CN106631777A - Method for synthesizing methyl gamma-chlorobutyrate - Google Patents
Method for synthesizing methyl gamma-chlorobutyrate Download PDFInfo
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- CN106631777A CN106631777A CN201611076541.8A CN201611076541A CN106631777A CN 106631777 A CN106631777 A CN 106631777A CN 201611076541 A CN201611076541 A CN 201611076541A CN 106631777 A CN106631777 A CN 106631777A
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- hydrogen chloride
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- chlorobutanoate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
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- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing methyl gamma-chlorobutyrate. The method comprises the following steps: 1) synthesis: mixing gamma-butyrolactone and methanol, cooling to -5-0 DEG C, introducing hydrogen chloride gas to the saturated state for the first time, and carrying out thermal reaction at -5-0 DEG C for 24-32 hours, wherein the hydrogen chloride gas is supplemented in the reaction period, and the mole ratio of the gamma-butyrolactone, methanol and total chlorine hydride is 1.0:(1.5-2.0):(1.8-2.5); 2) carrying out vacuum rotary evaporation on the reaction solution obtained in the step 1) to remove excessive chlorine hydride and methanol in the reaction so as to obtain a rotary evaporation bottom solution, wherein the removed chlorine hydride is absorbed by -5-0-DEG C cold methanol to form a chlorine hydride methanol solution; and 3) carrying out reduced pressure rectification on the rotary evaporation bottom solution obtained in the step 2) to obtain the methyl gamma-chlorobutyrate.
Description
Technical field
The present invention relates to a kind of synthetic method of γ-chlorobutanoate, the conjunction particularly with gamma-butyrolacton as initiation material
Into method.
Background technology
γ-chlorobutanoate (s-1) is the important intermediate for synthesizing cyclopropylamine, and cyclopropylamine is then quinolones antibacterial
Agent, insecticide, the important intermediate of agricultural chemicals.
At present, the synthetic method of γ-chlorobutanoate (that is, 4- chlorobutanoates) mainly has following several：
(1) thionyl chloride esterification by ring opening method.(synthesis technique of cyclopropylamine grinds patent CN101693660A, Gu Xiaobo et al.
Study carefully [D]. Institutes Of Technology Of Nanjing, 2005.) using thionyl chloride and alcohol be gamma-butyrolacton open loop, esterifying reagent come prepare γ-
Butyrate.Patent CN1125715 reports the ring-opening reaction using zinc chloride-copper chloride catalytic chlorination sulfoxide and gamma-butyrolacton.
The maximum shortcoming of the method is thionyl chloride Atom economy and environment friendly extreme difference, can discharge the hydrogen chloride of equimolar amounts with
Sulfur dioxide, and be difficult to recycle.
(2) high pressure chlorination hydrogen esterification by ring opening method.Patent US3711549 reports that high pressure (2MPa) high temperature (120 DEG C) is with anhydrous
Zinc chloride is catalyst, and hydrogen chloride gas carry out ring-opening reaction and generate γ-chloro-butyric acid with gamma-butyrolacton.γ-chloro-butyric acid and methyl alcohol
Carrying out esterification can generate γ-chlorobutanoate.The maximum shortcoming of the technique is that reaction need to be carried out in two steps, first step open loop
Reaction needs high-tension apparatus, and reaction temperature is high, and equipment investment is expensive.
(3) document (Noyce D S, Canfield J H.The Configuration of α-Methoxyadipic
Acid[J].J.am.chem.soc,1954(14):Normal pressure hydrogen chloride esterification by ring opening method 3630-3632.) is reported, concrete reaction
Condition is as follows：Gamma-butyrolacton is 1.0 with ethanol mol ratio：10.6, hydrogen chloride is passed through until ethanol solution saturation.It is anti-under room temperature
After answering 48 hours, reactant liquor can obtain MCPB-butyric acid) ethyl ester, yield 91% Jing after frozen water is washed, divides liquid, extraction, alkali cleaning, drying, rectifying.
Because the ethanol consumption of the method is significantly excessive, cause reactant concentration less, reaction rate is slow, the reaction time is little up to 48
When.Additionally, being affected by chemical balance, the maximum conversion rate of the higher raw material gamma-butyrolacton of temperature is lower.Ethanol and hydrogen chloride consumption
It is significantly excessive to cause the recovery load of rectifying recovery ethanol, unreacted hydrogen chloride big.In the method, if reducing the use of ethanol
Amount, the yield of product MCPB-butyric acid) ethyl ester can be reduced substantially.In the method, if reducing reaction temperature, product MCPB-butyric acid) ethyl ester
Although ultimate yield can increase, the reaction time can greatly prolong.
(4) patent CN102898307A reports the technique for making gamma butyrolactone Ring Opening Reagent using phosphorus trichloride, but the work
Skill still suffers from the shortcoming that Atom economy is low, environment friendly is poor.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of method that high atom economy synthesizes γ-chlorobutanoate,
It has the advantages that Atom economy height, environment friendly, reaction efficiency height, process is simple.
In order to solve above-mentioned technical problem, the present invention provides a kind of synthetic method of γ-chlorobutanoate, including following step
Suddenly：
1), synthesize：
- 5 DEG C～0 DEG C will be cooled to after gamma-butyrolacton and methyl alcohol mixing, be first passed through hydrogen chloride gas first to saturation,
Then -5 DEG C～0 DEG C of insulation reaction is carried out, the reaction time is 24～32 hours；During reaction, supplement is passed through hydrogen chloride gas
(for example, 3 times)；The gamma-butyrolacton, methyl alcohol, the mol ratio of hydrogen chloride total amount are 1.0：1.5～2.0：1.8～2.5；
The hydrogen chloride total amount refers to hydrogen chloride first and the supplementary consumption sum for being passed through hydrogen chloride；
Remarks explanation：Hydrogen chloride gas are passed through first to saturation, and as reaction constantly consumes hydrogen chloride, reaction system is changed into
Undersaturated condition, at this moment requires supplementation with and is passed through hydrogen chloride；
2), by step 1) gained reactant liquor carries out vacuum revolving, so as to steam reaction in excessive hydrogen chloride and steam
Methyl alcohol, obtains revolving kettle base solution；It is molten that the above-mentioned hydrogen chloride for steaming forms methanolic hydrogen chloride after being absorbed by -5 DEG C～0 DEG C of cold methanol
Liquid；
The revolving kettle base solution is γ-chlorobutanoate crude product；
3), by step 2) gained revolving kettle base solution carry out rectification under vacuum, obtain γ-chlorobutanoate.
Used as the improvement of the method for the synthesis γ-chlorobutanoate of the present invention, the method also includes step 4)：
4), circular response：
In -5 DEG C～0 DEG C, in step 2) obtained by hydrogen chloride methanol solution in add supplementary methyl alcohol, add γ-Ding Nei
Ester, hydrogen chloride gas first being passed through to saturation, then carrying out -5 DEG C～0 DEG C of insulation reaction, the reaction time is 24～32 little
When；During reaction, supplement is passed through hydrogen chloride gas (for example, 3 times)；The gamma-butyrolacton, methyl alcohol total amount (circular response methyl alcohol
Total amount), the mol ratio of hydrogen chloride total amount (circular response hydrogen chloride total amount) be 1:1.5～2.5:1.8～2.5；
The methyl alcohol total amount (circular response methyl alcohol total amount) refers to methyl alcohol and the methyl alcohol for supplementing in hydrogen chloride methanol solution
Consumption sum；
The hydrogen chloride total amount (circular response hydrogen chloride total amount) refers to hydrogen chloride in hydrogen chloride methanol solution, first
Hydrogen chloride is passed through the consumption sum of hydrogen chloride with supplement；
The reactant liquor of gained is repeated into above-mentioned steps 2) and step 3).
As the further improvements in methods of the synthesis γ-chlorobutanoate of the present invention：
The step 1) in, when supplement is passed through hydrogen chloride gas by the way of be passed through in batches.
Typically, supplement every one identical time and be passed through hydrogen chloride gas.
As the further improvements in methods of the synthesis γ-chlorobutanoate of the present invention：
The step 1) in, supplement is passed through the hydrogen chloride gas time-division and is passed through for 3 times.
As the further improvements in methods of the synthesis γ-chlorobutanoate of the present invention：
The step 2) in, using vacuum revolving gained in last circular response and it is cooled to -5 DEG C～0 DEG C cold
Hydrogen chloride gas (uncooled hydrogen chloride gas) obtained by vacuum revolving in this circular response are absorbed by methyl alcohol；So
By anhydrous sodium sulfate drying, the hydrogen chloride methanol solution of gained is recycled.
Remarks explanation：Contain water in hydrogen chloride gas obtained by vacuum revolving, it is therefore desirable to which follow-up anhydrous sodium sulfate is done
It is dry.
As the further improvements in methods of the synthesis γ-chlorobutanoate of the present invention：
The step 3) be：Under 25mmHg, 80.0 DEG C～85.0 DEG C cuts are collected, obtain γ-chlorobutanoate.
The present invention step 4) circular response in, be with step 2) obtained by hydrogen chloride methanol solution while substituting step
It is rapid 1) in part methyl alcohol and the partial hydrogen chloride gas being passed through first, repeat above-mentioned steps 1)～step 3) it is anti-
Answer and rectifying, i.e. corresponding synthesis step in circular response, its reaction temperature, time are equal to original step 1)
Synthesis.
In the step 2 of the present invention) in, due to hydrogen chloride gas (general methyl alcohol larger in the solubility of cold methanol：Chlorination
Hydrogen=1：0.9～1.1 mol ratio), uncooled hydrogen chloride gas are inhaled hence with -5 DEG C～0 DEG C of cold methanol
Receive, gained hydrogen chloride methanol solution reusable edible Jing after anhydrous sodium sulfate drying；The methyl alcohol of recovery can be used for absorbing hydrogen chloride
Gas.
In the present invention, reaction temperature is reduced to into -5 DEG C～0 DEG C, reaction balance forward direction can be promoted to carry out, raising is opened
Ring esterification limit, so as to improve the maximum conversion of gamma-butyrolacton.
In the present invention, supplementary hydrogen chloride gas are by the way of be passed through in batches, it is ensured that the hydrogen chloride in reaction system
Higher concentration is maintained, so as to shorten the reaction time.
The reaction equation of present invention synthesis γ-chlorobutanoate is as follows:
There is following technical advantage using method of the present invention synthesis γ-chlorobutanoate：
(1) the method Atom economy is high, has the advantages that environment friendly；
(2) one pot process γ-chlorobutanoate under temperate condition is the method achieved, equipment investment is little, post processing letter
It is single；
(3) the method methanol usage and hydrogen chloride consumption are few, and realize the recovery profit of unreacted methyl alcohol and hydrogen chloride
With.
Specific embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This.
Embodiment 1, a kind of synthetic method of MCPB-butyric acid) methyl esters, follow the steps below successively：
1), to equipped with adding gamma-butyrolacton 86.0g (1.0mol) in thermometer, the 250mL there-necked flasks of magnetic agitation,
Anhydrous CH3OH 48.0g (1.5mol), are cooled to 0 DEG C.It is slowly stirred under (rotating speed is about 60r/min), leads to in above-mentioned solution
Enter to be dried HCl gases, until solution saturation (now, the consumption of HCl is 1.8mol).Insulation reaction 24 hours, mends during reaction
Fill and be passed through 3 (interval time is equal) hydrogen chloride gas (supplement be passed through 3 times and is at the consumption of HCl to reactant liquor saturation
0.7mol), the common 2.5mol of the total intake of hydrogen chloride.
2), step 1) obtained by reactant liquor carry out vacuum revolving (vacuum 0.08MPa, 30.0 DEG C of temperature), steam excess
Methyl alcohol 14.4g (0.4mol) and hydrogen chloride.
Using -5 DEG C～0 DEG C of cold CH3OH 35.2g (1.1mol) absorb to above-mentioned uncooled HCl gases, altogether
Reclaim HCl gas 45g (1.2mol), gained HCl-CH3OH solution can be used for next batch reaction Jing after anhydrous sodium sulfate drying.
3), to step 2) vacuum revolving obtained by revolving kettle base solution carry out vacuum distillation, under 25mmHg, collect 80.0 DEG C
～85.0 DEG C of cuts, can obtain γ-chlorobutanoate product 133g, yield 98.1%, purity 99.1%.
4), circular response：
In -5 DEG C～0 DEG C, in step 2) gained hydrogen chloride methanol solution (by the hydrogen chloride of the methyl alcohol+1.2mol of 1.1mol
Composition) in, add as the methyl alcohol 0.4mol for supplementing, add gamma-butyrolacton 1.0mol, be passed through hydrogen chloride gas to saturation (HCl
Consumption be 0.6mol), insulation reaction 24 hours, during reaction supplement be passed through 3 (interval time is equal) hydrogen chloride gas extremely
Reactant liquor saturation (supplement be passed through 3 times, the consumption of HCl and for 0.7mol), the common 2.5mol of the total intake of hydrogen chloride.
The reactant liquor of gained is repeated into above-mentioned steps 2) and step 3).
Obtain MCPB-butyric acid) methyl esters product, yield 98.0%, purity 99.2%.
Explanation：Above-mentioned steps 4) described in " circular response " repeat 4 times after, the yield of gained MCPB-butyric acid) methyl esters is
97.9%, purity 99.2%.
According to above-mentioned data, we learn：Methyl alcohol is recycled with hydrogen chloride and do not affect final products yield and product
Purity.
Change methanol usage, hydrogen chloride consumption, the reaction temperature in embodiment 1, remaining step is equal to the step of embodiment 1
It is rapid 1)～step 3), respectively obtain 2～embodiment of embodiment 7.The yield of gained MCPB-butyric acid) methyl esters is as shown in table 1.
MCPB-butyric acid) methyl esters yield under table 1, different condition
Note：1) product middle ring γ-chlorobutanoate content >=99.0% of the gained of 1～embodiment of embodiment 7.
2) in 1～embodiment of embodiment 7, when stop reaction, reaction time 24h～32h.
Comparative example 1-1, by the step 1 of embodiment 1) in temperature made into " room temperature (20 DEG C) " by " 0 DEG C ", remaining is equal to reality
The step of applying example 1 1)～step 3).The yield of gained γ-chlorobutanoate is 87.8%, purity 99.0%.
Comparative example 1-2, by the step 1 of embodiment 1) in temperature " -15 DEG C " are made into by " 0 DEG C ", remaining is equal to embodiment 1
The step of 1)～step 3).At this temperature, reaction 52 hours are needed, gamma butyrolactone content is can be only achieved less than 1%, yield is
98.5%.
Comparative example 2, by the anhydrous CH in embodiment 13OH makes " 10.6mol " into by " 1.5mol ", is slowly stirred down, Xiang Rong
Be passed through in liquid and be dried HCl gases, until solution saturation (now, the consumption of HCl is 12.7mol).Insulation reaction 24 hours, period
Supplement is passed through 3 hydrogen chloride gas to saturation；The step of remaining is equal to embodiment 1 1)～step 3).Gained γ-chloro-butyric acid first
The yield of ester is 97.4%, purity 99.0%.
But, methanol usage is excessive in the case, causes step 2) and middle recovery methyl alcohol load increase.
Comparative example 3, " hydrogen chloride gas first will be first passed through to saturation, period supplement is passed through 3 chlorine in embodiment 1
Change hydrogen to reactant liquor saturation, the common 2.5mol of hydrogen chloride intake " make into " 2.5mol hydrogen chloride gas to be passed directly into when first
Body, is not supplemented with hydrogen chloride gas in course of reaction "；The step of remaining is equal to embodiment 1 1)～step 3).Gained γ-chlorine
The yield of methyl butyrate is 80%, purity 98.0%.
Finally, in addition it is also necessary to it is noted that listed above is only several specific embodiments of the invention.Obviously, this
It is bright to be not limited to above example, there can also be many deformations.One of ordinary skill in the art can be from present disclosure
The all deformations directly derived or associate, are considered as protection scope of the present invention.
Claims (6)
1. the method for synthesizing γ-chlorobutanoate, is characterized in that comprising the following steps：
1), synthesize：
- 5 DEG C～0 DEG C will be cooled to after gamma-butyrolacton and methyl alcohol mixing, first be passed through hydrogen chloride gas first to saturation, then
- 5 DEG C～0 DEG C of insulation reaction is carried out, the reaction time is 24～32 hours；During reaction, supplement is passed through hydrogen chloride gas；It is described
Gamma-butyrolacton, methyl alcohol, the mol ratio of hydrogen chloride total amount are 1.0：1.5～2.0：1.8～2.5；
The hydrogen chloride total amount refers to hydrogen chloride first and the supplementary consumption sum for being passed through hydrogen chloride；
2), by step 1) gained reactant liquor carries out vacuum revolving, so as to steam reaction in excessive hydrogen chloride and steam methyl alcohol,
Kettle base solution must be rotated；The above-mentioned hydrogen chloride for steaming forms hydrogen chloride methanol solution after being absorbed by -5 DEG C～0 DEG C of cold methanol；
The revolving kettle base solution is γ-chlorobutanoate crude product；
3), by step 2) gained revolving kettle base solution carry out rectification under vacuum, obtain γ-chlorobutanoate.
2. the method for synthesis γ-chlorobutanoate according to claim 1, is characterized in that the method also includes step 4)：
4), circular response：
In -5 DEG C～0 DEG C, in step 2) obtained by hydrogen chloride methanol solution in add supplementary methyl alcohol, add gamma-butyrolacton, logical
Enter hydrogen chloride gas first to saturation, then carry out -5 DEG C～0 DEG C of insulation reaction, the reaction time is 24～32 hours；Instead
During answering, supplement is passed through hydrogen chloride gas；The gamma-butyrolacton, methyl alcohol total amount, the mol ratio of hydrogen chloride total amount are 1:1.5～
2.5:1.8～2.5；
The methyl alcohol total amount refers to the consumption sum of the methyl alcohol in hydrogen chloride methanol solution and the methyl alcohol for supplementing；
The hydrogen chloride total amount refers to that the hydrogen chloride in hydrogen chloride methanol solution, hydrogen chloride first are passed through hydrogen chloride with supplement
Consumption sum；
The reactant liquor of gained is repeated into above-mentioned steps 2) and step 3).
3. the method for synthesis γ-chlorobutanoate according to claim 1 and 2, is characterized in that：
The step 1) in, when supplement is passed through hydrogen chloride gas by the way of be passed through in batches.
4. the method for synthesis γ-chlorobutanoate according to claim 3, is characterized in that：
The step 1) in, supplement is passed through the hydrogen chloride gas time-division and is passed through for 3 times.
5. the method for synthesis γ-chlorobutanoate according to claim 1 and 2, is characterized in that：
The step 2) in, using vacuum revolving gained in last circular response and it is cooled to -5 DEG C～0 DEG C of cold first
Hydrogen chloride gas obtained by vacuum revolving in this circular response are absorbed by alcohol；Then Jing anhydrous sodium sulfate dryings, gained
Hydrogen chloride methanol solution recycled.
6. the method for synthesis γ-chlorobutanoate according to claim 1 and 2, is characterized in that：
The step 3) be：Under 25mmHg, 80.0 DEG C～85.0 DEG C cuts are collected, obtain γ-chlorobutanoate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107721850A (en) * | 2017-09-29 | 2018-02-23 | 山东国邦药业股份有限公司 | A kind of preparation method of cyclopropylamine intermediate γ chloro methyl butyrates |
| CN113009012A (en) * | 2021-02-22 | 2021-06-22 | 北京诺康达医药科技股份有限公司 | Detection method of 4-chlorobutyric acid |
| CN109369432B (en) * | 2018-11-02 | 2021-06-25 | 永农生物科学有限公司 | Preparation method of (S) -4-chloro-2-aminobutyrate |
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| GB2008111A (en) * | 1977-11-16 | 1979-05-31 | Degussa | A process for the production of gamma -Chlorocarboxylic Acid Esters |
| CN102557938A (en) * | 2011-12-23 | 2012-07-11 | 成都玉岭生物科技有限公司 | Production method of methyl 4-chlorobutyrate |
| CN102898307A (en) * | 2012-09-18 | 2013-01-30 | 浙江大学 | Synthetic method of methyl 4-chlorobutyrate |
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2016
- 2016-11-30 CN CN201611076541.8A patent/CN106631777B/en not_active Expired - Fee Related
Patent Citations (3)
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|---|---|---|---|---|
| GB2008111A (en) * | 1977-11-16 | 1979-05-31 | Degussa | A process for the production of gamma -Chlorocarboxylic Acid Esters |
| CN102557938A (en) * | 2011-12-23 | 2012-07-11 | 成都玉岭生物科技有限公司 | Production method of methyl 4-chlorobutyrate |
| CN102898307A (en) * | 2012-09-18 | 2013-01-30 | 浙江大学 | Synthetic method of methyl 4-chlorobutyrate |
Non-Patent Citations (2)
| Title |
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| DONALD S. NOYCE AND JAMES H. CANFIELD: "The Configuration of α-Methoxyadipic Acid", 《J. AM. CHEM. SOC.》 * |
| 侯仲轲 等: "4-氯丁酸甲酯的绿色合成研究", 《精细化工中间体》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107721850A (en) * | 2017-09-29 | 2018-02-23 | 山东国邦药业股份有限公司 | A kind of preparation method of cyclopropylamine intermediate γ chloro methyl butyrates |
| CN107721850B (en) * | 2017-09-29 | 2020-07-03 | 山东国邦药业有限公司 | Preparation method of cyclopropylamine intermediate gamma-methyl chlorobutyrate |
| CN109369432B (en) * | 2018-11-02 | 2021-06-25 | 永农生物科学有限公司 | Preparation method of (S) -4-chloro-2-aminobutyrate |
| CN113009012A (en) * | 2021-02-22 | 2021-06-22 | 北京诺康达医药科技股份有限公司 | Detection method of 4-chlorobutyric acid |
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