CN105418406A - 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method - Google Patents
3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method Download PDFInfo
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- CN105418406A CN105418406A CN201510921506.0A CN201510921506A CN105418406A CN 105418406 A CN105418406 A CN 105418406A CN 201510921506 A CN201510921506 A CN 201510921506A CN 105418406 A CN105418406 A CN 105418406A
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- difluoro
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- difluoro cyclobutyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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- 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
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- 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
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
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Abstract
The invention relates to a 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method. The method mainly solves the technical problem of existing preparing methods that the price of the raw material 3-oxo-cyclobutylcarboxylic acid or 3-methylenecyclobutane-carbonitrile and the price of the fluoro reagent DAST are high, and therefore large-scale production can not be conducted. According to the 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method, conventional methyl acrylate and 1,1-dichloro-2,2-difluoroethylene which are easy to obtain are taken as raw materials, and 3,3-gem-difluoro cyclobutanecarboxylic acid is obtained through addition, hydrolysis and hydrogenation. Please see the description for the chemical equation. The 3,3-gem-difluoro cyclobutanecarboxylic acid industrial preparation method is simple, practical and quite low in preparing cost.
Description
Technical field
The present invention relates to the preparation method of a kind of 3,3-together with difluoro cyclobutyl formate, particularly 3,3-of a kind of practicability and effectiveness together with the industrialized process for preparing of difluoro cyclobutyl formate.
Background technology
3,3-together with difluoro cyclobutyl formate be preparation some medicines key intermediate, generally with 3-oxo ring fourth carboxylic acid for prepared by starting raw material, also have the reaction scheme that minority bibliographical information is starting raw material with 3-oxo cyclobutyronitrile.But above two kinds of expensive raw material price, two synthetic methods are applicable to preparation a small amount of in the lab 3,3-together with difluoro cyclobutyl formate.Up to the present, the industry of practicability and effectiveness is prepared 3,3-and is had no report together with the method for difluoro cyclobutyl formate.
Once report two kinds of conventional preparation methods in document, method one, with 3-oxo ring fourth carboxylic acid for raw material, with benzyl bromine protection carboxylic acid, be then obtained by reacting two fluoro things with fluoro reagent DAST; Last hydrogenation deprotection, obtains target product 3,3-together with difluoro cyclobutyl formate; Method two, with 3-methylene radical cyclobutyl formonitrile HCN for raw material, initial oxidation is ketone, then reacts with fluoro reagent DAST, obtains two fluoro things; Finally hydrolysis obtains target product carboxylic acid.
Document synthetic route 1:
Document synthetic route 2:
Analyze above two kinds of preparation methods, we find that the subject matter of suitability for industrialized production target product is raw material and fluoro reagent cost intensive, and the yield of fluoro step is undesirable.Therefore, we consider to find cheap starting raw material, use fluoro raw material to replace expensive fluoro reagent, and good for yield step are put into the second half section of synthetic route.
Summary of the invention
The object of this invention is to provide the industrialized process for preparing of a kind of 3,3-together with difluoro cyclobutyl formate, mainly solving that raw material that existing preparation method exists and fluoro reagent costliness cause can not the technical problem of large-scale production.
technical scheme of the present invention: a kind of 3,3-, together with difluoro cyclobutyl formate industrialized process for preparing, comprises the following steps, with methyl acrylate and 1 that is conventional, that be easy to get, chloro-2, the 2-difluoroethylenes of 1-bis-are raw material, pass through addition, hydrolysis, hydrogenation three-step reaction obtains 3,3-together with difluoro cyclobutyl formate.
concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, with methyl acrylate and chloro-2, the 2-difluoroethylenes of 1,1-bis-as starting raw material, solvent-free reaction, 150 DEG C of reactions, warp and water azeotropic distillation purifying obtain chloro-3, the 3-difluoro ring fourth methyl-formiates of 2,2-bis-.Hydrolysis reaction is with potassium hydroxide or aqueous sodium hydroxide solution for alkali, and 15-20 DEG C of reaction 1-3 hour, obtains chloro-3, the 3-bis-fluoro-1-alkene ring fourth carboxylic acids of 2-.Hydrogenation take methyl alcohol as solvent, and palladium carbon is catalyzer, and add the triethylamine of chloro-3, the 3-bis-fluoro-1-alkene ring fourth carboxylic acid equivalents with 2-, 45-50 DEG C of reaction is obtained by reacting target product 3,3-for 18-20 hour together with difluoro cyclobutyl formate.
beneficial effect of the present invention: reaction process of the present invention is selected rationally, and which employs economy and be easy to get, can the methyl acrylate of large-scale production and chloro-2, the 2-difluoroethylenes of 1,1-bis-be raw material, by addition, hydrolysis, hydrogenation obtains 3,3-together with difluoro cyclobutyl formate.Its overall yield reaches 44-53%.The invention solves existing 3,3-and be confined to laboratory preparation together with difluoro cyclobutyl formate preparation technology, there is no the problem of large-scale production, provide a kind of practicability and effectiveness, lower-cost 3,3-together with the industrialized process for preparing of difluoro cyclobutyl formate.
Embodiment
The following example contributes to understanding the present invention, but is not limited to content of the present invention.
the synthesis of chloro-3, the 3-difluoro ring fourth methyl-formiates of 2,2-bis-
Chloro-for 1,1-bis-2,2-difluoroethylenes (618g, 4.64mol) are cooled to-10-0 DEG C, and methyl acrylate (200g, 2.32mol) mixes, and adds autoclave.Reacting by heating to 150 DEG C, reaction 15-20 hour, obtains the reaction solution containing product.
Get above-mentioned reaction solution 50g, with sodium hydroxide adjusted to ph 5-7, be then evaporated to 50-100mL, add 100mL water, normal pressure concentrates, and collects distillate, with dichloromethane extraction (100mL*3), concentrated organic phase obtains 16g fine work (yield 65 ~ 70%).Nuclear-magnetism characterizes
1hNMR (CDCl
3) 9.78 (1H, s), 3.23 (1H, m), 3.10 (1H, m), 2.80 (1H, m).
chloro-3, the 3-bis-fluoro-1-alkene ring fourth carboxylic acids of 2-
Preparation mass percentage concentration is the aqueous sodium hydroxide solution (250mL) of 20%.Control charge temperature 5-15 DEG C, chloro-for 2,2-bis-3,3-difluoro rings fourth methyl-formiate (96g, 0.44mol) are added in above-mentioned aqueous sodium hydroxide solution in batches.After having fed in raw material, continue at 15-20 DEG C of reaction 1-3 hour.Follow the tracks of reaction to terminate, add water (100mL), then uses concentrated hydrochloric acid adjust ph to 1-2, then use methyl tertiary butyl ether (150mL*3) to extract.By concentrated for organic phase dry, obtain 57g sterling (yield 75 ~ 80%).Nuclear-magnetism characterizes
1hNMR (CDCl
3): 9.78 (1H, s), 3.23 (2H, t, J=3.6Hz).
3,3-is together with difluoro cyclobutyl formate
By chloro-for 2-3,3-bis-fluoro-1-alkene ring fourth carboxylic acid (56.9g, 0.34mol), triethylamine (68g, 0.68mol), 10% wet palladium carbon (5.7g) is added in methyl alcohol (570mL).Control hydrogen pressure 45-50psi, temperature 45-50 DEG C, reaction 18-20 hour.Follow the tracks of reaction to terminate, be cooled to 20-25 DEG C, Filtration of catalyst.It is in 5% sodium bicarbonate aqueous solution (270mL) that the organic phase that filtration obtains is added to mass percentage concentration, is evaporated to 350-400mL, then uses concentrated hydrochloric acid adjust ph to 1-2, continues with methylene dichloride (200mL*3) extraction.Organic phase will be obtained concentrated dry, obtain 42g product (yield 90 ~ 95%).Nuclear-magnetism characterizes
1hNMR (CDCl
3): 11.07 (1H, s), 3.01 (1H, m), 2.90 (4H, m).
Claims (5)
1. one kind 3,3-together with difluoro cyclobutyl formate industrialized process for preparing, to it is characterized in that with methyl acrylate that is conventional, that be easy to get and chloro-2, the 2-difluoroethylenes of 1,1-bis-, for raw material, obtaining 3,3-together with difluoro cyclobutyl formate by addition, hydrolysis, hydrogenation three-step reaction; Described reaction formula is
。
2. according to claim 13,3-together with difluoro cyclobutyl formate industrialized process for preparing, it is characterized in that, the first step addition reaction: solvent-free reaction, product and water azeotropic distillation purifying obtain chloro-3, the 3-difluoro ring fourth methyl-formiates of 2,2-bis-; Second step hydrolysis reaction: sodium hydroxide or potassium hydroxide aqueous solution make alkali; 3rd step hydrogenation: take methyl alcohol as solvent, palladium carbon is catalyzer, adds triethylamine, obtains 3,3-difluoro cyclobutyl formate through conventional aftertreatment.
3. according to claim 23,3-together with difluoro cyclobutyl formate industrialized process for preparing, it is characterized in that, the first step addition reaction: 150 DEG C of reaction 15-20 hour.
4. according to claim 23,3-together with difluoro cyclobutyl formate industrialized process for preparing, it is characterized in that, in second step hydrolysis reaction, 2,2-bis-chloro-3, it is in 20% aqueous sodium hydroxide solution that 3-difluoro ring fourth methyl-formiate is added to mass percentage concentration at 5-15 DEG C, 15-20 DEG C of reaction 1-3 hour.
5. according to claim 23,3-together with difluoro cyclobutyl formate industrialized process for preparing, it is characterized in that, in the 3rd step hydrogenation, adds equivalent triethylamine and makes alkali, and 45-50 DEG C is reacted 18 ~ 20 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187761B (en) * | 2016-07-19 | 2018-09-21 | 江苏苏利精细化工股份有限公司 | A kind of new process of synthesis 3,3- difluoro ring butyric acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4277490A (en) * | 1978-12-04 | 1981-07-07 | Commonwealth Scientific And Industrial Research Organization | Insecticidal 1-(2-naphthyl)-cyclobutane carboxylate |
| DE3917043A1 (en) * | 1989-05-25 | 1990-11-29 | Bayer Ag | New 6-cyclo-butyl-1,2,4-triazinone derivs. - useful as herbicides and plant growth regulators |
| US5169427A (en) * | 1990-06-08 | 1992-12-08 | Bayer Aktiengesellschaft | Herbicidal cycloalkyl-substituted thiadiazolyloxyacetamides |
-
2015
- 2015-12-14 CN CN201510921506.0A patent/CN105418406A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4277490A (en) * | 1978-12-04 | 1981-07-07 | Commonwealth Scientific And Industrial Research Organization | Insecticidal 1-(2-naphthyl)-cyclobutane carboxylate |
| DE3917043A1 (en) * | 1989-05-25 | 1990-11-29 | Bayer Ag | New 6-cyclo-butyl-1,2,4-triazinone derivs. - useful as herbicides and plant growth regulators |
| US5169427A (en) * | 1990-06-08 | 1992-12-08 | Bayer Aktiengesellschaft | Herbicidal cycloalkyl-substituted thiadiazolyloxyacetamides |
Non-Patent Citations (1)
| Title |
|---|
| WILLIAM R. DOLBIER等: "3,3-difluorocyclobutene. Synthesis and Reaction with Diazomethane", 《J. ORG. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187761B (en) * | 2016-07-19 | 2018-09-21 | 江苏苏利精细化工股份有限公司 | A kind of new process of synthesis 3,3- difluoro ring butyric acid |
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Application publication date: 20160323 |