WO2016128999A1 - Process of preparation of compounds having chf 2c(o) group - Google Patents
Process of preparation of compounds having chf 2c(o) group Download PDFInfo
- Publication number
- WO2016128999A1 WO2016128999A1 PCT/IN2016/050052 IN2016050052W WO2016128999A1 WO 2016128999 A1 WO2016128999 A1 WO 2016128999A1 IN 2016050052 W IN2016050052 W IN 2016050052W WO 2016128999 A1 WO2016128999 A1 WO 2016128999A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- preparation
- chf
- group
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052740 iodine Chemical group 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 description 4
- CRLSHTZUJTXOEL-UHFFFAOYSA-N 2,2-difluoroacetyl fluoride Chemical compound FC(F)C(F)=O CRLSHTZUJTXOEL-UHFFFAOYSA-N 0.000 description 3
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 3
- -1 difluoroacetic acid ester Chemical class 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- OAWAZQITIZDJRB-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)Cl OAWAZQITIZDJRB-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
Definitions
- the present invention relates to the process of preparation of compounds having CHF 2 C(0) group .
- the U.S. Patent Application No. 2007/0191632 describes a process involving reduction of esters of chlorodifluoroacetic acid with zinc to produce difluoroacetic acid ester. It is further known that the esters of difluoroacetic acid can also be prepared by treating difluoroacetic acid with alcohol in presence of mineral acids such as sulphuric acid or phosphoric acid.
- the above process suffers from the drawback that the starting material chlorodifluoroacetic acid ester as well as difluoroacetic acid are readily not available. Furthermore, in case of reduction of chlorodifluoroacetic acid ester, the reaction generates zinc waste, thus making it industrially unfavorable.
- the present inventors have observed that carrying out the reaction of difluoroacetic acid fluoride with ethanol at 50°C makes the reaction unsafe due to the rapid and uncontrolled expulsion of HF gas.
- the present inventors observed that upon considerable lowering of reaction temperature, the same reaction proceeds to give favourable results without compromising the safety aspects, thus making it more industrially viable.
- An object of the present invention is to provide a process for the preparation of compound of Formula I,
- R is selected from hydrogen and Ci-Ce alkyl group
- the present invention provides a process for the preparation of compound of Formula I, comprising;
- R is selected from hydrogen and Ci-Ce alkyl group
- X is selected from fluorine, chlorine, bromine and iodine
- R is selected from hydrogen and Ci-Ce alkyl group
- step b) isolating compound of Formula I from the reaction mixture of step wherein step a) takes place at a temperature of not more than about 15°C.
- the present invention provides a process for the preparation of compound of Formula I, comprising;
- X is selected from fluorine, chlorine, bromine and iodine
- R is selected from hydrogen and Ci-Ce alkyl group
- step b) isolating compound of Formula I from the reaction mixture of step a), wherein step a) takes place at a temperature of not more than about 15°C.
- the compound of Formula II may be prepared by any method known in the art, for example, known in the Indian Patent No. 262804 or U.S. Patent No. 5,710,317.
- the step a) is carried out at a temperature of about 8°C to about 15°C, for about 3 hours to about 7 hours.
- the compound of Formula I is isolated by any of the methods in the art, for example, evaporation, distillation and layer separation or mixture thereof.
- the compound of Formula I as obtained by present invention, has purity of about 98% to about 99%.
- the compound of Formula I may be ethyl difluoroacetate.
- the term 'about' refers to a variation of 10% on the higher and lower side of specified parameter.
- the difluoroacetyl fluoride (65g) was passed through two towers containing 3 lg ethanol in each at a temperature of 8°C to 10°C at a rate of 16g to 25g per hour till the first tower depletes to level of 0.1% of ethanol by gas chromatography area.
- the reaction mass in first tower was distilled to separate hydrogen fluoride and ethyl difluoroacetate. Now, the second tower becomes the first tower and new tower containing fresh ethanol was introduced and the process was continued to obtain the title compound.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the process of preparation of compounds having CHF2C(O) group.
Description
PROCESS OF PREPARATION OF COMPOUNDS HAVING
CHF2C(0) GROUP
Field of Invention
The present invention relates to the process of preparation of compounds having CHF2C(0) group .
Background of Invention
The U.S. Patent Application No. 2007/0191632 describes a process involving reduction of esters of chlorodifluoroacetic acid with zinc to produce difluoroacetic acid ester. It is further known that the esters of difluoroacetic acid can also be prepared by treating difluoroacetic acid with alcohol in presence of mineral acids such as sulphuric acid or phosphoric acid. The above process suffers from the drawback that the starting material chlorodifluoroacetic acid ester as well as difluoroacetic acid are readily not available. Furthermore, in case of reduction of chlorodifluoroacetic acid ester, the reaction generates zinc waste, thus making it industrially unfavorable.
The U.S. Patent No. 5,710,317 describes a process for the preparation of ethyl difluoroacetate by reacting difluoroacetic acid fluoride with ethanol at 50°C.
The present inventors have observed that carrying out the reaction of difluoroacetic acid fluoride with ethanol at 50°C makes the reaction unsafe due to the rapid and uncontrolled expulsion of HF gas. The present inventors observed that upon considerable lowering of reaction temperature, the same reaction proceeds to give favourable results without compromising the safety aspects, thus making it more industrially viable.
Object of the Invention
An object of the present invention is to provide a process for the preparation of compound of Formula I,
Formula I
Wherein R is selected from hydrogen and Ci-Ce alkyl group
Summary of the Invention
The present invention provides a process for the preparation of compound of Formula I, comprising;
Formula I
Wherein R is selected from hydrogen and Ci-Ce alkyl group
a) reacting compound of Formula II with compound of Formula III, and
Formula II Formula III
where X is selected from fluorine, chlorine, bromine and iodine; R is selected from hydrogen and Ci-Ce alkyl group
b) isolating compound of Formula I from the reaction mixture of step wherein step a) takes place at a temperature of not more than about 15°C.
Detailed Description of the Invention
In an aspect, the present invention provides a process for the preparation of compound of Formula I, comprising;
Formula I a) reacting compound of Formula II with compound of Formula III to obtain a reaction mixture, and
Formula II Formula III
where X is selected from fluorine, chlorine, bromine and iodine; R is selected from hydrogen and Ci-Ce alkyl group
b) isolating compound of Formula I from the reaction mixture of step a), wherein step a) takes place at a temperature of not more than about 15°C.
The compound of Formula II may be prepared by any method known in the art, for example, known in the Indian Patent No. 262804 or U.S. Patent No. 5,710,317. The step a) is carried out at a temperature of about 8°C to about 15°C, for about 3 hours to about 7 hours. The compound of Formula I is isolated by any of the methods in the art, for example, evaporation, distillation and layer separation or mixture thereof.
The compound of Formula I, as obtained by present invention, has purity of about 98% to about 99%. The compound of Formula I may be ethyl difluoroacetate.
The term 'about' refers to a variation of 10% on the higher and lower side of specified parameter.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example
Preparation of Ethyl difluoroacetate
The difluoroacetyl fluoride (65g) was passed through two towers containing 3 lg ethanol in each at a temperature of 8°C to 10°C at a rate of 16g to 25g per hour till the first tower depletes to level of 0.1% of ethanol by gas chromatography area. After completion of addition, the reaction mass in first tower was distilled to separate hydrogen fluoride and ethyl difluoroacetate. Now, the second tower becomes the first tower and new tower containing fresh ethanol was introduced and the process was continued to obtain the title compound.
Yield (%): 85
Purity (%): 99.5
Claims
1. A process for the preparation of compound of Formula I, comprising:
Formula I where R is selected from hydrogen and Ci-Ce alkyl group a) reacting compound of Formula II with compound of Formula III to obtain a reaction mixture, and
Formula II Formula III where X is selected from fluorine, chlorine, bromine and iodine; R is selected from hydrogen and Ci-Ce alkyl group
b) isolating compound of Formula I from the reaction mixture of step a), wherein step a) takes place at a temperature of not more than about 15°C.
2. The process as claimed in claim 1, wherein the step a) is carried out at a temperature in the range of 8°C to 15°C.
3. The process as claimed in claim 1, wherein the step a) is carried out for a time period in the range of 3 hours to about 7 hours.
4. The process as claimed in claim 1, wherein the isolation of compound of Formula I is carried out by evaporation, distillation and layer separation or mixture thereof.
5. The compound of Formula I, as obtained from process as claimed in claim 1, having purity of about 98% to about 99%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN393/DEL/2015 | 2015-02-11 | ||
| IN393DE2015 | 2015-02-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2016128999A1 true WO2016128999A1 (en) | 2016-08-18 |
Family
ID=56615090
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2016/050052 WO2016128999A1 (en) | 2015-02-11 | 2016-02-11 | Process of preparation of compounds having chf 2c(o) group |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2016128999A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336767A (en) * | 2018-11-26 | 2019-02-15 | 山东永浩新材料科技有限公司 | A kind of dehydration synthetic method of ethyl difluoro |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0694526A1 (en) * | 1994-07-27 | 1996-01-31 | Rohm And Haas Company | Process for preparation of fluorinated beta-keto ester |
| WO2006005612A1 (en) * | 2004-07-14 | 2006-01-19 | Syngenta Participations Ag | Process for the preparation of 4,4-difluoro-3-oxobutanoic acid esters |
-
2016
- 2016-02-11 WO PCT/IN2016/050052 patent/WO2016128999A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0694526A1 (en) * | 1994-07-27 | 1996-01-31 | Rohm And Haas Company | Process for preparation of fluorinated beta-keto ester |
| WO2006005612A1 (en) * | 2004-07-14 | 2006-01-19 | Syngenta Participations Ag | Process for the preparation of 4,4-difluoro-3-oxobutanoic acid esters |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336767A (en) * | 2018-11-26 | 2019-02-15 | 山东永浩新材料科技有限公司 | A kind of dehydration synthetic method of ethyl difluoro |
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