CN108456143A - Asymmetry prepares (S) -3- aminomethyl -5- methylhexanoic acids - Google Patents
Asymmetry prepares (S) -3- aminomethyl -5- methylhexanoic acids Download PDFInfo
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- CN108456143A CN108456143A CN201710095366.5A CN201710095366A CN108456143A CN 108456143 A CN108456143 A CN 108456143A CN 201710095366 A CN201710095366 A CN 201710095366A CN 108456143 A CN108456143 A CN 108456143A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of methods that asymmetry prepares 5 methylhexanoic acid of (S) 3 aminomethyl, it is characterised in that：Synthesis step includes：Using 3 isobutylglutaric acids be raw material successively by carrying out ring-closure reaction with nitrogenous reagent, asymmetric open loop being carried out with (S) (+) 1 phenyl ethylamine, Hoffmann rearrangement, amide hydrolysis four-step reaction obtain 5 methylhexanoic acid of (S) 3 aminomethyl.Compared with prior art, raw material of the present invention is cheap and easy to get, reaction step is shorter, reaction condition is mild, avoids using easily system poison and easily makes quick-fried reagent, and total recovery is up to 72%, and isobutyl adds bar product purity to be more than 99%, ee values are more than 99%, have extraordinary application prospect in industry's enlarging production.
Description
Technical field
The invention belongs to chemical medicines, and in particular to a kind of asymmetry prepares (S) -3- aminomethyl -5- methylhexanoic acids
Method.
Background technology
(S) -3- aminomethyls -5- methylhexanoic acids, general entitled Pregabalin are a kind of amino fourths researched and developed by Pfizer
Sour (GABA) receptor antagonist, for treating peripheral neuralgia and partial seizure.In July, 2004 obtain European Union approval and
Britain's Initial Public Offering obtains FDA approval listings, trade name Lyrica in December, 2004.(S) -3- aminomethyls -5- methylhexanoic acids
It is mainly worked by adjusting the pressure dependency calcium channel in central nervous system, passes through the load of neutral amino acid after taking orally
The intestinal transport mechanism that body mediates absorbs, and bioavilability is high.Compared with the Gabapentin clinically used, Pregabalin resists
Convulsion effect is stronger, adverse reaction smaller, has many advantages, such as that dosage is low, it is few to take number, has both antianxiety, has wide city
Field foreground, is the substitute products of Gabapentin, market prospects are boundless.
(S) preparation method of -3- aminomethyls -5- methylhexanoic acids is divided into chemical method and bioanalysis, prepared by the biology of the product
Technique is due to conversion ratio and concentration of substrate is relatively low so that bioanalysis, which only rests on laboratory stage, can not be applied to industrialization amplification
Production, and chemical process relatively stablizes so that industrial production (S) -3- aminomethyl -5- methylhexanoic acids generally use chemistry
Method.The preparation of chemical method is broadly divided into three categories at present：
The first kind is first to synthesize pregabalin racemate, splits to obtain Pregabalin using chiral resolving agent.
CN100410242 is disclosed obtains 3- isobutyl group glutarimides with 3- isobutylglutaric acids and urea progress ring-closure reaction, after
Pregabalin racemate is obtained through Hoffmann rearrangement, (S)-mandelic acid is split to obtain Puri bar as chiral resolving agent
Woods, synthetic route are as follows：
The shortcomings that such method synthesis, is too low (24%) for resolution yield, and Pregabalin enantiomter (R types) discarding is made
At wastage of material.
It is raw material that second class, which is using chipal compounds, and the generation of Pregabalin enantiomter is avoided from source.
It is raw material through 9 steps that Organic Process Research＆Development 1997,1,26-38, which are disclosed using L-Leu,
Pregabalin is prepared, synthetic route is as follows：
This method route is tediously long, and severe reaction conditions, total recovery is relatively low, is not suitable for industrialized production.
It is target configuration compound that third class, which is by using asymmetric catalyst control primary product,
J.Org.Chem.2003,68,5731-5734 is reported prepares Pregabalin using method of asymmetric synthesis.First matched using chirality
Body [(R, R)-(Me-DuPHOS) Rh (COD)] BF4Midbody compound 3- cyano -5- methyl-hex- 3- olefin(e) acid ethyl esters are carried out
Asymmetric hydrogenation obtains Pregabalin with optical activation using series reaction.Catalyst valence selected by this method
Lattice are expensive, and recycling and recycling are more difficult, and severe reaction conditions, industrialized production is obstructed.
Invention content
In order to overcome drawbacks described above of the existing technology, the invention discloses a kind of asymmetry to prepare (S) -3- ammonia first
The method of base -5- methylhexanoic acids.
Concrete technology route is as follows：
Including,
Step a：3- isobutylglutaric acids carry out ring-closure reaction with nitrogenous reagent and obtain 3- isobutyl group glutarimide (chemical combination
Object III)；
Step b：Compound III reacts asymmetric open loop with (S)-(+) -1- phenyl ethylamines and obtains compound IV；
Step c：Compound IV carries out Hoffmann rearrangement reaction prepare compound V；
Step d：Compound V obtains (S) -3- aminomethyl -5- methylhexanoic acids (compound I) through amide hydrolysis.
Furtherly, nitrogenous reagent described in step a is urea, ammonium hydroxide or carbonic acid hydrogen ammonium, preferably urea.
Furtherly, ring-closure reaction described in step a carries out at 100~200 DEG C.
Furtherly, the molar ratio of 3- isobutylglutaric acids and nitrogenous reagent is 1 in step a:1~1:3.
Furtherly, the molar ratio of (S)-(+) -1- phenyl ethylamines and compound III are 1 in step b:1~3:1, preferably
1.5：1.
Furtherly, reaction carries out at -20~-10 DEG C in step b.
Furtherly, in step c Hoffmann rearrangement reaction be in NaOH, KOH or LiOH solution, sodium hypobromite, bromine/
Sodium hydroxide, sodium hypochlorite, NCS or the lower progress of NBS effects, preferably bromine/sodium hydroxide.
Furtherly, amide hydrolysis carries out under the conditions of alkaline solution NaOH, KOH or LiOH in step d.
Compared with prior art, raw material of the present invention is cheap and easy to get, reaction step is shorter, reaction condition is mild, avoids using
Easily system is malicious and easily makes quick-fried reagent, and total recovery is up to 72%, and isobutyl adds bar product purity to be more than 99%, ee values and is more than 99%, in work
There is extraordinary application prospect in industry amplification production.
Specific implementation mode
The technology contents of the present invention are further elaborated with reference to specific embodiment, its purpose is to better
Understand present disclosure, but the scope of the present invention is not limited thereto.
The synthesis of embodiment 1 (S) -3- aminomethyl -5- methylhexanoic acids
(1) preparation of compound III
3- isobutylglutaric acids (1kg) and urea (0.64kg) are added into 5L round-bottomed flasks, reaction mixture is at 180 DEG C
Reaction 2 hours is cooled to 80 DEG C, and water (1L) is added, and ethyl alcohol (2L), activated carbon (50g), 80 DEG C are heated 0.5 hour, heat filtering,
Crystallisation by cooling, filtering, dry white crystalline compound III (0.83kg, yield：92%).
(2) preparation of compound IV
Toluene (2.7L), (S)-(+) -1- phenyl ethylamines (0.88kg) and DMAP (5.9g) are added into 6L round-bottomed flasks, -
Compound III (0.83kg) is added portionwise in flask and (is added within 1 hour) at 20~-10 DEG C, reaction is stirred at -20~-10 DEG C
It mixes 3 hours.Washed reaction liquid, drying, reduced pressure, after crystallized to obtain compound IV (1.42kg, yield with toluene：
90%), ee 99.4%.
(3) preparation of compound V
NaOH (0.78kg) is added in 3L isopropyl alcohol and waters, stirring is cooled to 10 DEG C, and compound IV is added
Bromine (0.7kg) is slowly added dropwise in (1.42kg), stirring to whole dissolvings, is warming up to 60 DEG C of reaction 2h, cooling, ethyl acetate extraction
Take (1L*3), it is dry, be concentrated under reduced pressure, after crystallized to obtain compound V (1.32kg, yield with n-hexane：92%), ee is
99.5%.
(4) preparation of (S) -3- aminomethyl -5- methylhexanoic acids (compound I)
By compound V (1.32kg), NaOH (0.19kg), THF (3.5L) and water (0.7L) are added in 6L round-bottomed flasks,
After 65 DEG C are stirred to react 6 hours, 6N hydrochloric acid solution tune PH=7 are cooled to 0 DEG C of filtering, water washing 2 times, and isopropanol washs 2 times,
Isopropanol/water=1 is used afterwards:1 is recrystallized to give (S) -3- aminomethyl -5- methylhexanoic acid (0.73kg, yield：95%), product is pure
Degree is 99.5%, ee 99.7%.
The synthesis of embodiment 2 (S) -3- aminomethyl -5- methylhexanoic acids
(1) preparation of compound III
3- isobutylglutaric acids (1kg) and 40% ammonium hydroxide (0.68kg) are added into 5L round-bottomed flasks, reaction mixture exists
100 DEG C are reacted 2 hours, are cooled to 80 DEG C, water (1L) are added, ethyl alcohol (2L), activated carbon (50g), 80 DEG C are heated 0.5 hour, heat
Filtering, crystallisation by cooling, filtering, dry white crystalline compound III (0.81kg, yield：90%).
(2) preparation of compound IV
Toluene (2.7L), (S)-(+) -1- phenyl ethylamines (0.88kg) and DMAP (5.9g) are added into 6L round-bottomed flasks, -
Compound III (0.81kg) is added portionwise in flask and (is added within 1 hour) at 20~-10 DEG C, reaction is stirred at -20~-10 DEG C
It mixes 3 hours.Washed reaction liquid, drying, reduced pressure, after crystallized to obtain compound IV (1.39kg, yield with toluene：
90%), ee 99.2%.
(3) preparation of compound V
NaOH (0.75kg) is added in 3L isopropyl alcohol and waters, stirring is cooled to 10 DEG C, and compound IV is added
Bromine (0.62kg) is slowly added dropwise in (1.39kg), stirring to whole dissolvings, is warming up to 50 DEG C of reaction 2h, cooling, ethyl acetate extraction
Take (1L*3), it is dry, be concentrated under reduced pressure, after crystallized to obtain compound V (1.32kg, yield with n-hexane：94%), ee is
99.3%.
(4) preparation of (S) -3- aminomethyl -5- methylhexanoic acids (compound I)
By compound V (1.32kg), KOH (0.26kg), THF (3.5L) and water (0.7L) are added in 6L round-bottomed flasks,
After 65 DEG C are stirred to react 6 hours, 6N hydrochloric acid solution tune PH=7 are cooled to 0 DEG C of filtering, water washing 2 times, and isopropanol washs 2 times,
Isopropanol/water=1 is used afterwards:1 is recrystallized to give (S) -3- aminomethyl -5- methylhexanoic acid (0.72kg, yield：93%), product is pure
Degree is 99.3%, ee 99.5%.
The synthesis of embodiment 3 (S) -3- aminomethyl -5- methylhexanoic acids
(1) preparation of compound III
3- isobutylglutaric acids (1kg) and ammonium hydrogen carbonate (1.26kg) are added into 5L round-bottomed flasks, reaction mixture exists
180 DEG C are reacted 2 hours, are cooled to 90 DEG C, water (1L) are added, ethyl alcohol (2L), activated carbon (50g), 80 DEG C are heated 0.5 hour, heat
Filtering, crystallisation by cooling, filtering, dry white crystalline compound III (0.82kg, yield：91%).
(2) preparation of compound IV
Toluene (2.7L), (S)-(+) -1- phenyl ethylamines (0.88kg) and DMAP (5.9g) are added into 6L round-bottomed flasks, -
Compound III (0.82kg) is added portionwise in flask and (is added within 1 hour) at 20~-10 DEG C, reaction is stirred at -20~-10 DEG C
It mixes 3 hours.Washed reaction liquid, drying, reduced pressure, after crystallized to obtain compound IV (1.45kg, yield with toluene：
93%), ee 99.1%.
(3) preparation of compound V
NaOH (0.8kg) is added in 3L isopropyl alcohol and waters, stirring is cooled to 10 DEG C, and compound IV is added
Bromine (0.65kg) is slowly added dropwise in (1.45kg), stirring to whole dissolvings, is warming up to 70 DEG C of reaction 2h, cooling, ethyl acetate extraction
Take (1L*3), it is dry, be concentrated under reduced pressure, after crystallized to obtain compound V (1.29kg, yield with n-hexane：88%), ee is
99.4%.
(4) preparation of (S) -3- aminomethyl -5- methylhexanoic acids (compound I)
By compound V (1.29kg), LiOH (0.16kg), THF (3.5L) and water (0.7L) are added in 6L round-bottomed flasks,
After 65 DEG C are stirred to react 6 hours, 6N hydrochloric acid solution tune PH=7 are cooled to 0 DEG C of filtering, water washing 2 times, and isopropanol washs 2 times,
Isopropanol/water=1 is used afterwards:1 is recrystallized to give (S) -3- aminomethyl -5- methylhexanoic acid (0.71kg, yield：94%), product is pure
Degree is 99.4%, ee 99.3%.
Claims (7)
1. a kind of method that asymmetry prepares (S) -3- aminomethyl -5- methylhexanoic acids (compound I), which is characterized in that synthesis road
Line is as follows：
Including,
Step a：3- isobutylglutaric acids carry out ring-closure reaction with nitrogenous reagent and obtain 3- isobutyl group glutarimide (compounds
III)；
Step b：Compound III and (S)-(+) -1- phenyl ethylamines carry out asymmetric ring opening reaction and obtain compound IV；
Step c：Compound IV carries out Hoffmann rearrangement reaction prepare compound V；
Step d：Compound V carries out amide hydrolysis and obtains (S) -3- aminomethyl -5- methylhexanoic acids (compound I).
2. the method as described in claim 1, it is characterised in that：Nitrogenous reagent described in step a is urea, ammonium hydroxide or carbonic acid hydrogen
Ammonium.
3. the method as described in claim 1, it is characterised in that：Ring-closure reaction described in step a carries out at 100~200 DEG C.
4. the method as described in claim 1, it is characterised in that：(S)-(+) -1- phenyl ethylamines and compound III's rubs in step b
You are than being 1:1~3:1.
5. the method as described in claim 1, it is characterised in that：The temperature of asymmetric ring opening reaction described in step b is -20
~-10 DEG C.
6. the method as described in claim 1, it is characterised in that：In step c Hoffmann rearrangement reaction be in NaOH, KOH or
In LiOH solution, carried out under sodium hypobromite, bromine/sodium hydroxide, sodium hypochlorite, NCS or NBS effect.
7. the method as described in claim 1, it is characterised in that：Amide hydrolysis described in step d alkaline solution NaOH,
It is carried out under the conditions of KOH or LiOH.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479966A (en) * | 2020-12-11 | 2021-03-12 | 南京工业大学 | Method for synthesizing rolipram |
| CN114249687A (en) * | 2021-12-31 | 2022-03-29 | 江西金丰药业有限公司 | Synthesis process of 3-isobutyl glutarimide |
| CN115960037A (en) * | 2023-01-08 | 2023-04-14 | 太仓市茜泾化工有限公司 | Preparation process of 3-isobutyl glutarimide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101268037A (en) * | 2005-09-19 | 2008-09-17 | 特瓦制药工业有限公司 | Novel asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| WO2008118427A2 (en) * | 2007-03-22 | 2008-10-02 | Teva Pharmaceutical Industries Ltd. | Synthesis of (s)-(+)-3-(aminomethyl)-5-methyl hexanoic acid |
| CN104496832A (en) * | 2014-11-21 | 2015-04-08 | 浙江美诺华药物化学有限公司 | Synthetic method of pregabalin |
-
2017
- 2017-02-22 CN CN201710095366.5A patent/CN108456143A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101268037A (en) * | 2005-09-19 | 2008-09-17 | 特瓦制药工业有限公司 | Novel asymmetric synthesis of (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid |
| WO2008118427A2 (en) * | 2007-03-22 | 2008-10-02 | Teva Pharmaceutical Industries Ltd. | Synthesis of (s)-(+)-3-(aminomethyl)-5-methyl hexanoic acid |
| CN104496832A (en) * | 2014-11-21 | 2015-04-08 | 浙江美诺华药物化学有限公司 | Synthetic method of pregabalin |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479966A (en) * | 2020-12-11 | 2021-03-12 | 南京工业大学 | Method for synthesizing rolipram |
| CN112479966B (en) * | 2020-12-11 | 2022-05-17 | 南京工业大学 | Method for synthesizing rolipram |
| CN114249687A (en) * | 2021-12-31 | 2022-03-29 | 江西金丰药业有限公司 | Synthesis process of 3-isobutyl glutarimide |
| CN115960037A (en) * | 2023-01-08 | 2023-04-14 | 太仓市茜泾化工有限公司 | Preparation process of 3-isobutyl glutarimide |
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