CN110156732A - A kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid - Google Patents
A kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid Download PDFInfo
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- NPDKTSLVWGFPQG-SSDOTTSWSA-N (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-SSDOTTSWSA-N 0.000 title claims abstract description 18
- 238000010189 synthetic method Methods 0.000 title claims abstract description 16
- 230000003287 optical effect Effects 0.000 title claims abstract description 13
- -1 3- isobutylglutaric acid acid anhydride Chemical class 0.000 claims abstract description 20
- NPDKTSLVWGFPQG-UHFFFAOYSA-N 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)CC(CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-UHFFFAOYSA-N 0.000 claims abstract description 10
- SHZIWNPUGXLXDT-UHFFFAOYSA-N caproic acid ethyl ester Natural products CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000007792 addition Methods 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 238000013517 stratification Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- UATSLDZQNXAKMA-UHFFFAOYSA-N 3-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(CC(O)=O)CC(O)=O UATSLDZQNXAKMA-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 230000036632 reaction speed Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 230000007812 deficiency Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- CVKMFSAVYPAZTQ-UHFFFAOYSA-N 2-methylhexanoic acid Chemical compound CCCCC(C)C(O)=O CVKMFSAVYPAZTQ-UHFFFAOYSA-N 0.000 description 2
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 2
- 229960001233 pregabalin Drugs 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 102000005915 GABA Receptors Human genes 0.000 description 1
- 108010005551 GABA Receptors Proteins 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/20—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- 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 Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Analytical Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to fine chemistry industry production technical fields, specifically disclose a kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid the following steps are included: step 1, synthesizes 2- cyano -5- methyl -2- alkene ethyl hexanoate；Step 2 synthesizes 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester；Step 3 synthesizes 3- isobutylglutaric acid acid anhydride；Step 4 synthesizes (±) -3- carbamoylmethyl -5- methylhexanoic acid；Step 5 synthesizes (R) -3- carbamoylmethyl -5- methylhexanoic acid.The present invention overcomes the deficiencies in the prior art, provide that a kind of cost of material is low, and reaction speed is fast, simple and easy synthetic method is suitble to large-scale industrial production, has very high economic benefit.
Description
Technical field
The present invention relates to fine chemistry industry production technical fields, particularly belong to a kind of optical voidness (R) -3- carbamoylmethyl -5-
The synthetic method of methylhexanoic acid.
Background technique
Pregabalin (Pregabalin, PGB) is a kind of novel GABA receptor resistance that Pfizer Inc. develops
Stagnant dose, has become treatment neuralgia is more efficient, one of drug conveniently, safely；3- aminomethyl -5- methylhexanoic acid is to prepare
The key intermediate of Pregabalin.
At present the country prepare technique of 3- aminomethyl -5- methylhexanoic acid there is also: reaction speed is slow, prices of raw materials height,
The problems such as conversion ratio is low, and resolving agent toxicity is big.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods gram of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid
The deficiencies in the prior art have been taken, have provided that a kind of cost of material is low, and reaction speed is fast, simple and easy synthetic method is suitble to big
Technical scale metaplasia produces, and has very high economic benefit.
To solve the above problems, the technical solution used in the present invention is as follows:
A kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid, comprising the following steps:
Step 1 synthesizes 2- cyano -5- methyl -2- alkene ethyl hexanoate: ethyl cyanoacetate is added in the reaction flask of 500ml
56.5g (0.5mol) and n-hexane 100ml is stirred evenly and is slowly dropped into addition triethylene diamine 0.5g and isopentyl aldehyde 43g again
(0.5mol), solution colour gradually become light yellow, are stirred at room temperature, then heat up with water segregator reflux water-dividing, and reaction is not to having
Until thering is moisture to go out, cooling；It is concentrated under reduced pressure；
Step 2 synthesizes 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester: straight in step 1 products therefrom
It connects and diethyl malonate 72.2g (0.5mol) and triethylene diamine 5g is added, be stirred to react 10 hours, be directly added into hydrochloric acid
500ml is heated to reflux until the reaction is complete, is extracted after being cooled to room temperature, and is concentrated under reduced pressure；
Step 3 synthesizes 3- isobutylglutaric acid acid anhydride: in the 3- isobutyl group -2- cyano -4- ethoxy carbonyl that step 2 obtains
It is directly added into base-pentanedioic acid diethyl ester acetic anhydride 76.5g (0.75mol), heating reaction is reduced to room temperature, and concentration removes acetic acid
Acid anhydride and acetic acid；
Step 4 synthesizes (±) -3- carbamoylmethyl -5- methylhexanoic acid: diluting 3- isobutyl group penta with methyl tertiary butyl ether(MTBE)
The ammonium hydroxide of 100ml mass fraction 10% is added in the reaction flask of 500ml, 3- isobutyl group penta is added dropwise after cooling down for dicarboxylic anhydride
The t-butyl methyl ether solution 80ml of dicarboxylic anhydride, is stirred to react after being warmed to room temperature, isolated organic phase, and washing, is taken out at decoloration
Filter, washing, drying；
Step 5 synthesizes (R) -3- carbamoylmethyl -5- methylhexanoic acid: the sweet ammonia of D- benzene being added in the reaction flask of 250ml
Acid butyl ester 26.2g and isopropanol solvent 85.2ml after heating for dissolving, is added (±) -3- carbamoylmethyl -5- methylhexanoic acid, protects
Temperature is slowly stirred, and keeps circular response complete, cooling, crystallization, suction filtration, drying.
Further, in the step 1, control temperature range heats up at 0-5 DEG C, fraction water device water-dividing when isopentyl aldehyde is added dropwise
To 90-100 DEG C.
Further, in the step 2, when extraction, uses methylene chloride for extractant, extraction no less than 2 times, will extract
Methylene chloride afterwards mutually merges, and 100ml water is added, and phase of fetching water after stratification, decoloration filters, and adjusting PH is 1-2, uses dichloro
Methane extraction obtains 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester after dry, concentration.
Further, in the step 3, petroleum ether and ethyl acetate are added in 3- isobutylglutaric acid acid anhydride, and (volume ratio is
3-5:0.2-0.4) mixed solution recrystallizes, and filters, and a small amount of cold petroleum ether, 20 DEG C of vacuum drying are purified.
Further, in the step 4, organic phase adjusts PH between 0.5-1 with the hydrochloric acid of 6mol/L.
Compared with prior art, implementation result of the invention is as follows by the present invention:
A kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid of the present invention uses triethylene two
Amine is reacted as catalyst, is shortened the reaction time, is reduced side reaction, reduces production cost；Using the sweet ammonia of D- benzene
Acid butyl ester carries out racemization fractionation to (±) -3- carbamoylmethyl -5- methylhexanoic acid as resolving agent, reduces the cost of resolving agent,
Reduce the toxicity of resolving agent, it is more safe and environment-friendly.
The present invention provides a kind of cost of material is low, reaction speed is fast, and simple and easy synthetic method is suitble to extensive work
Industry metaplasia produces, and has very high economic benefit.
Detailed description of the invention
Fig. 1 is synthetic route chart of the present invention.
Specific embodiment
The present invention will be further described with reference to the examples below, but the present invention is not limited to these instances, and is being de-
Under the premise of from present inventive concept, carried out by it is any improvement be within the scope of the present invention.
Embodiment 1
A kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid of the present invention, including it is following
Step:
Ethyl cyanoacetate 56.5g (0.5mol) and n-hexane 100ml, stirring is added in step 1 in the reaction flask of 500ml
Control temperature range is at 0-5 DEG C after uniformly, then is slowly dropped into and triethylene diamine 0.5g and isopentyl aldehyde 43g (0.5mol) is added, molten
Liquid color gradually becomes light yellow, is stirred at room temperature, then is warming up to 90-100 DEG C, and with water segregator reflux water-dividing, reaction is not to having
Until thering is moisture to go out, cooling；It is concentrated under reduced pressure, obtains 2- cyano -5- methyl -2- alkene ethyl hexanoate；
Step 2 is directly added into diethyl malonate 72.2g (0.5mol) and triethylene two in step 1 products therefrom
Amine 5g is stirred to react 10 hours, is directly added into hydrochloric acid 500ml, be heated to reflux until the reaction is complete, extracts after being cooled to room temperature,
It is concentrated under reduced pressure, obtains 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester；
Step 3 is directly added into 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester that step 2 obtains
Acetic anhydride 76.5g (0.75mol), heating reaction are reduced to room temperature, and concentration removes acetic anhydride and acetic acid, obtains 3- isobutyl group penta
Petroleum ether and ethyl acetate (volume ratio 3-5:0.2-0.4) mixed solution is added in dicarboxylic anhydride in 3- isobutylglutaric acid acid anhydride
Recrystallization filters, and a small amount of cold petroleum ether, 20 DEG C of vacuum drying are purified；
Step 4 dilutes 3- isobutylglutaric acid acid anhydride with methyl tertiary butyl ether(MTBE), 100ml is added in the reaction flask of 500ml
The t-butyl methyl ether solution 80ml of 3- isobutylglutaric acid acid anhydride is added dropwise after cooling down, rises to for the ammonium hydroxide of mass fraction 10%
Be stirred to react after room temperature, isolated organic phase, with the hydrochloric acid of 6mol/L adjust PH to wash, decolourize, filter between 0.5-1,
(±) -3- carbamoylmethyl -5- methylhexanoic acid is obtained after washing, drying；
D-PG butyl ester 26.2g and isopropanol solvent 85.2ml is added in the reaction flask of 250ml, adds for step 5
After heat of solution, (±) -3- carbamoylmethyl -5- methylhexanoic acid is added, heat preservation is slowly stirred, and keeps circular response complete, cooling, analysis
Crystalline substance filters, is dried to obtain 36.2g (R) -3- carbamoylmethyl -5- methylhexanoic acid, yield 86.26%.
Embodiment 2
Ethyl cyanoacetate 56.5g (0.5mol) and n-hexane 100ml, stirring is added in step 1 in the reaction flask of 500ml
Control temperature range is at 0-5 DEG C after uniformly, then is slowly dropped into and triethylene diamine 0.5g and isopentyl aldehyde 43g (0.5mol) is added, molten
Liquid color gradually becomes light yellow, is stirred at room temperature, then is warming up to 90-100 DEG C, and with water segregator reflux water-dividing, reaction is not to having
Until thering is moisture to go out, cooling；It is concentrated under reduced pressure, obtains 2- cyano -5- methyl -2- alkene ethyl hexanoate；
Step 2 is directly added into diethyl malonate 72.2g (0.5mol) and triethylene two in step 1 products therefrom
Amine 5g is stirred to react 10 hours, is directly added into hydrochloric acid 500ml, be heated to reflux until the reaction is complete, uses dichloro after being cooled to room temperature
Methane extracts 2 times, is concentrated under reduced pressure, obtains 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester；
Methylene chloride extracted is mutually merged, 100ml water is added, phase of fetching water after stratification, decoloration filters, and adjusts
PH is 1-2, is extracted with dichloromethane, and obtains 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester after dry, concentration；
Step 3 is directly added into 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester that step 2 obtains
Acetic anhydride 76.5g (0.75mol), heating reaction are reduced to room temperature, and concentration removes acetic anhydride and acetic acid, obtains 3- isobutyl group penta
Petroleum ether and ethyl acetate (volume ratio 3-5:0.2-0.4) mixed solution is added in dicarboxylic anhydride in 3- isobutylglutaric acid acid anhydride
Recrystallization filters, and a small amount of cold petroleum ether, 20 DEG C of vacuum drying are purified；
Step 4 dilutes 3- isobutylglutaric acid acid anhydride with methyl tertiary butyl ether(MTBE), 100ml is added in the reaction flask of 500ml
The t-butyl methyl ether solution 80ml of 3- isobutylglutaric acid acid anhydride is added dropwise after cooling down, rises to for the ammonium hydroxide of mass fraction 10%
Be stirred to react after room temperature, isolated organic phase, with the hydrochloric acid of 6mol/L adjust PH to wash, decolourize, filter between 0.5-1,
(±) -3- carbamoylmethyl -5- methylhexanoic acid is obtained after washing, drying；
D-PG butyl ester 26.2g and isopropanol solvent 85.2ml is added in the reaction flask of 250ml, adds for step 5
After heat of solution, (±) -3- carbamoylmethyl -5- methylhexanoic acid is added, heat preservation is slowly stirred, and keeps circular response complete, cooling, analysis
Crystalline substance filters, is dried to obtain 42.6g (R) -3- carbamoylmethyl -5- methylhexanoic acid, yield 90.39%.
Above content is only to present inventive concept example and explanation, affiliated those skilled in the art couple
Described specific embodiment does various modifications or additions or is substituted in a similar manner, without departing from invention
Conceive or beyond the scope defined by this claim, is within the scope of protection of the invention.
Claims (5)
1. a kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid, it is characterised in that: including following step
It is rapid:
Step 1 synthesizes 2- cyano -5- methyl -2- alkene ethyl hexanoate: ethyl cyanoacetate is added in the reaction flask of 500ml
56.5g(0.5mol) with n-hexane 100ml, stirs evenly and be slowly dropped into addition triethylene diamine 0.5g and isopentyl aldehyde 43g again
(0.5mol), solution colour gradually become light yellow, are stirred at room temperature, then heat up with water segregator reflux water-dividing, and reaction is not to having
Until having moisture to go out, cooling is concentrated under reduced pressure；
Step 2 synthesizes 3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester: directly adding in step 1 products therefrom
Enter diethyl malonate 72.2g(0.5mol) and triethylene diamine 5g, it is stirred to react 10 hours, is directly added into hydrochloric acid 500ml, adds
Heat reflux until the reaction is complete, is extracted after being cooled to room temperature, is concentrated under reduced pressure；
Step 3 synthesizes 3- isobutylglutaric acid acid anhydride: in the 3- isobutyl group -2- cyano -4- carbethoxyl group-penta two that step 2 obtains
Acetic anhydride 76.5g(0.75mol is directly added into acetoacetic ester), heating reaction is reduced to room temperature, and concentration removes acetic anhydride and second
Acid；
Step 4 synthesizes (±) -3- carbamoylmethyl -5- methylhexanoic acid: diluting 3- isobutylglutaric acid with methyl tertiary butyl ether(MTBE)
The ammonium hydroxide of 100ml mass fraction 10% is added in the reaction flask of 500ml, 3- isobutylglutaric acid acid anhydride is added dropwise after cooling down for acid anhydride
T-butyl methyl ether solution 80ml, be stirred to react after being warmed to room temperature, isolated organic phase, washing, decoloration, filter, washing,
It is dry；
Step 5 synthesizes (R) -3- carbamoylmethyl -5- methylhexanoic acid: D-PG fourth being added in the reaction flask of 250ml
After heating for dissolving, (±) -3- carbamoylmethyl -5- methylhexanoic acid is added in ester 26.2g and isopropanol solvent 85.2ml, and heat preservation is slow
Slow stirring, keeps circular response complete, cooling, crystallization, suction filtration, drying.
2. a kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid according to claim 1, special
Sign is: in the step 1, control temperature range is warming up to 90-100 at 0-5 DEG C, fraction water device water-dividing when isopentyl aldehyde is added dropwise
℃。
3. a kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid according to claim 1, special
Sign is: in the step 2, when extraction, uses methylene chloride for extractant, and extraction no less than 2 times, by dichloromethane extracted
Alkane mutually merges, and 100ml water is added, and phase of fetching water after stratification, decoloration filters, and adjusting PH is 1-2, is extracted with dichloromethane, and does
3- isobutyl group -2- cyano -4- carbethoxyl group-pentanedioic acid diethyl ester is obtained after dry, concentration.
4. a kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid according to claim 1, special
Sign is: in the step 3, petroleum ether and ethyl acetate (volume ratio 3-5:0.2- being added in 3- isobutylglutaric acid acid anhydride
0.4) mixed solution recrystallizes, and filters, and a small amount of cold petroleum ether, 20 DEG C of vacuum drying are purified.
5. a kind of synthetic method of optical voidness (R) -3- carbamoylmethyl -5- methylhexanoic acid according to claim 1, special
Sign is: in the step 4, organic phase adjusts PH between 0.5-1 with the hydrochloric acid of 6mol/L.
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