the reaction was completed, it is evaporated under reduced pressure, boils off in system THF.Water phase is extracted with 2 × 250mL methyl tertiary butyl ether(MTBE), is subsequently cooled to 5 DEG C, is added after being adjusted to PH=2~3 with 4N HCl Enter solid NaCl, is extracted 3 times with 1.1L ethyl acetate.Merge organic phase, with 300mL saturated common salt water washing, liquid separation, organic phase With the dry 2h of anhydrous sodium sulfate, filtering, after filtrate concentration grease, at white solid, weight 219.2g, yield after standing 94.3%.

The synthesis of (2. 2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid (IM2):

Example IV

60.0g (0.26mol) N-Boc-L- hydroxy-proline, 600mL methylene chloride, 60.30g are added into 1L reaction flask (0.26mol) TCCA, stirs and is cooled to room temperature, and 2.02g (0.012mol) TEMPO (reaction is added in batches into reaction flask Heat release), charging rate is controlled, using temperature in -3 DEG C, filtering obtains white solid 40.12g, yield 67% after filtrate concentration.

Embodiment five

Addition 60.08g (0.26mol) N-Boc-L- hydroxy-proline into 1L reaction flask, 600mL methylene chloride, 60.28g (0.26mol) TCCA, stirs and is cooled to room temperature, and 2.01g (0.012mol) TEMPO is added in batches into reaction flask (exothermic heat of reaction) controls charging rate, using temperature in -5 DEG C.Filtering obtains white solid 38.51g, yield after filtrate concentration 64.5%.

Embodiment six

Addition 60.05g (0.26mol) N-Boc-L- hydroxy-proline into 1L reaction flask, 600mL methylene chloride, 60.25g (0.26mol) TCCA, stirs and is cooled to room temperature, and 2.05g (0.012mol) TEMPO is added in batches into reaction flask (exothermic heat of reaction) controls charging rate, using temperature in 0 DEG C.Filtering obtains white solid 35.02g, yield after filtrate concentration 58.6%.

The synthesis of (3. 2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid (IM3):

Embodiment seven

Under nitrogen protection, 38.94g (0.169mol) (2S)-N-Boc-4- oxo-pyrrolidine -2- is added into 1L reaction flask Carboxylic acid, 77.8g (0.227mol) methoxymethyl triphenylphosphonium phosphonium chloride, 500mL THF are cooled to -3 DEG C, are added in batches 47.0g (0.137mol) potassium tert-butoxide.15 DEG C of reactions are warming up to, salmon pink solution is obtained, are cooled to -3 DEG C, 40g is added dropwise The 150mL THF solution of (0.17mol, 1eq) after being added dropwise, is warming up to 15 DEG C of reaction 12h, it is molten that saturated sodium bicarbonate is added dropwise Liquid quenching reaction.500mL water is added in evaporating solvent under reduced pressure, stirs 30min, filtering, filter cake 3 × 50mL water washing.Merge water Phase, is extracted with the methyl tertiary butyl ether(MTBE) of 250mL × 2, and water phase is continued to employ.40% citric acid is added in water phase, adjusts PH=3~4, then Three times with the extraction of 800mL ethyl acetate, merge organic phase, dried, filtered with anhydrous sodium sulfate, obtain grease after filtrate concentration 33.3g, yield 76.2%.

Embodiment eight

Under nitrogen protection, 38.96g (0.169mol) (2S)-N-Boc-4- oxo-pyrrolidine -2- is added into 1L reaction flask Carboxylic acid, 78.11g (0.227mol) methoxymethyl triphenylphosphonium phosphonium chloride, 500mL THF are cooled to -5 DEG C, are added in batches 47.05g (0.137mol) potassium tert-butoxide.10 DEG C of reactions are warming up to, salmon pink solution is obtained, are cooled to -5 DEG C, 39.97g is added dropwise The 150mL THF solution of (0.17mol, 1eq) after being added dropwise, is warming up to 10 DEG C of reaction 10h, it is molten that saturated sodium bicarbonate is added dropwise Liquid quenching reaction.500mL water is added in evaporating solvent under reduced pressure, stirs 30min, filtering, filter cake 3 × 50mL water washing.Merge water Phase, is extracted with the methyl tertiary butyl ether(MTBE) of 250mL × 2, and water phase is continued to employ.40% citric acid is added in water phase, adjusts PH=3~4, then Three times with the extraction of 800mL ethyl acetate, merge organic phase, dried, filtered with anhydrous sodium sulfate, obtain grease after filtrate concentration 29.8g, yield 68.2%.

Embodiment nine

Under nitrogen protection, 39.05g (0.169mol) (2S)-N-Boc-4- oxo-pyrrolidine -2- is added into 1L reaction flask Carboxylic acid, 77.9g (0.227mol) methoxymethyl triphenylphosphonium phosphonium chloride, 500mL THF are cooled to 0 DEG C, are added in batches 49.98g (0.137mol) potassium tert-butoxide is warming up to 20 DEG C of reactions, obtains salmon pink solution, is cooled to 0 DEG C, and 40.05g is added dropwise The 150mL THF solution of (0.17mol, 1eq) after being added dropwise, is warming up to 20 DEG C of reaction 14h, it is molten that saturated sodium bicarbonate is added dropwise Liquid quenching reaction.500mL water is added in evaporating solvent under reduced pressure, stirs 32min, filtering, filter cake 3 × 50mL water washing.Merge water Phase, is extracted with the methyl tertiary butyl ether(MTBE) of 250mL × 2, and water phase is continued to employ.40% citric acid is added in water phase, adjusts PH=3~4, then Three times with the extraction of 800mL ethyl acetate, merge organic phase, dried, filtered with anhydrous sodium sulfate, obtain grease after filtrate concentration 30.9g, yield 70.7%.

The synthesis of (4. 4S)-N-Boc-4-- methoxy-L-PROLINE (TM):

Embodiment ten

10.2g (0.04mol) (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is added into 250mL flask, 100mL water, tert-butylamine 29.2g (0.04mol), three times with air in nitrogen displacement bottle, then three times with nitrogen in hydrogen displacement bottle, 23 DEG C of reaction 12h, filtering, filtrate adjust PH=3~4, the extraction of 2 × 100mL ethyl acetate with citric acid, and combining extraction liquid is used in combination Anhydrous sodium sulfate dries, filters, and obtains white solid after filtrate concentration, recrystallizes to obtain product 4.01g with ethyl acetate/n-hexane, Yield 33.9%.

Embodiment 11

10.18g (0.04mol) (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is added into 250mL flask, 100mL water, tert-butylamine 29.22g (0.04mol), three times with air in nitrogen displacement bottle, then with nitrogen three in hydrogen displacement bottle It is secondary, it is 20 DEG C of reaction 10h in temperature, filters, filtrate adjusts PH=3~4 with citric acid, and the extraction of 2 × 100mL ethyl acetate is closed And extract liquor and dried, filtered with anhydrous sodium sulfate, after filtrate concentration white solid, recrystallized with ethyl acetate/n-hexane Obtain product 3.81g, yield 32.2%.

Embodiment 12

10.21g (0.04mol) (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is added into 250mL flask, 100mL water, tert-butylamine 29.18g (0.04mol), three times with air in nitrogen displacement bottle, then with nitrogen three in hydrogen displacement bottle It is secondary, 25 DEG C of reaction 15h of temperature.Filtering, filtrate adjust PH=3~4 with citric acid, and the extraction of 2 × 100mL ethyl acetate merges extraction It takes liquid and is dried, filtered with anhydrous sodium sulfate, obtain white solid after filtrate concentration, recrystallized to obtain production with ethyl acetate/n-hexane Product 3.90g, yield 24.6%.

Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this In the scope of the claims of invention.

Claims (8)

1. one kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method, it is characterised in that: including following step It is rapid:
A. using L- hydroxy-proline as starting material, the step of obtaining N-Boc-L- hydroxy-proline is protected by Boc;
B. N-Boc-L- hydroxy-proline is dissolved in solvent and reacts to obtain (2S)-N- with tetramethyl piperidine nitrogen oxides The step of Boc-4- oxo-pyrrolidine -2- carboxylic acid;
C. (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid and methoxymethyl triphenylphosphonium phosphonium chloride are dissolved in solvent and are carried out Wittig reacts the step of (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid is made;
D. the hydrogenated reaction soluble in water of (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid and tert-butylamine is made (4S)-N-Boc-4-- methoxy-L-PROLINE;
2. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 1, special Sign is: in step a, L- hydroxy-proline being dissolved in after water adjusts PH=8~9 and is heated to 20~25 DEG C, is added dropwise (Boc) 2O's THF solution extracts after the THF in 20~25 DEG C of insulation reaction 16-19h, removing system, is subsequently cooled to 0~5 DEG C.
3. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 2, special Sign is: being heated to 23 DEG C after adjusting pH value, the THF solution of (Boc) 2O is added dropwise, in 23 DEG C of insulation reaction 18h, vacuum distillation is removed It is extracted after removing the THF in system with methyl tertiary butyl ether(MTBE), is subsequently cooled to 3 DEG C, be added after being adjusted to PH=2~3 with 4N HCl Solid NaCl, then be extracted with ethyl acetate 3 times, merge organic phase, with saturated common salt water washing, liquid separation, the anhydrous sulphur of organic phase Sour sodium is dry.
4. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 3, special Sign is: in step b, N-Boc-L- hydroxy-proline being dissolved in methylene chloride and is added after TCCA tetramethyl piperazine is added in batches Pyridine nitrogen oxides.
5. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 4, special Sign is: in step c, (2S)-N-Boc-4- oxo-pyrrolidine -2- carboxylic acid, methoxymethyl triphenylphosphonium phosphonium chloride, THF is mixed It is cooled to -5~0 DEG C after conjunction, potassium tert-butoxide is added in batches, is warming up to 10~20 DEG C to being cooled to -5~0 after salmon pink solution DEG C, 10~20 DEG C of reaction 10-14h are warming up to after THF solution then is added dropwise.
6. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 5, special Sign is: being cooled to -3 DEG C after mixing, potassium tert-butoxide is added in batches, be warming up to 15 DEG C to being cooled to -3 after salmon pink solution DEG C, 15 DEG C of reaction 12h are warming up to after THF solution is then added dropwise, saturated sodium bicarbonate solution quenching reaction is added dropwise, removes under reduced pressure molten It adds water and stirs and filters after agent, 40% citric acid is added after being extracted with methyl tertiary butyl ether(MTBE) in water phase, adjust PH=3~4, so After be extracted with ethyl acetate three times, merge organic phase dried, filtered with anhydrous sodium sulfate, filtrate concentration.
7. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 6, special Sign is: in step d, (2S)-N-Boc-4- methoxyl group methene pyrrolidines -2- carboxylic acid being dissolved in water and is added after tert-butylamine respectively 10-15h is reacted at being 20~25 DEG C in temperature after nitrogen, hydrogen displacement.
8. the synthetic method of one kind (4S)-N-Boc-4-- methoxy-L-PROLINE according to claim 7, special Sign is: with air in nitrogen displacement bottle three times afterwards with nitrogen in hydrogen displacement bottle three times, the mistake after temperature is 23 DEG C of reaction 12h It filters and filtrate is adjusted into PH=3~4 with citric acid, ethyl acetate extraction, combining extraction liquid is simultaneously with anhydrous sodium sulfate drying, mistake Filter obtains white solid after filtrate concentration, is recrystallized with ethyl acetate/n-hexane.
CN201910830617.9A 2014-12-29 2014-12-29 One kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method CN110372559A (en)

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