CH645617A5 - Trifluoroethylating agent, its preparation and its use for the introduction of a trifluoroethyl group into a nucleophilic compound - Google Patents

Description

The invention relates to a compound of the formula I:

F (CF2) nS020CH2CF3 (I)

where n is an integer from 3 to 8, their preparation and their use for introducing a 2,2,2-trifluoroethyl group into a nucleophilic compound.

British Patent Nos. 1143481, 1178124, 1179125 also describe methods for introducing a 2,2,2-trifluoroethyl group, but without disclosing the alkylating agents of Formula I.

It has now surprisingly been found that a significant improvement in the trifluoroethylation process is achieved by using the compounds according to the invention. The numbers 4, 5 and 6 are preferred for n. A particularly preferred alkylating agent is 2,2,2-trifluoroethyl perfluoro-n-butanesulfonate (n = 4).

The compounds of the formula I can be prepared analogously to methods known per se (cf. GB Patent No. 1143481), e.g. by reacting a compound of formula II:

F (CF2) nS02X (II)

with 2,2,2-trifluoroethanol in the presence of an acid-binding agent, where n is as defined above and X is fluorine or chlorine, preferably fluorine. The process 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. Diethyl ether or dioxane, dimethylformamide, tetrahydrofuran, carried out.

Suitable acid binding agents are e.g. Alkali or alkaline earth metal hydroxides or carbonates or nitrogen-containing bases, such as pyridine, diisopropylamine and preferably triethylamine.

This initially exothermic reaction can be carried out at temperatures between -15 and +60, preferably -15 to + 20 ° C. Normally you work under normal pressure. The process can also be carried out in a closed vessel. The end products are isolated and purified using customary methods.

The perfluorinated alkanesulfonyl derivatives of formula II are known and can e.g. can be obtained by the methods described in GB Patent No. 758467 and No. 1099240, respectively.

2,2,2-trifluoroethanol is also known and is produced by methods known per se.

The alkylating agents of formula I and the process for their preparation are also the subject of the invention.

The compounds of the formula I according to the invention can be used in a whole series of trifluoroethylation processes on nucleophilic compounds. Examples of such compounds are benzophenones, benzisoxazoles, anilines, diazepines, aryloxy compounds, organic mercaptans, phosphorus-containing esters and other organic amines. Examples of individual processes in which the compounds of the formula I can be used are listed schematically below.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

645 617

c (R)

(r) p

^ Ss ^ -HHCOCH ^

D (R) FtgX

(I)

ch, cf_

f Ä J

ncoch2y

30th

35

E. (r)

nhch2cii2y

(i). (r)

? H2CF3 «nch2ch2y f- (R) P-U ^ / °

(I)

G.

(R)

• hsT!

(I)

? H2CF3

(R) ^ t-O:

In the above process schemes, (R) p means one or more, identical or different substituents from halogen, alkyl, 65 alkoxy and the like. The like., and Y stands for halogen. Examples of compounds that 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) - [lH] -1,4-benzodiazepine. The trifluoroethylation reactions are advantageously carried out in anhydrous, polar, aprotic solvents such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide and sulfolane or mixtures thereof with other solvents such as hydrocarbons, e.g. Benzene, toluene; halogenated hydrocarbons, e.g. Dimethylene chloride, chloroform; Ether, such as diethyl ether or dioxane.

In processes involving a compound that has both a carbonyl and an amine group, the ratio of N-alkylation to O-alkylation largely depends on the polarity of the reaction mixture. In reactions like the one described above and others, it is sometimes advantageous - insofar as the starting materials allow it - that these are in the form of a salt, e.g. with an alkali or alkaline earth metal cation. Such salts can be prepared in a known manner either before the reaction with the compounds of the formula I or, if desired, in situ.

Reaction temperatures depend on the starting materials used, but are generally between 0 and 60 ° C, preferably - e.g. in reactions A to G - between 20 and 60 ° C.

The method according to the invention can be used to produce very different types of compounds, such as e.g. the known, pharmaceutically active products of the above-mentioned processes A to C or the known starting materials (for pharmaceutically active substances), which are obtained by the above-mentioned processes D to G.

Further examples of compounds which can be trifluoroethylated by the process according to the invention can be seen from GB Patent No. 1143481.

The following examples illustrate the invention.

Example 1:

315 g of perfluorobutanesulfonyl fluoride and 100 g of 2,2,2-trifluoroethanol in 200 ml of tetrahydrofuran are cooled to a temperature of -10 ° C or lower with salt water. A solution of 100 g of triethylamine in 200 ml of tetrahydrofuran is then slowly added dropwise, keeping the temperature at -10 ° C or lower. After the addition is complete, the mixture is stirred for a further 30 min and the reaction mixture is then slowly poured onto 2.5 l of ice water.

The lower layer is separated, washed with water and dried over sodium sulfate. Vacuum distillation gives 2,2,2-trifluoroethyl perfluoro-n-butane sulfonate; Bp 141 ° C (50 ° C / 30 mbar).

Example 2:

The following compounds of the formula I can be prepared in an analogous manner by using appropriate starting materials: starting material (° C.) end product

C3F7S020F Kp. 36 C3F7S020CH2CF3

CsF „SO2OFKp.90 CsFuSOîOCHjCFj

CeF! 3S020F Kp. 114-115 C6F13S020CH2CF3

C7FI5S020FKp. 135 C, F15S020CH2CF3

C8F17S020FKp. 155 C8F17S020CH2CF3

Example 3:

Preparation of 7-chloro-l, 3-dihydro-5-phenyl-l- (2,2,2-trifluoroethyl) - [2H] -1,4-benzodiazepin-2-one

A solution of 30 g desmethyldiazepam and 7 g sodium methoxide in 350 ml toluene and 50 ml dimethylformamide is stirred vigorously at 60 ° C. for 15 minutes. The reaction mixture is then cooled to room temperature and 50 g of 2,2,2-trifluoro-ethyl perfluoro-n-butanesulfonate in 30 ml of toluene are added dropwise, after which the mixture is heated to 40 ° C. for 4 h. This mixture is then again cooled to room temperature and poured onto 0.5 l of water. The organic phase is separated off,

645 617

4th

washed with water, dried over sodium sulfate and evaporated in a rotary evaporator. After recrystallization from methanol, the title product is obtained. M.p. 164-166 ° C.

Example 4:

Preparation of 5-chloro-2- [(2,2,2-trifluoroethyl) amino] benzophenone A mixture of 80 g of 5-chloro-2- (tosylamino) benzophenonium trium salt (prepared in the usual way), 50 ml of 2.2 , 2-trifluoro-ethyl perfluoro-n-butanesulfonate and 200 ml of dimethylformamide are boiled under reflux for 3 h. The reaction mixture is then poured onto 11 ice water with stirring and filtered, resulting in a white-cream-colored product. This is heated and the water which separates out is separated off. The rest is then covered with 150 ml of 98% sulfuric acid and stirred vigorously at 80 ° C. for 1 h. The reaction mixture is cooled, poured onto ice water and neutralized with concentrated NaOH solution. After recrystallization from isopropanol, the title product melts at approximately 100 ° C.

Example 5:

The following compounds can also be prepared by the methods mentioned herein.

a) 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -l- (2,2,2-trifluoro-ethyl) - [2H] -l, 4-benzodiazepin-2-one (mp. 124-127 ° C), which can be converted into the corresponding thion by reaction with P2S5 in dioxane (mp. 83-85 ° C).

5 b) 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -1 - (2,2,2-trifluoroethyl) - [lH] -1,4-benzodiazepine (mp. 83-85 ° C ).

c) 5-chloro-l- (2,2,2-trifluoroethyl) -3-phenyl-2, l-benzisoxazolium salt.

d) N- (2,2,2-trifluoroethyl) -p-chloroaniline (bp. 116-119 ° C / 16 mm).

io e) 5-chloro-2 - [(2,2,2-trifluoroethyl) amino] -2'-chlorobenzophenone.

f) 5-Chloro-2 - [(2,2,2-trifluoroethyl) amino] -2'-fluorobenzophenone.

g) 5-Chloro-2- [N- (2,2,2-trifluoroethyl) chloroacetamide] benzophenone.

15 h) 5-Chloro-2- [N- (2,2,2-trifluoroethyl) bromoacetamide] benzophenone.

i) 5-chloro-2- [N- (2,2,2-trifluoroethyl) bromoacetamide] -2'-fluoro-benzophenone.

j) 2 - [(2-bromoethyl) - (2,2,2-trifluoroethyl) amino] -5-chlorobenzo-

20 phenone.

k) 2 - [(2-bromoethyl) - (2,2,2-trifluoroethyl) amino] -5-chloro-2'-fluoro-benzophenone.

R

Claims (9)

645 617 1. Compound of formula (I): F (CF2) nS020CH2CF3 (I) where n is an integer between 3 and 8. 2. A compound according to claim 1, wherein n is 4, 5 or 6. 2nd PATENT CLAIMS 3. 2,2,2-trifluoroethyl perfluoro-n-butanesulfonate according to claim 1. 4. A process for the preparation of a compound according to claim 1, characterized in that a compound of formula (II): F (CF2) nS02X (II) wherein n is as defined in claim 1, and X is fluorine or chlorine, reacted with 2,2,2-trifluoroethanol. 5. A method according to claim 4, which is carried out in the presence of an acid-binding agent and under anhydrous conditions. 6. The use of a compound of formula (I): F (CF2) nS020CH2CF3 (I) where n is an integer between 3 and 8 for introducing a trifluoroethyl group into a nucleophilic compound. 7. Use according to claim 6, wherein the compound of formula (I) used is 2,2,2-trifluoroethyl perfluoro-n-butanesulfonate. 8. Use according to one of claims 6 or 7, wherein the nucleophilic compound is one of the following: (R) (R) (R) H (R) » (R) (R) p H (R) • NC H (R) (R) wherein (R) p represents one or more, identical or different substituents from the group halogen, alkyl or alkoxy and Y represents halogen. 9. Use according to one of claims 6 or 7, wherein the nucleophilic compound 7-chloro-l, 3-dihydro-5-phenyl- [2H] -l, 4-benzodiazepin-2-one; 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) - [lH] -l, 4-benzodiazepine or amino-5-chlorobenzophenone.