GB2065112A - Agent for Trifluoroethylation of Nucleophilic Compound - Google Patents
Agent for Trifluoroethylation of Nucleophilic Compound Download PDFInfo
- Publication number
- GB2065112A GB2065112A GB8037131A GB8037131A GB2065112A GB 2065112 A GB2065112 A GB 2065112A GB 8037131 A GB8037131 A GB 8037131A GB 8037131 A GB8037131 A GB 8037131A GB 2065112 A GB2065112 A GB 2065112A
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- GB
- United Kingdom
- Prior art keywords
- compound
- trifluoroethyl
- formula
- chloro
- trifluoroethylation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the introduction of a 2,2,2-trifluoroethyl group into a nucleophilic compound using a 2,2,2- trifluoroethylation agent of the formula I F(CF2)nSO2OCH2CF3 I wherein n represents a whole number from 3 to 8.
Description
SPECIFICATION
Improved Alkylation Process
The present invention relates to an improved process for the alkylation of nucleophilic compounds and to reagents suitable for carrying out this process.
In particular the invention concerns a process for the introduction of a 2,2,2-trifluoroethyl group into a nucleophilic compound which comprises reacting said compound with a 2,2,2-trifluoroethylation agent of the formula I F(CF2)nSo2oCH2CF3 wherein n represents a whole number from 3 to 8.
British Patents Nos. 1,143,481, 1,179,124 and 1,179,124 describe processes for the introduction of the 2,2,2-trifluoroethyl group but do not disclose the compounds of the formula
It has now surprisingly been found that by employing the reagents according to the invention a marked improvement in the efficacy of the trifluoroethylation process is obtained. Particularly preferred for n are whole numbers from 4 to 6. A particularly preferred reagent in this respect is 2,2,2trifluoroethyl perfluoro-n-butane sulphonate (n=4).
The compounds of the formula I can be prepared analogously to known methods (c.f. British
Patent No. 1,143,481) for example by reacting a compound of the formula II F(CF2)nS02X II with 2,2,2-trifluoroethanol in the presence of an acid acceptor whereby n has the meaning assigned to it above and X represent chlorine or fluorine, preferably fluorine.
The reaction is carried out under anhydrous conditions and preferably in an inert solvent such as a hydrocarbon (e.g. toluene, benzene) a halogenated hydrocarbon (e.g. methylene dichloride, chloroform) or an ether e.g. diethyiether or dioxane, dimethylformamide, tetrahydrofuran.
Suitable acid acceptors are e.g. alkali- or alkaline-earth-metal hydroxides or carbonates or nitrogen containing bases such as pyridine, diisopropylamine and preferably triethylamine.
The initially exothermic reaction may be performed at a temperature of between -1 50C and +600C preferably --15 OC and +200 C. Normal pressure is usually employed although the reaction may be performed in a sealed reactor. The end products are separated and purified in conventional manner.
The hyperfluorinated alkanesulfonyl derivatives of the formula II are known and may be obtained e.g. by methods described in British Patents 758,467 or 1,099,240. The 2,2,2-trifluoroethanol is also known and may be prepared by conventional methods.
The reagents of the formula I also form part of the invention as does the process for preparing them.
The compounds of the formula I can be employed according to the invention in a wide range of trifluoroethylation reactions with nucleophilic compounds. Examples of such compounds are benzophenones, benzisoxazoles, anilines, diazepines, aryloxy compounds, organic mercaptans, phosphorous esters, other organic amines. Examples of specific processes in which the compounds of the formula I can be employed may be schematically illustrated as follows:
In the above reaction schemes (R)p represents one or more, same or different substituents selected from halogen alkyl, alkoxy and the like and Y represents halogen.Examples of compounds which can be prepared in this way are the pharmacologically active substances 7-chloro-1 ,3-dihydro- 5-phenyl- 1 -(2,2,2-trifluoroethyl)-2H- 1 ,4-benzodiazepin-2-one; 7-chloro- 1 ,3-dihydro-5-(2- fluorophenyl)-1 -(2,2,2-trifluoroethyl)- 1 H-1 ,4-benzodiazepine.
The trifluoroethylation reactions according to the invention are advantageously carried out in
anhydrous polar aprotic solvents such as dimethylformamide, dimethylsulphoxide, dimethylacetamide and sulpholane, or mixtures of these with other solvents such as hydrocarbons e.g. benzene, toluene;
halogenated hydrocarbons e.g. dimethylene chloride, chloroform; ethers such as dimethylether or dioxane.
In reactions involving compounds containing both an amine and a carbonyl group the ratio of Nalkylation to O-alkylation is governed by the polarity of the reaction medium. In reactions such as those
described above and others, where the starting materials allow it, it is sometimes advantageous for
them to be present in the form of a salt, for example with an alkali- of alkaline-earth-metal cation. Such
salts can be prepared in known manner either prior to reaction with compounds of the formula I or if
desired in situ.
Reaction temperatures employed depend on the starting materials involved but will in general lie
between OOC and 600C preferably, for examlple in the case of the reactions A--H, 206C and 600C.
A wide variety of products may be produced by the process of the invention, for example, the
known pharmaceutically active products of processes A to C above, or the known intermediates for
pharmaceutically active compounds produced by processes D to H above.
Further examples of compounds which can be trifluoroethylated according to the present invention can be found in British Patent 1,143,481.
The following examples illustrate the invention.
Example 1 2,2,2-Trifluoroethyl-perfluoro-n-butane Sulphonate
315 g of perfluorobutanesulphonyl fluoride and 100 g of 2,2,2-trifluoroethanoi in 200 ml of tetrahydrofuran were cooled with brine to a temperature of -1 00C or lower. A solution of 100 g of triethylamine in 200 ml of tetra-hydrofuran was then slowly added dropwise whereby the temperature was maintained at --100C or lower. After addition was complete stirring was continued for a further 30 minutes and immediately following this, the reaction mixture was slowly poured into 2.51 of ice/water.
The lower layer was separated, washed again with water and dried over sodium sulphate.
Vacuum distillation produced 2,2,2-trifluoroethylperfluoro-n-butanesulphonate b.p. 141 0C (50"C/30mbar).
Example 2
In an analogous manner, using the appropriate starting materials the following compounds of the formula I can be prepared:
Starting material End pro duct
C3F7SO2OF b.p. 360C C3F7SO2OCH2CF3 CsF1rSO2OF b.p. 900C C5F,,SO2OCH2CF3
C6F,3SO2OF b.p. 114-11 50C C8F,3SO2OCH2CF3 CwFr5SO2OF b.p. 1 350C C7F,5SO2OCH2CF3 C8F,7SO2OF b.p. 1 550C C8F,7SO2OCH2CF3
Example 3
Preparation of 7-chloro-1 ,3-dihydro-5-phenyl-1 -(2,2,2-trifluoroethyl)-2H-1 A-benzodiazepin-2- one.
A solution of 30 g desmethyldiazepam and 7 g of sodium methoxide in 350 ml of toluene and 50
ml of dimethylformamide was vigorously stirred at 600C for 1 5 minutes. The reaction mixture was then
cooled to room temperature and 50 g of 2,2,2-trifluoroethylperfluoro-n-butanesulphonate in 30 ml of
toluene added dropwise thereto after which the mixture was warmed to 400C for 4 hours. This mixture
was then again cooled to room temperature and poured on to 0.51 of water. The organic phase was
separated, washed with water, dried over sodium sulphate and evaporated in a rotary evaporator. After
recrystallisation from methanol the title product is obtained, m.p. 1 64-1 66 OC.
Example 4
Preparation of 5-chloro-2 [(2,2,2trifluornethyl)amino]benzophenone.
A mixture of 80 g of 5-chloro-2-(tosylamino)benzophenone sodium salt (prepared in conventional
manner), 50 ml of 2,2,2-trifluoroethyl perfluoro-n-butanesulphonate and 200 ml dimethylformamide was boiled under reflux for 3 hours. The reaction mixture was then poured with stirring into a litre of a
mixture of ice and water and filtered giving a whitish cream product. This was then heated and the water which separates decanted off. The residue was then covered with 1 50 ml of 98% sulphuric acid and vigorously stirred at 800C for 1 13 hours. The reaction mixture was cooled, poured on to a mixture of
ice and water and neutralised with concentrated NaOH solution. After recrystallisation of the filtered
product from isopropanol the title product is obtained m.p. 100--101 OC.
Example 5
Following the procedure set out hereinbefore, the following compounds may be prepared.
a) 7-Chloro-1 ,3-dihydro-5-(2-fluorophenyl)-1 -(2,2,2-trifluoroethyl)-2H-1 ,4-benzodiazepin-2-one, m.p. 124-1 C, which can be reacted with P2S5 in dioxane to give the corresponding thione, m.p.
138-1 390C.
b) 7-Chloro-1 ,3-dihydro-5-(2-fluorophenyl)- 1 -(2,2,2-trifluoroethyl)- 1 H- 1 ,4-benzodiazepine, m.p.
83--859C.
c) 5-Chloro-l -(2,2,2-trifluoroethyl-3-phenyl-2,1 -benzisoxazolium salt.
d) N-(2,2,2-trifluoroethyl)-p-chloroaniline, m.p. 11 6-11 90C/1 6mm.
e) 5-Chloro-2-[(2,2,2-trifluoroethyl)amino]-2'-chlorobenzophenone.
f) 5-Chloro-2-[(2,2,2-trifluoroethyl)amino]-2'-fluoro-benzophenone.
g) 5-Chloro-2-[N-(2,2,2-trifluoroethyl)chloroacetamidojbenzophenone.
h) 5-Chloro-2-[N-(2,2,2-trifluoroethyl)bromoacetamido]-benzophenone.
i) 5-Chloro-2-[N-(2,2,2-trifluoroethyl)bromoacetamido]-2'-fluoro-benzophenone.
j) 2-[(2-bromoethyl)-(2,2,2-trifluoroethyl)amino]-5-chloro-benzophenone.
k) 2-[(2-bromoethyl)-(2,2,2-trifluoroethyl)amino]-5-chloro-2'-fluoro-benzophenone.
Claims (12)
1. A process for the introduction of a 2,2,2-trifluoroethyl group into a nucleophilic compound which comprises reacting said compound with a 2,2,2-trifluoroethylation agent of the formula I F(CF2)nSo20CH2CF3 wherein n represents a whole number from 3 to 8.
2. A process as claimed in Claim 1 wherein the compound of the formula I employed therein is 2,2,2-trifluoroethylperfluoro-n-butanesulphonate.
3. A process as claimed in Claim 1 or Claim 2 wherein the compound obtained is selected from the group consisting of
wherein (R)p represents one or more same or different substituents selected from halogen, alkyl or alkoxy and Y represents halogen.
4. A process as claimed in any one of Claims 1 to 3 wherein the compound obtained is 7-chloro 1 ,3-dihydro-5-phenyl- 1 -(2,2,2-trifluoroethyl)-2 H- 1 ,4-benzodiazepin-2-one; 7-chloro- 1 ,3-dihydro-5- (2-fluorophenyl)-1 -(2,2,2-trifluoroethyl)-1 H-1 ,4-benzodiazepine or 2,2,2-trifluoroethylamino-5-chlorobenzophenone.
5. A compound of the formula I F(CF2)nSo2oCH2CF3 wherein n represents a whole number from 3 to 8.
6. A compound as claimed in Claim 5 wherein n represents a whole number from 4 to 6.
7. 2,2,2-Trifluoroethyl-perfluoro-n-butanesulphonate.
8. A process for preparing a compound as claimed in Claim 5 which comprises reacting a compound of formula II F(CF2)nS02X 11 wherein n is as defined above and X represents fluorine or chlorine preferably fluorine with 2,2,2trifluoroethanol.
9. A process as claimed in Claim 8 when carried out in the presence of an acid acceptor and under substantially anhydrous conditions.
10. The use of a compound according to Claim 5, 6 or 7 for the trifluoroethylation of nucleophilic compounds.
11. A trifluoroethylated compound whenever prepared by a process according to any one of
Claims 1 to 4.
12. A process according to any one of Claims 1 to 4, 8 and 9 substantially as hereinbefore described with reference to the examples.
1 3. A compound according to Claim 5, 6 or 7 substantially as hereinbefore described with reference to the examples.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8037131A GB2065112B (en) | 1979-11-23 | 1980-11-19 | Agent for trifluoroethylation of nucleophilic compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7940623 | 1979-11-23 | ||
GB8037131A GB2065112B (en) | 1979-11-23 | 1980-11-19 | Agent for trifluoroethylation of nucleophilic compound |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2065112A true GB2065112A (en) | 1981-06-24 |
GB2065112B GB2065112B (en) | 1983-11-09 |
Family
ID=26273670
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8037131A Expired GB2065112B (en) | 1979-11-23 | 1980-11-19 | Agent for trifluoroethylation of nucleophilic compound |
Country Status (1)
Country | Link |
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GB (1) | GB2065112B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0646575A1 (en) * | 1993-09-30 | 1995-04-05 | Minnesota Mining And Manufacturing Company | Process for preparing fluorocarbon fluoroalkanesulfonates |
EP1010696A1 (en) * | 1998-12-14 | 2000-06-21 | SSP Co., Ltd. | Method of preparing Oxoquazepam |
EP1283201A1 (en) * | 2001-08-10 | 2003-02-12 | A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. | Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-n-(2-piperidyl-methyl)-benzamide (flecanide) |
US7759512B2 (en) * | 2008-07-21 | 2010-07-20 | 3M Innovative Properties Company | Aqueous methods for making fluorinated sulfonate esters |
CN102076658A (en) * | 2008-05-29 | 2011-05-25 | 罗地亚管理公司 | Method for the sulphonylation of a hydroxylated organic compound |
-
1980
- 1980-11-19 GB GB8037131A patent/GB2065112B/en not_active Expired
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0646575A1 (en) * | 1993-09-30 | 1995-04-05 | Minnesota Mining And Manufacturing Company | Process for preparing fluorocarbon fluoroalkanesulfonates |
US5550273A (en) * | 1993-09-30 | 1996-08-27 | Minnesota Mining And Manufacturing Company | Process for preparing fluorocarbon fluoroalkanesulfonates |
EP1010696A1 (en) * | 1998-12-14 | 2000-06-21 | SSP Co., Ltd. | Method of preparing Oxoquazepam |
US6252067B1 (en) * | 1998-12-14 | 2001-06-26 | Ssp Co., Ltd. | Method of preparing oxoquazepam |
KR100630375B1 (en) * | 1998-12-14 | 2006-09-29 | 히사미쓰 메디카루 가부시키가이샤 | Method of preparing oxoquazepam |
EP1283201A1 (en) * | 2001-08-10 | 2003-02-12 | A.M.S.A. ANONIMA MATERIE SINTETICHE E AFFINI S.p.A. | Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-n-(2-piperidyl-methyl)-benzamide (flecanide) |
US6599922B2 (en) | 2001-08-10 | 2003-07-29 | A.M.S.A. Anonima Materie Sintetiche E Affini S.P.A. | Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide (FLECAINIDE) |
CN102076658A (en) * | 2008-05-29 | 2011-05-25 | 罗地亚管理公司 | Method for the sulphonylation of a hydroxylated organic compound |
CN102076658B (en) * | 2008-05-29 | 2013-10-30 | 罗地亚管理公司 | Method for sulphonylation of hydroxylated organic compound |
US7759512B2 (en) * | 2008-07-21 | 2010-07-20 | 3M Innovative Properties Company | Aqueous methods for making fluorinated sulfonate esters |
CN102105442A (en) * | 2008-07-21 | 2011-06-22 | 3M创新有限公司 | Aqueous methods for making fluorinated sulfonate esters |
CN102105442B (en) * | 2008-07-21 | 2014-08-06 | 3M创新有限公司 | Aqueous methods for making fluorinated sulfonate esters |
Also Published As
Publication number | Publication date |
---|---|
GB2065112B (en) | 1983-11-09 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19921119 |