FI74271C - Analogous process for the preparation of therapeutically useful 1,1,2-t riphenylpropane and propane derivatives. - Google Patents

Description

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(Fl) (21) Patent application - Patentansökning 80258 ^ + (22) Application date - Ansökningsdag 15.08 .8 0

National Board of Patents and Registration (23) Start date - Giitighetsdag 15.08.80

Patent-och reflisterstyrelsen (41) Date of publication - Biivit offentiig ^ Q2 βι (44) Date of dispatch and of publication. - -jq qq q ·,

Ansökan utlagd och utl.skriften publicerad y. y. / (86) Kv. application - Int ansökan (32) (33) (31) Pyydetty etuoikeus - Begärd priority 15.08.79 Hungary-Hungary (HU) G0-1455 (71) EGYT Gyogyszervegyeszet i Gyar, Kereszturi u. 30-38, Budapest, Hungary-Hungary (HU) (72) Gizella Abraham, Szeged, Tibor Horvath, Budapest, Lajos Toldy,

Budapest, Janos Borvendeg, Budapest, Endre Csanyi, Budapest,

Eva Kiss, Budapest, Ilona Hermann nee Szente, Budapest,

Kalman Tory, Budapest, Hungary-Hungary (HU) (7 * 0 Oy Koi ster Ab (5 * 0 Analog method for the preparation of therapeutically useful 1,1,2-triphenylpropane and propylene derivatives - Analogiförfarande för framställning av terapeutiskt användbara 1,1,2 -triphenylpropane- and -propender i vat

The invention relates to an analogous process for the preparation of new therapeutically useful 1,1,2-triphenylpropane and propylene derivatives of the general formula (I) A B -.

1 1 / ΓΛ CF— C - C - (7 “OR, (I) I I w

X Y

wherein A and B represent hydrogen or together form a valence bond, X and Y are the same or different and represent a phenyl group or a phenyl group having a halogen substituent in the para position, 274271 is an azido-C 1-8 alkyl group or a group having general formula (II) wherein R 2 -CH 2 -CH 2 -N (II) wherein R 2 and R 2 are independently hydrogen or a C 1-4 alkyl or C 2-4 hydroxyalkyl group or R 2 and R 3 together with the adjacent nitrogen atom form a heptamethyleneimino- , morpholino, N- / lower alkyl7piperazino, N-hydroxyalkyl / piperazino or nitroguanidino, provided that when A and B together form a valence bond and X and Y both represent phenyl, R 1 does not mean dimethylaminoethyl, diethylamino or a morpholinoethyl group in the case of the (Z) -isomers, and for the preparation of mixtures of stereoisomers and isomers thereof and acid addition salts of basic compounds of the general formula (I).

It is known that some triphenylalkene derivatives have estrogenic properties / GrundayJ. Chem. Rev. 57 (1958) 281; Carter P.R. et al. J. Chem. Soc. 1948, 150; Buu-Hoi N.P. et al. Chim. Ther. 1969, 327; Middleton W.J. et al. J. Med. Chem. 14 (1971) 1193; U.S. Patent 3,712,929 [7 · Corresponding derivatives having a basic substituent on the phenyl ring have predominantly antiestrogenic effects / Collins D.J. et al. J. Med. Chem. 14 (1971) 952-). The two main representatives of these compounds are 1- [N- (2-diethylaminoethoxy) phenyl] -1,2-diphenyl-2-chloroethylene (Clomifen) and (Z) -1- [4- (2-dimethylaminoethoxy) phenyl] -1-1. , 2-diphenyl-1-butene (Tamoxifen) -x. Palopoli F.P. et al. J. Med. Chem. 10 (1966) 84; Bedford G.R. et al. Nature 212 (1966) 733. Although both of these compounds have antiestrogenic (estrogen-suppressing and slightly estrogenic-promoting) properties, the former compound is mainly used to induce ovulation by Murray M. et al. J. Obstet. Gynaec. Br. Commonw. 78 (1971) 11087 and for the treatment of oligospermia £ Potts J.F. J. Am. Med. Ass. 231 (1975) 3 74271 9077, while the main field of application of Tamoxifen is in the treatment of breast tumors / Cole M.P. et al. Brit. J. Cancer 1971, 270 /. However, the disadvantage of both compounds is that adverse side effects such as ocular lesions occur with long-term use / Silverman H.J. Am. J. Optom. 49 (1972) 335; Roch L.M. et al. Cancer Treatment Rep. 62 (1978) 3157, liver damage / Martindale, The Extra Pharmacopoeia XXVII, 1392 (1977), The Pharmaceutical Press, London67 and thrombosis / Nevasaari K. et al. Lancet 946 (197817.

The process according to the invention provides novel compounds which have a better potency than the potency of the known compounds and which have a more specific effect than the effect of the known compounds and which cause only minor adverse side effects.

The novel compounds obtained by the method of the invention act in various ways on the endocrine system and effectively inhibit the growth of breast tumors experimentally induced by 7,12-dimethylbenz (a) anthracene (DMBA).

The term "alkyl group", used alone or in combination (such as alkoxy, azidoalkyl or hydroxyalkyl), means a straight-chain or branched saturated aliphatic hydrocarbon group having 1 to 6, preferably 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, n-isopropyl). -butyl, sec-butyl, etc., preferably methyl or ethyl). The term "halogen" embraces all four halogens, i. fluorine, chlorine, bromine and iodine.

In a preferred subgroup A of the compounds of general formula (I), A and B together form a valence bond.

Particularly preferred compounds of general formula (I) are the following derivatives: (E) -1,2-diphenyl-3,3,3-trifluoro-1H, 4- [T- (4-methylpiperazino) ethoxy] - phenylpropylene, (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- [2- (2-hydroxyethylamino) ethoxy] phenyl] propylene and (E) -1-74- (2-azidoethoxy) ) phenyl-1,2-diphenyl-3,3,3-trifluoropropene, and pharmaceutically acceptable acid addition salts thereof.

The basic compounds of general formula (I) form acid addition salts with mineral or organic acids 4, 7,471, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, lactic acid, methanesulfonic acid, sulfonic acid, p-toluene sulfate.

The compounds of general formula (I) may exist as different stereoisomers, such as (Z) and (E) isomers, threo and erythro isomers. All stereoisomers and mixtures thereof and their preparation are within the scope of the invention.

The process according to the invention for the preparation of 1,1,2-triphenylpropane and propylene derivatives of the general formula (I) and their stereoisomers and isomeric mixtures and salts is characterized in that the phenoxyalkyl halide or sulfonate of the general formula (III) IF / "Λ cf3 - c - c-^ y-o-ch2-ch2-z (hi) in which A, B, X and Y have the same meaning as above and Z represents a halogen or sulfonyloxy group is reacted with an amine of the general formula R R 2 and R 2 are as defined above, or with an alkali metal azide, and the resulting azido derivative is reduced, if desired, and the resulting amino derivative is converted, if desired, to the corresponding nitroguanidino derivative, and if desired, the individual stereoisomers are separated from the resulting isomeric mixture and, if desired, acidified. or released from its acid addition salt.

The process of the invention is preferably carried out by heating the starting material of general formula (III) with an amine of general formula R 1 H 2 NH in an inert solvent or diluent (such as alcohol, aqueous alcohol, acetone, etc.) with an acid scavenger (such as excess potassium carbonate or amine reactant). in the presence of or reacted with an alkali metal azide in dimethylformamide or preferably in aqueous 2-methoxyethanol. If desired, the azido derivative obtained can be reduced in a manner known per se, for example by means of an alkali metal hydride or hydrogen in the presence of a palladium / carbon catalyst.

In the starting materials of general formula (III), Z is preferably a halogen atom (fluorine, chlorine, bromine or iodine), an alkylsulfonyloxy group (e.g. a methylsulfonyloxy group) or an arylsulfonyloxy group (e.g. an optionally substituted phenylsulfonyloxy group such as phenylsulfonyloxy, sulfonyloxy or p-bromophenylsulfonyloxy group).

The individual stereoisomers can be isolated from their mixture by methods known per se, such as fractional crystallization.

The basic compounds of general formula (I) can be converted into their acid addition salts by reacting them with a suitable acid in an inert solvent. Of the acid addition salts, those formed with pharmaceutically acceptable acids are preferred. The bases can be liberated from the corresponding acid addition salts by treatment with strong bases.

The starting materials of general formula (III) are novel compounds. The preparation of the new starting materials is detailed in the examples.

The endocrinological and anticancer effects of the novel compounds obtained by the method of the invention are demonstrated by the following tests. The compounds to be tested are as follows: a. (E) -1,2-Diphenyl-3,3,3-trifluoro-1- <4- [2- (R) (2-hydroxyethyl) amino] ethoxy] phenyl> propylene , b. (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- [2- (4-methyl-piperazino) ethoxy] phenyl] propylene, c. (E) -1,2-diphenyl-3,3-trifluoro-1- [4- [N- (2-hydroxyethylamino) ethoxy] phenyl] propylene, d. (E) -1,2-diphenyl-3,3,3-trifluoro-1-ZJ- (2-morpholinoethoxy) phenyl] propene, e. (E) -1-Z4- (2-diethylaminoethoxy) phenyl 1,2-diphenyl-3,3,3-trifluoropropene, f. (E) -1- [N- (2-azidoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene, 6 74271 g. (E) -1,2-diphenyl-3,3,3-trifluoro-1 - [(2-nitroguanidino) ethoxy] phenylpropene.

The antiestrogenic effect was determined by the method of Harper M.J.K. et al. / J. Reprod. Fert. 13 (1967) 101 /. 24-day-old female rat pups were handed daily with 5 ug / kg estradiol for three days. The test compound was also administered orally once daily for three days. On the fourth day, the animals were sacrificed, their uteri removed and weighed. The values showing the antiestrogenic activity of some compounds of the invention (inhibition of the uterotropic effect of estradiol) are shown in Table 1.

The antiestrogenic potency of some of the compounds listed in Table 1 is similar to that of Clomifen or Tamoxifen, which were used as reference substances.

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The estrogenic (uterotropic) effect was determined by the method of Dorfman R.J. ^ Endocrinology 55 (1954) 65_7. 24-day-old female rats were treated with a single daily oral dose of test compounds. On the fourth day, the animals were sacrificed, their uteri removed and weighed. The estrogenic (uterotropic) activity values of some of the compounds of the invention are shown in Table 2. Ethynyl estradiol, a highly potent estrogenic agent, and Clomife and Tamoxifen, two known antiestrogenic agents, were also tested and their activity values are also shown.

The compounds shown in Table 2 generally have a low estrogenic effect or, in the dosage range of 0.1 to 1.0 mg / kg, have a slightly lower effect than Tamoxifen.

9 74271

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The stimulatory effect on luteinizing hormone (LH) secretion was determined as follows: 24-day-old female rat pups were treated subcutaneously with the test compound for two consecutive days. Two hours after the second treatment, the animals were bled and the plasma level of luthenizing hormone was determined by radioimmunoassay. At subcutaneous doses of 1 mg / kg, test compounds caused a marked increase in plasma LH levels. The results are shown in Table 3.

Table 3

Effect on LH level increase in female rat pups

Percentage increase in LH level compared to control animals studied

Tamoxifen 117 a 134 b 106 c 39

Note: Studies were performed in groups of 4 or 5 animals.

Dosage: 2x1 mg / kg s.c.

The effect of the new compounds on hormone-dependent tumors was studied by the method of Griswold P. et al. / Cancer Research 26 (1966) 21697 for 7,12-dimethylbenz (a) anthracene (DMBA) -induced breast tumor. Treatment was started when the tumor weight had increased to about 500 mg and the animals were treated for three months with oral doses of 20 mg / kg of the active substance administered three times a week. Tumor sizes were measured as described by the above authors and according to the method of Jordan V.C. et al. / "Europ. J. Cancer 12 (1976) 419 ?, the tumor volume was determined according to the method of Griswold. The animals were observed for another two months after the end of the treatment period and the tumors were also measured during this latter period.

i n 74271

A relative efficacy index was introduced to demonstrate the efficacy of test compounds. To calculate the relative efficacy index, the number of animals that experienced permanent or transient improvement or relief at different times was determined and evaluated according to the following table: permanent improvement 10 points transient improvement 8 points sustained relief 6 points short relief or steady state 4 points

Changes in the average number of tumors during the treatment period were evaluated according to the following scale: no increase in the number of tumors in any animal 8 points the average number of tumors doubled 6 points even greater increase in the number of tumors 0 points

According to the above scales, the scores determined for individual animals were added together and the result was expressed as a percentage of the score corresponding to the greatest effect (permanent improvement). This percentage is a relative impact index.

The results of the tests are shown in Table 4, in which case the numbers in parentheses have the following meanings: (1) permanent improvement; (2) temporary healing; (3) lasting relief; (4) short-term relief; (5) unchanged state.

12 74271

Table 4 Inhibitory effect of DMBA-induced breast cancer in rats

Tested _Effect_ Relative compound (1) (2) (3) (4) (5) 'Efficacy- ___index_ Untreated comparison - 25/25 0

Tamoxifen_2 / 5_1 / 5 _-_ 1 / 5_1 / 5_70_ a 1/5 1/5 - 3/5 - 65 b - 3/4 1/4 - 60 c 2/5 1/5 1/5 - 1/5 78 d 4/5 - 1/5 90 e 1/5 - 3/5 - 1/5 72 f 2/5 2/5 1/5 - 85 g _-_ 1 / 4_3 / 4 _-_-_ 73_

The novel compounds can be formulated into pharmaceutical compositions containing as active ingredient one or more compounds of general formula (I) as individual isomers or mixtures of isomers or as acid addition salts of basic compounds of general formula (I) together with customary inert, solid or liquid pharmaceutical carriers. These pharmaceutical compositions can be used both in human therapy and for veterinary purposes to affect the endocrine system. Some of the compounds of general formula (I) can also be used for the treatment of tumors, since they experimentally inhibit the growth of DMBA-induced tumors very effectively. The pharmaceutical compositions can be advantageously used as orally administrable preparations (such as tablets, capsules, powder mixtures, solutions, suspensions, emulsions, medicated beverages, etc.) or as parenterally administrable preparations (e.g., injectable solutions or suspensions). These compositions may contain conventional inert, solid or liquid carriers (such as starch, lactose, magnesium stearate, silica, magnesium carbonate, polyvinylpyrrolidone, water, etc.). The content of active ingredients in the compositions generally ranges from 0.05 to 98%. The pharmaceutical compositions may also contain conventional pharmaceutical additives or extenders, such as emulsifying, dispersing, wetting or disintegrating agents, buffers, and the like.

The pharmaceutical compositions can be prepared according to methods commonly used in the pharmaceutical industry.

13 74271

The daily dosage of the compounds of the invention depends on several factors, such as the age and general health of the patient, the severity of the disease, the efficacy of the individual compounds, etc. The daily oral dosage generally ranges from about 0.01 to 10 mg / kg body weight.

However, the above values are indicative only, as higher or lower doses may be used if necessary.

The invention is illustrated in more detail by the following examples.

Example 1

Preparation of erythro- and threo-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholinoethoxy) -phenyl] -propane

A mixture of 1.20 g (2.67 mmol) of erythro-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane and 4.80 g morpholine, heated to boiling point, then cooled, diluted with 50 ml of ether and washed with water until neutral. The ether solution is dried, evaporated to dryness and the residue is crystallized from hexane. 1.02 g (83.6%) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholinoethoxy) phenyl] propane are obtained; mp. 112-115 ° C.

Analysis for C 27 H 28 F 3 NO 2: Calculated: C 71.19 H 6.20 F 12.51 N 3.08% Found: C 71.07 H 6.37 F 12.71 N 2.97%.

A mixture of 3.60 g (8 mmol) of threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane and 14 g of morpholine is heated to reflux and the procedure is as described above. The product obtained is crystallized from hexane to give 2.85 g (78.3%) of threo-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholinoethoxy) phenyl] propane; mp. 88-91 ° C.

Analysis for C 27 H 28 F 3 NO 2: Calculated: C 71.19 H 6.20 F 12.51 N 3.08% Found: C 71.24 H 6.44 F 12.45 N 3.03%.

The starting materials, erythro and threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane, are prepared as follows:

Solution containing 456 g (1.17 mol) of benzyltriphenylphosphonium chloride / Vfittig G. Chem. Ber. 87 (1954) 13 in 17 ml of dry ethanol is added to a solution of 27 g (1.17 g atoms) of sodium in 500 ml of dry ethanol at 0-2 ° C. A solution of 204 g (1.17 mol) of 2,2,2-144271 trifluoroacetophenone in 100 ml of dry ethanol is combined with the resulting mixture and the mixture is allowed to stand overnight. The solution is evaporated to dryness, the residue is taken up in 800 ml of petroleum ether, filtered and the filter cake is washed. The filtrate is evaporated to dryness and the residue is distilled in vacuo. 268 g (92.5%) of 1,2-diphenyl-3,3,3-trifluoropropene are obtained; tr. 107-109 ° C / 0.2 mmHg; mp. 58-61 ° C.

Analysis for C 15 H 11 F 3: Calculated: C 72.57 H 4.47 F 22.96% Found: C 72.49 H 4.23 F 23.20%.

268 g (1.08 mol) of the product obtained above are hydrogenated at 20 [deg.] C. for 6-8 hours in 4000 ml of acetic acid in the presence of 20 g of 10% palladium / carbon catalyst. The solution is evaporated and the residue is distilled in vacuo. 252 g (93.3%) of 1,2-diphenyl-3,3,3-trifluoropropane are obtained, b.p. 94-96 ° C / 0.1 mmHg, n = 1.5100.

Analysis according to the formula: calculated: C 71.98 H 5.26 F 22.75% found: C 72.12 H 5.44 F 22.50%.

5 g (0.02 mol) of benzoyl peroxide are added to a solution of 250 g (1 mol) of the above product in 2,500 ml of carbon tetrachloride and a solution of 176 g (1.1 mol) of bromine in 500 ml is then added to the mixture. in carbon tetrachloride, at 50 ° C for 30 minutes. The resulting mixture is boiled for two hours, then cooled, washed with sodium thiosulphate solution, sodium hydrogen carbonate solution and then with water, dried and evaporated to dryness. The residue is crystallized from 1,260 ml of ethanol to give 140 g (42.6%) of erythro-1-bromo-1,2-diphenyl-3,3,3-trifluoropropane; mp. 164-165 ° C.

Analysis for C 15 H 12 Br 2 O 3: Calculated: C 54.73 H 3.67 Br 24.28 F 17.32% Found: C 54.97 H 3.93 Br 23.98 F 17.36%.

The mother liquor is evaporated to about one third of its original volume. 130 g (39.5%) of threo-1-bromo-1,2-diphenyl-3,3,3-trifluoropropane differ; mp. 91-94 ° C.

Analysis for C 15 H 12 BrF 3: Calculated: C 54.73 H 3.67 Br 24.28 F 17.32% Found: C 54.86 H 3.82 Br 24.01 F 17.27%.

is 74271

The NMR spectra of the compounds correspond to the structures shown.

270 g (0.82 mol) of the erythro-threo isomer mixture obtained above are dissolved in 2,500 ml of anisole, 110 g (0.83 mol) of anhydrous aluminum trichloride are added to the stirred solution at 6 ° C, and the mixture is allowed to stand at room temperature overnight. over the bar. The reaction mixture is poured into a mixture of 4 kg of crushed ice and 600 ml of 36% aqueous hydrochloric acid and extracted with 3 liters of chloroform. The organic solution is washed with aqueous sodium hydrogen carbonate solution and then with water, dried and evaporated to dryness. The dry residue is crystallized from 750 ml of isopropanol and the crude product obtained (162 g, 55%, m.p. 121-126 ° C) is recrystallized from 1500 ml of isopropanol. 109 g (37%) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) propane are obtained; mp. 129-131 ° C.

Analysis calculated for C 22 H 19 F 3 O: C 74.14 H 5.37 F 16.00% Found: C 74.08 H 5.47 F 15.75%.

Specifications: 3050, 3025, 2995, 2950, 2925, 2900, 2830 Cri v) c = c 1605, 1580, 1508 and 808, 786, 758, 702

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The mother liquor obtained in the first crystallization step is evaporated to dryness, the residue is taken up in 300 ml of hexane and filtered. The crude product obtained (96 g, 25%, m.p. 89-101 ° C) is recrystallized from 960 ml of isopropanol to give 41.4 g (14%) of erythro-1,2-diphenyl-3,3,3- trifluoro-1- (4-methoxyphenyl) propane; mp. 108-111 ° C.

Analysis for C 22 H 19 F 3 O: Calculated: C 74.14 H 5.37 F 16.00% Found: C 74.23 H 5.18 F 16.17%.

Spectral values: V u 3090, 3060, 3025, 3010, 2960, 2940, 2915, 2840 CH

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£ = 6.4 - 7.6 (m), 14 H.

° ie 74271 100 g (0.28 mol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) propane are heated with 300 g of pyridine hydrochloride for three hours at 200-220 ° C. The mixture is cooled, diluted with 700 ml of chloroform, washed with water until neutral, dried and evaporated to dryness. The residue is crystallized from a 1: 2 mixture of chloroform and hexane to give 85.7 g (90%) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane; mp. 123-Analysis for C 21 H 17 F 3: Calculated: C 73.67 H 5.01 F 16.65% Found: C 73.56 H 4.92 F 16.78%.

40 g (0.11 mol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) propane are reacted with 120 g of pyridine hydrochloride as described above. The resulting erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane is crystallized from a 1: 2 mixture of chloroform and hexane to give 32.5 g (84.5%). product; mp. 114-117 ° C.

Analysis for C 21 H 17 F 3 O: Calculated: C 73.67 H 5.01 F 16.65% Found: C 73.52 H 4.97 F 16.71%.

A mixture of 85.6 g (0.25 mol) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane, 400 ml of 1,2-dibromoethane and 18.5 g (0.33 mol) of powdered potassium hydroxide, boiled with stirring. The reaction mixture is diluted with 1.5 liters of dichloromethane, washed with 10% aqueous hydrochloric acid and water, dried and the solvent and excess 1,2-dibromoethane are removed by distillation in vacuo. The residue is crystallized from benzene to give 97.7 g (87%) of threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane; mp. 144-151 ° C.

Analysis for C 23 H 20 BrF 3 O: Calculated: C 61.48 H 4.49 Br 17.78 F 12.68% Found: C 61.55 H 4.57 Br 17.63 F 12.71%.

30 g (87.6 mmol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane are reacted with 1,2-dibromoethane as described above. The resulting erythro-1- [4- (2-bromoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane is crystallized from benzene to give 27.9 g (71%) of product; mp. 130-133 ° C.

I? 74271

Analysis for C 23 H 20 BrF 3 O: Calculated: C 61.48 H 4.49 Br 17.78 F 12.68% Found: C 61.60 H 4.63 Br 17.60 F 12.77%.

Example 2

Preparation of threo-1,2-diphenyl-3,3,3-trifluoro-1- [4- [2- (2-hydroxyethylamino) ethoxy] phenyl} propane

A mixture of 6.74 g (15 mmol) of threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane prepared as in Example 1 was obtained. , 15 g (150 mmol) of 2-aminoethanol and 15 ml of 2-methoxyethanol are boiled for 0.5 hours. The reaction mixture is cooled, diluted with 200 ml of chloroform, washed with water, dried and evaporated to dryness. The residue is crystallized from a 1: 1 mixture of benzene and hexane to give 4.32 g (67%) of the desired compound; mp. 120-122 ° C.

Analysis for the formula: C 69.90 H 6.10 F 13.27 N 3.26% Found: C 69.71 H 6.15 F 13.17 N 3, 35%.

Example 3

Preparation of erythro-1,2-diphenyl-3,3,3-trifluoro-1- <4- {2- [bis- (2-hydroxyethyl) aminopyethoxy} phenyl} propane

Erythro-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane (8.98 g, 20 mmol) prepared as described in Example 1 is dissolved in 42 g (400 mmol). diethanolamine and the solution is heated at 100-120 ° C for 0.5 hours. The reaction mixture is treated as in Example 2 and the residue is crystallized from a 1: 2 mixture of isopropanol hydrochloric acid solution and ether. 5.98 g (58.7%) of the desired compound are obtained; mp. 190-195 ° C.

Analysis for the Formula C27H3iclF3NO3: Calculated: C 63.59 H 6.13 Cl 6.95 F 11.18 N 2.75% Found: C 63.41 H 6.29 Cl 7.08 F 10.98 N 2 .80%.

Example 4

Preparation of erythro-1- [4- (2-azidoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane

A solution of 3.25 g (50 mmol) of sodium azide in 11 ml of water is added to a solution of 11.2 g (25 mmol) of the erythro-1- [2- (2-bromoethoxy) -phenyl] prepared according to Example 1. -1,2-Diphenyl-3,3,3-trifluoropropane in 112 ml of 2-methoxyethanol and a mixture of 18 74271 are boiled for one hour. The reaction mixture is evaporated to dryness, 20 ml of toluene are added to the residue and the mixture is evaporated to dryness again to remove residual 2-methoxyethanol. The solid is triturated with water, filtered and washed with water. The crude product is recrystallized twice from ethanol. 7.83 g (76%) of the desired product are obtained; mp. 144-148 ° C.

Analysis for C 23 H 20 F 3 N 3 O: Calculated: C 67.14 H 4.90 F 13.85 N 10.21% Found: C 67.35 H 5.15 F 13.94 N 10.06%.

Example 5

Preparation of erythro-1- [4- (2-aminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane 5.15 g (12.5 mmol) of the erythro-1- [4- (2-Azidoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropane is hydrogenated for about one hour in a mixture of 100 ml of methanol and 40 ml of tetrahydrofuran using 0.6 g of 5- % palladium / carbon catalyst. The solution is evaporated to dryness and the residue is crystallized from hexane. 3.86 g (80.2%) of the desired product are obtained; mp. 125-127 ° C.

Analysis for the Formula c23H22F3NO: Calculated: C 71.67 H 5.75 F 14.80 N 3.63% Found: C 71.87 H 5.71 F 14.80 N 3.54%.

Example 6 Preparation of (E) * -1- [4- (2-azidoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene 9.83 g (22 mmol) of (E) -1 4- [4- (2-Bromoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene is dissolved in 100 ml of 2-methoxyethanol, a solution containing 2.86 g (44 mmol) is added. sodium azide in 10 ml of water and the mixture is boiled for one hour. The reaction mixture is treated as in Example 4 and the product is crystallized twice from ethanol. 7.40 g (82%) of the desired compound are obtained; mp. 73-75 ° C.

Analysis for C 23 H 18 F 3 N 3 O 3, Caan: Calculated: C 67.47 H 4.43 F 13.92 N 10.27% Found: C 67.61 H 4.45 F 13.77 N 10.11%.

The starting material (E) -1- [4- (2-bromoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene is prepared as follows; 45.4 g (0.2 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone / fralker D. et al .: J. Org. Chem. 30 (1965) 32407 is added to a solution of 44.7 g (0.1 mol) of the threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3 prepared according to Example 1. -trifluoropropane in 225 ml of dry benzene and the mixture is stirred and boiled for 30 hours. The reaction mixture is cooled and the separated 2,3-dichloro-5,6-dicyano-1,4-hydroquinone is filtered off. The filtrate is evaporated to dryness, the residue is taken up in 100 ml of chloroform and the separated 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is filtered off. The filtrate is diluted with 400 ml of chloroform, washed with 10% aqueous sodium hydrogen carbonate solution and then with water, dried and evaporated to dryness. The residue is crystallized from 220 ml of ethanol to give 34.4 g (77%) of crude product, melting at 110-118 ° C. The crude product, which is a 4: 1 mixture of E and Z isomers, is recrystallized from 200 ml of ethanol. 29.5 g (66%) of the E-isomer are obtained, m.p. 118-120 ° C.

Analysis for C 23 H 18 BrF 3 O: Calculated: C 61.67 H 4.06 Br 17.87 F 12.74% Found: C 61.80 H 4.15 Br 17.59 F 12.90%.

Spectral values: 3060, 3020, 2920, 2900, 2850

Vc = c 1590, 1495 YAR 815, 822, 759, 705 r = 4.08 (t), 2 H

«BrCH- = 3'46 (t) '2 H

SAr = 6'4 - 7'4 (m) '14 H ·

The mother liquor obtained above is evaporated and the residue is crystallized several times from ethanol. 2.14 g (4.8 g) of (Z) -1- [4- (2-bromoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene are obtained; mp. 135-138 ° C.

Spectral values: 3080, 3060, 3030, 2935, 2870

Lii

Uc = c 1610, 1510 YAr 832, 770, 760, 715

<5och_ = 4'28 (t) '2 H * BrCH2 = 3'59 (t)' 2 H

SAr = 6.8 - 7.4 (m), 14 H

Example 7 Preparation of (E) -1- [4- (2-aminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene 20 7 4 2 71 7.40 g (18 mmol) ( E) -1- [4- (2-Azidoethoxy) -phenyl] -1,2-di-phenyl-3,3,3-trifluoropropene prepared as described in Example 6 is dissolved in 100 ml of methanol, 0.70 g of 5 % palladium / carbon catalyst and the mixture is hydrogenated for about one hour. The catalyst is removed by filtration, the solution is evaporated to dryness and the residue is crystallized from hexane. 3.63 g (52.3%) of the desired compound are obtained; mp. 71-76 ° C.

Analysis for C 23 H 20 F 3 NO: Calculated: C 72.05 H 5.26 F 14.87 N 3.65% Found: C 72.36 H 5.30 F 14.88 N 3.52%.

Example 8 Preparation of (E) -1,2-diphenyl-3'-3,3-trifluoro-1- [4- (2-morpholinoethoxy) phenyl] propene

A mixture of 3.34 g (7.5 mmol) of (E) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene prepared according to Example 6 and 13 g of morpholine, boil for one hour. The reaction mixture is treated as in Example 1 and the crude product is crystallized from hexane. 2.80 g (82.4%) of the desired product are obtained; mp. 84-89 ° C.

Analysis according to the formula 02 ^ 25 ^ 1 ^ 02: calculated: C 71.51 H 5.78 F 12.57 N 3.09% found: C 71.80 H 5.98 F 12.70 N 3.28%.

Example 9 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- {4- [12- (methylpiperazino) -ethoxy] -phenyl] -propene 4.0 g of N-methylpiperazine are added 4, To 47 g (10 mmol) of a solution of (E) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene prepared according to Example 6 in 80 ml of dry ethanol and the mixture is boiled for six hours. The reaction mixture is evaporated to dryness and treated as described in Example 1. The product is crystallized from hexane. 3.45 g (74%) of the desired product are obtained; mp. 94-97 ° C.

Analysis for C 28 H 29 F 3 N 2 O: Calculated: C 72.08 H 6.27 F 12.22 N 6.00% Found: C 72.27 H 6.32 F 12.28 N 5.77%.

I, 2i 74271

Example 10 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- <4- [2- [4- (2-hydroxyethyl) piperazino] ethoxy] phenyl] propene

A mixture of 1.79 g (4 mmol) of (E) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene prepared according to Example 6 and 10.4 g of 1- (2-hydroxyethyl) piperazine, heated for one hour. The mixture is treated as in Example 1 and the product is crystallized from hexane. 1.35 g (68%) of the desired product are obtained; mp. 70-81 ° C.

Analysis for C 29 H 31 F 3 N 2 O 2: Calculated: C 70.14 H 6.29 F 11.48 N 5.64% Found: C 70.15 H 5.65 F 11.36 N 5.48%.

Example 11 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- [2- (2-hydroxyethylamino) ethoxy] phenyl] propylene 6.71 g (15 mmol) of Example 6 (E) -1- [4- (2-bromoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene is dissolved in a mixture of 9.15 g of 2-aminoethanol and 15 ml of 2 -metoksietanolia. The solution is boiled for 30 minutes and then treated as described in Example 2. The product is crystallized from a 1: 1 mixture of ethyl acetate and hexane. 5.29 g (83%) of the desired product are obtained; mp. 96-98 ° C.

Analysis according to the formula: calculated: C 70.24 H 5.66 F 13.33 N 3.28% found: C 70.42 H 5.80 F 13.39 N 3.23%.

Example 12 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- [bis (2-hydroxyethyl) amino] ethoxy] phenyl] propylene

A solution of (E) -1- / 4- (2-bromoethoxy) -phenyl-1,2-diphenyl-3,3,3-trifluoropropene (7.15 g, 16 mmol) prepared according to Example 6 16.8 in diethanolamine, is heated at 120-140 ° C for 0.5 hours and then treated as in Example 2. The product is crystallized from a 1: 1 mixture of ethyl acetate and hexane. 5.66 g (75%) of the desired product are obtained; mp. 113.5-116 ° C.

Analysis for C 27 H 28 F 3 NO 3: Calculated: C 68.78 H 5.99 F 12.09% Found: C 68.75 H 5.78 F 12.13%.

Example 13 Preparation of 1- [4- (2-azidoethoxy) -phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propene 22,74271 11.63 g (25 mmol) of 1- [4- (2-Bromoethoxy) -phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propane is converted to the azido derivative as described in Example 4. The product is crystallized from ethanol to give 8.54 g (80%) of the desired product; mp. 62-64 ° C.

Analysis for C 23 H 14 F 4 N 3 O: Calculated: C 64.63 H 4.01 F 17.78 N 9.83% Found: C 64.71 H 4.13 F 17.74 N 9.63%.

The starting 1- [4- (2-bromoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene is prepared by the methods described in Examples 1 and 6 as follows: 4 '-fluoro-2,2,2-trifluoroacetophenone Harkes FE et al., J. Org. Chem. 32 (1967) 1311-187 is reacted with benzyltriphenylphosphonium chloride in the presence of an ethanolic solution of sodium ethoxide. 1-Phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propene is obtained in a yield of 91%; tr. 110-114 ° C / 0.2 mmHg; mp. 43-45 ° C. Analysis for C 15 H 15 F 4 O 4: Calculated: C 67.67 H 3.79 F 28.54% Found: C 67.83 H 3.90 F 28.33%.

This compound is hydrogenated in the presence of a palladium / carbon catalyst to give 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propane (yield 91.7%); tr. 100-104 ° C / 0.2 mmHg; n ^ = = 1.4980. Analysis for C 18 H 15 F 2 F 4: Calculated: C 67.16 H 4.51 F 28.33% Found: C 67.30 H 4.68 F 28.18%.

The above product is brominated in carbon tetrachloride and the brominated product is crystallized from ethanol. 1-Bromo-1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propane is obtained (yield 48.2%); mp. 144-146 ° C.

Analysis for C 15 H 11 BrF 4: Calculated: C 51.90 H 3.19 Br 23.02 F 21.89% Found: C 51.70 H 3.18 Br 23.06 F 22.03%.

i 23 74271

The borated product is reacted with anisole in the presence of aluminum trichloride. The resulting 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -1- (4-methoxyphenyl) propane (mixture of isomers) is crystallized from isopropanol. Yield: 79.8%, m.p. 152-167 ° C.

Analysis for C 22 H 18 F 4 O: Calculated: C 70.58 H 4.85 F 20.30% Found: C 70.80 H 4.78 F 20.40%.

The above product is heated with pyridine hydrochloride and the resulting 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -1- (4-hydroxyphenyl) propane is reacted directly without purification with 1,2-dibromoethane in the presence of potassium hydroxide with heating. . The resulting 1- [4- (2-bromoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propane is crystallized from isopropanol; 15-20 ml of isopropanol are used per 1 g of crude product. The first fraction, which is a mixture of isomers, melts at 170-175 ° C.

Analysis for C 23 H 19 BrF 4 O: Calculated: C 59.11 H 4.10 Br 17.10 F 16.26% Found: C 58.88 H 4.21 Br 16.96 F 16.50%.

The mother liquor is evaporated to dryness and the solid is crystallized from benzene. Use 5 ml of benzene per gram of solid. The second fraction obtained, which is a mixture of isomers, melts at 100-110 ° C.

Analysis for the Formula ^ -HH 2 gBrF 2 O: Calculated: C 59.11 H 4.10 Br 17.10 F 16.26% Found: C 58.96 H 4.07 Br 17.05 F 16.32%.

The above two fractions are combined and boiled with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone for 25 hours as shown in Example 6. The product is crystallized from ethanol. 1- [4- (2-Bromoethoxy) -phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propane is obtained (yield 66.5%); mp. 115-118 ° C.

Analysis for C 23 H 17 BrF 4 O: Calculated: C 59.37 H 3.68 Br 17.17 F 16.33% Found: C 59.48 H 3.87 Br 17.19 F 16.51%.

Example 14 Preparation of 1- [4- (2-aminoethoxy) -phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propene 24,74271

A solution of 8.54 g (20 mmol) of 1- [4- (2-azidoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) prepared according to Example 13 ) -propylene in 170 ml of methanol, hydrogenated for about one hour using 0.9 g of 5% palladium / carbon catalyst. The solution is evaporated to dryness and the product is crystallized from hexane. 4.51 g (56.4%) of the title compound are obtained; mp. 83-89 ° C.

Analysis for C 23 H 19 F 4 NO: Calculated: C 68.82 H 4.77 F 18.93 N 3.49% Found: C 68.94 H 4.99 F 18.83 N 3.33%.

Example 15 Preparation of 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -1- [4- (2-morpholinoethoxy) phenyl] propene 3.25 g (7 mmol) of Example 13 1- [4- (2-bromoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propane prepared according to Example 1 is reacted with morpholine as described in Example 1. The product is crystallized from hexane. 2.5 g (75.7%) of the desired compound are obtained; mp. 67-69 ° C.

Analysis for C 27 H 25 F 4 NO 2: Calculated: C 68.78 H 5.35 F 16.12 N 2.97% Found: C 68.62 H 5.94 F 16.40 N 3.14%.

Example 16 Preparation of 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -1- [4- (2-morpho] aminoethoxy) phenyl] propylene 3.25 g (7 mmol) of 1 [4- (2-Bromoethoxy) -phenyl] -2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -propene is reacted with morpholino as described in Example 1. The product is crystallized from hexane. 3.03 g (92%) of the desired compound are obtained; mp. 95-96 ° C.

25 74271

Analysis for C 27 H 25 F 4 NO 2: Calculated: C 68.78 H 5.35 F 16.12 N 2.97% Found: C 68.96 H 5.83 F 15.98 N 3.00%.

The starting 1- [4- (2-bromoethoxy) phenyl] -2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propene is prepared by the method of Example 1 as follows: 2.2 , 2-Trifluoroacetogenone is reacted with triphenyl- (4-fluorobenzyl) -phosphonium chloride {Jones RA Australian J. Chem.

18 (1965) 903-_6? with ethanol in the presence of sodium ethoxide.

2-Phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -propene is obtained (90% yield); tr. 105-107 ° C / 0.2 mmHg; mp. 35-41 ° C.

Analysis for C 15 H 10 F 4 iron: calculated: C 67.67 H 3.79 F 28.54% found: C 67.58 H 3.95 F 28.50%.

The above product is hydrogenated over a palladium / carbon catalyst to give 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propane in 94% yield; tr. 95-100 ° C / 0.3 mmHg.

Analysis for C 15 H 12 F 4: Calculated: C 67.16 H 4.51 F 28.33% Found: C 67.22 H 4.73 F 28.40%.

The product obtained is brominated in carbon tetrachloride and the resulting 1-bromo-2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propane is crystallized from ethanol. Use 3.5 ml of ethanol per gram of solids. The first fraction obtained, which is a mixture of isomers, melts at 143-145 ° C.

Analysis for C 15 H 11 BrF 4: Calculated: C 51.90 H 3.19 Br 23.02 F 21.89% Found: C 51.91 H 3.13 Br 22.92 F 22.06%.

The mother liquor is evaporated to about one third of its original volume. The second fraction obtained, which is a mixture of isomers, melts at 69-76 ° C. Analysis for the Formula C 1 H 2 Cl 2 BrF 2: Calculated: C 51.90 H 3.19 Br 23.02 F 21.89% Found: C 51.74 H 3.33 Br 23.08 F 22.02% .

The overall yield is 76%.

The above fractions are combined and reacted with anisole in the presence of aluminum trichloride. The resulting 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -1- (4-methoxyphenyl) propane is crystallized from ethanol. Use 4 mg of ethanol per gram of 26 7 4 2 71 solids. The first fraction, which is a mixture of isomers, melts at 120-127 ° C.

Analysis for the formula ('22H18F4 ^: Calculated: C 70.58 H 4.85 F 20.30% Found: C 70.81 H 5.01 F 20.35%.

The mother liquor is concentrated to about one-sixth of its original volume. The second fraction obtained, which is a mixture of isomers, melts at 84-95 ° C.

Analysis for C 22 H 18 F 4 O: Calculated: C 70.58 H 4.85 F 20.30% Found: C 70.72 H 4.92 F 20.18%.

The total yield is 78.8%.

The above fractions (mixtures of isomers) are combined and heated with pyridine hydrochloride. The crude 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -1- (4-hydroxyphenyl) propene obtained is reacted directly without purification with 1,2-dibromoethane in the presence of potassium hydroxide. The resulting 1- [4- (2-bromoethoxy) phenyl, 7-2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propane is crystallized from ethanol. Use 4 ml of ethanol per gram of solid. The first fraction, which is a mixture of isomers, melts at 119-123 ° C.

Analysis for C 23 H 19 BrF 4 O: Calculated: C 59.11 H 4.10 Br 17.10 F 16.26% Found: C 59.30 H 4.16 Br 17.03 F 16.26%.

The mother liquor is evaporated to about half its original volume. The second fraction obtained, which is a mixture of isomers, melts at 72-74 ° C.

Analysis for C 23 H 19 BrF 4 O: Calculated: C 59.11 H 4.10 Br 17.10 F 16.26% Found: C 59.27 H 4.30 Br 17.13 F 16.36%.

The above fractions (mixtures of isomers) are combined and reacted with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in benzene with boiling as described in Example 6. The reaction mixture is then treated as described in Example 6 and the product is crystallized from isopropanol. 1- [4- (2-Bromoethoxy) -phenyl] -2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -propene is obtained, yield 58.4%; mp. 142-144 ° C.

27 7 4 2 71

Analysis for the Formula ^ 23 ^ 17 ^ ^ 4 ^: Calculated: C 59.37 H 3.68 Br 17.17 F 16.33% Found: C 59.20 H 3.90 Br 17.36 F 16.20% .

Example 17 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-12-4- (2-heptamethyleneiminoethoxy) phenyl-7-propene 2.32 9 (20 mmol) heptamethyleneimine is added to a solution of 4.47 g (10 mmol) of (E) -1- [4- (2-bromoethoxy) phenyl] -7,2,2-diphenyl-3,3,3-trifluoropropene prepared according to Example 6, and the mixture is boiled for 5 hours. The reaction mixture is evaporated to dryness. The procedure is then as described in Example 1 and the product is crystallized from hexane to give 3.22 g (67%) of the desired product, m.p. 73-77 ° C.

Analysis calculated for C 30 H 32 F 3 NO: C 75.13 H 6.73 F 11.88 N 2.92% Found: C 75.11 H 6.75 F 11.88 N 2.98%.

Example 18 Preparation of (E) -1-ZJ- (2-diethylaminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene picrate 5.37 g (12 mmol) of (E) -1-Zjp prepared according to Example 6 (2-Bromoethoxy) phenyl-7- [2-diphenyl-3,3,3-trifluoropropene is boiled with 8.8 g of diethylamine for five hours. The reaction mixture is diluted with 50 ml of benzene, washed with water until neutral, dried and evaporated to dryness. The residue is dissolved in 20 ml of 95% ethanol and a solution of 3.22 g (14 mmol) of picric acid in 32 ml of 95% ethanol is added. The separated crystals are removed by filtration, washed with ethanol and ether. 6.46 g (80.4%) of the desired product are obtained; mp. 131-135 ° C.

Analysis for C 33 H 31 F 3 N 4 O 2: Calculated: C 59.28 H 4.67 F 8.52 N 8.40% Found: C 59.55 H 4.78 F 8.73 N 8.35%.

Example 19 Preparation of (E) -1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene sulfate 28,74271 0.03 mL (0.55 mmol) from 98% sulfuric acid is added to a solution of 0.205 g (0.5 mmol) of (E) -1- [4- (2-dimethylaminoethoxy) -phenyl] -1H-1,2-diphenyl-3,3,3-trifluoropropene in 1.5 ml of isopropanol . The separated crystals are removed by filtration, washed with ether and the crude product is crystallized from isopropanol. 0.22 g (84.6%) of the desired product is obtained; mp. 150-153 ° C.

Analysis for C 25 H 26 F 3 NO 5 S: Calculated: C 58.93 H 5.14 F 11.19 N 2.75 S 6.29% Found: C 59.07 H 5.30 F 11.29 N 2.70 S 6.45 %.

The starting material (E) -1- [4- (2-dimethylaminoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluorioroene is prepared as follows.

10 ml of a 40% aqueous solution of dimethylamine are added to a solution of 5.37 g (12 mmol) of (E) -1- [4- (2-bromoethoxy) -phenyl] -1,2-diphenyl-3 prepared according to Example 6. , 3,3-trifluoropropene in 10 ml of ethanol. The mixture is allowed to stand for 3-4 days, then evaporated to dryness, the residue is diluted with 50 ml of benzene, the solution obtained is washed with water until neutral, dried and evaporated to dryness. The residue is crystallized from hexane. 4.26 g (86.2%) of (E) -1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene are obtained; mp. 90-91 ° C.

Analysis for C 25 H 24 F 2 NO: Calculated: C 72.98 H 5.88 F 13.85 N 3.40% Found: C 72.80 H 5.51 F 14.01 N 3.53%.

Example 20 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- <4- (2- [4- (2-hydroxyethyl) -piperazino] -ethoxy] -phenyl> -propene mesylate

A solution of 0.2 g (2 mmol) of methanesulfonic acid in 2 ml of isopropanol is added to a solution of 0.50 g (1 mmol) of (E) -1,2-diphenyl-3,3 prepared according to Example 10. 3-Trifluoro-1- <4- {2- [4- (2-hydroxyethyl) -piperazino] -ethoxy} -phenyl] -propene in 1 ml of isopropanol. The separated crystals are removed by filtration and washed with ether. 0.58 g (96.7%) of the desired compound are obtained; mp. 203-209 ° C.

29 7 4 2 71

Analysis for C 31 H 39 F 3 N 2 O 8 S 2: Calculated: C 54.06 H 5.71 F 8.28 N 4.07 S 9.31% Found: C 53.71 H 5.90 F 8.42 N 3 .81 S 9.03%.

Example 21 Preparation of (E) -1-ZJ- (2-aminoethoxy) phenyl-E-1,2-diphenyl-3,3,3-trifluoropropene tosylate

A solution of 0.20 g (1 mmol) of p-toluenesulfonic acid in 1 ml of isopropanol is added to a solution of 0.30 g (0.8 mmol) of the (E) -1- / 4- ( 2-aminoethoxy) -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene in 0.5 ml of isopropanol. The separated crystals are removed by filtration and washed with ether. 0.37 g (84%) of the desired compound is obtained; mp. 162-163 ° C. Analysis for C3qH28F3 ^ 4 ^: Calculated: C 64.85 H 5.08 F 10.26 N 2.52 S 5.77% Found: C 64.98 H 5.03 F 10.53 N 2.23 S 5.93%.

Example 22 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- (2-hydroxyethylamino) ethoxy] phenyl-propylene citrate

A solution of 0.13 g (0.6 mmol) of citric acid hydrate in 0.8 ml of acetone is added to a solution of 0.21 g (0.5 mmol) of (E) -1 prepared according to Example 11. 2-Diphenyl-3,3,3-trifluoro-1- [4- [2- (2-hydroxyethylamino) ethoxy] phenyl] propene in 0.2 ml of acetone. The mixture is cooled, the separated crystals are removed by filtration and washed with acetone. 0.18 g (58%) of the desired compound is obtained; mp. 127-129 ° C.

Analysis for C 31 H 32 F 3 NO 9: Calculated: C 60.09 H 5.21 F 9.20 N 2.26% Found: C 60.18 H 5.13 F 9.24 N 2.37%.

Example 23 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-nitroguanidinoethoxy) phenyl] propylene

A solution of 3.83 g (10 mmol) of (E) -1-L- (2-aminoethoxy) phenyl) -7,2,2-diphenyl-3,3,3-7,7-2 prepared according to Example 7 was prepared. 71 trifluoropropene and 1.22 g (9 mmol) of 2-methyl-1-nitro-2-isothiourea / Fishbein L. et al. J. Am. Chem. Soc. 76 (1954) in 1877/25 ml of ethanol, boil for one hour. The reaction mixture is evaporated to dryness and the residue is crystallized from methanol. 2.78 g (66%) of the desired compound are obtained; mp. 112-116 ° C (dec.).

Analysis for C 24 H 21 F 3 N 4 O 3: Calculated: C 61.27 H 4.50 F 12.12 N 11.91% Found: C 61.21 H 4.80 F 12.27 N 11.62%.

Example 24 Preparation of (Z) -1,2-diphenyl-3,3,3-trifluoro-1- [4- [2- (2-hydroxyethylamino) ethoxy] phenyl] propene fumarate 0.59 g (1.17 mmol) of Example The (Z) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene prepared according to 6 is dissolved in a mixture of 1.34 g of 2-aminoethanol and 1.5 ml of 2 The solution is boiled for 30 minutes and then treated as described in Example 2. The crude product is crystallized from a 1: 3 mixture of ethyl acetate and hexane to give 0.35 g (70%) of the title compound, mp 81-83 ° C. The free base is dissolved in 1.5 ml of ethanol and an ethanolic solution containing 0.12 g (1 mmol) of fumaric acid is added, the separated crystals are filtered off and washed with ether to give 0.28 g (62.2%) of the desired compound; 172 ° C.

Analysis for C 29 H 28 F 3 NO 6: Calculated: C 64.08 H 5.19 F 10.49 N 2.58% Found: C 64.40 H 5.32 F 10.65 N 2.85%.

Example 25 Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- {4- [2- (N-methyl-2-hydroxyethylamino) ethoxy] phenyl] propylene

A solution of 3.58 g (8 mmol) of (E) -1- [4- (2-bromoethoxy) phenyl] -7,2,2-diphenyl-3,3,3-trifluoropropene (Example 6) and 6, 0 g (80 mmol) of N-methylaminoethanol in 10 ml of isopropanol are boiled for 30 minutes, after which the reaction mixture is treated as described in Example 1. The crude product is crystallized from hexane to give 3.05 g (86.4%) of the title product; mp. 66-68 ° C.

Analysis for the Formula C2g H2g F2NO2: Calculated: C 70.73 H 5.94 F 12.91 N 3.17% Found: C 70.67 H 5.94 F 13.04 N 3.00% i 31 74271

Example 26 (E) -1,2-Diphenyl-3,3,3-trifluoro-1- {¢ -12- (4-methylpiperazino) ethoxy] phenyl} propylene

A solution of 4.62 g of (10 nunol) (E) -1,2-diphenyl-3,3,3-trifluoro-1- [N- (2-mesyloxyethoxy) phenyl] propene (m.p. 71-7 ° C). C) in 80 ml of ethanol, combined with 4.0 g (40 mmol) of N-methylpiperazine and the resulting mixture is boiled for 5 hours. The reaction mixture is evaporated to dryness and then treated as described in Example 1. The product is recrystallized from hexane.

Yield 3.16 g (68%), m.p. 96-99 ° C.

Analysis for the mulch of formula C 28 H 29 F 3 N 2 O: Calculated: C 72.08 H 6.27 F 12.22 N 6.00% Found: C 71.94 H 6.45 F 12.34 B 5.83%.

Claims (5)

32 74271 An analogous process for the preparation of therapeutically useful 1,1,2-triphenylpropane and propylene derivatives of the general formula (I) AB .__ '1 / TA CFt - C - C— {' 0R, 3. l \ - / 1 ( I) XY wherein A and B both represent hydrogen or together form a valence bond, X and Y are the same or different and represent a phenyl group or a phenyl group having a halogen substituent in the para position is an azido-C 1-6 alkyl group or a group having general formula (II) R 2 -ch 2 -ch 2 -n 2 (II) R 3 wherein R 2 and R 3 are independently hydrogen or a C 1-6 alkyl or C 2-4 hydroxyalkyl group or R 2 and R 3 together with an adjacent nitrogen atom form heptamethyleneimino, morpholino, N- (lower alkyl) piperazino, N- (hydroxyalkyl) piperazino or nitroguanidino, provided that when A and B together form a valence bond and X and Y both represent phenyl, does not mean dimethylaminoethyl. , diethylaminoethyl or morpholinoethyl group (Z) in the case of isomers, and for the preparation of mixtures of stereoisomers and isomers thereof and acid addition salts of basic compounds of general formula (I), characterized in that the phenoxyalkyl halide or sulfonate of general formula (III) i 33 7 4 2 71 AB cf3 - C - ^ (3-o-ch2-ch2-z (III) XY wherein A, B, X and Y are as defined above and Z represents a halogen or sulfonyloxy group is reacted with an amine of the general formula R 1, NH, wherein R 2 and R 1 is as defined above, or with an alkali metal azide, and the resulting azido derivative is reduced, if desired, and the resulting amino derivative is converted, if desired, to the corresponding nitroguanidine derivative; and if desired, the individual stereoisomers are separated from the resulting mixture of isomers, and if desired, the basic compound of general formula (I) is converted into its acid addition salt or liberated from its acid addition salt. Process for the preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- {4- [2- (2-hydroxyethylamino) ethoxy] phenyl} propylene according to Claim 1, characterized in that appropriate The starting materials. Process for the preparation of (E) -1- [4- (2-azidoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene according to Claim 1, characterized in that suitable starting materials are used. 54 7 4 2 71 1. An analogous formulation for the therapeutic use of the 1,1,1-triphenylpropane and oceanic compounds of the all-pine form (I) AB _ cf3 - f - 0 * 1 II) XY color A and B for the use of all forms of the image in the valence bonding, X and Y are still or substituted with a phenyl group or a phenyl group with a halogen substituent in the para-position, with an azido-C 1-6 alkyl group or a group with the substituent form In (II) R 2 -ch 2 -ch 2 -n ^ (II) R3 color R2 and R3 are selected from the group consisting of C1-4-alkyl-alkyl or C2-4-hydroxyalkyl groups or R2 and R3 are substituted with the same amino acids as heptamethylenimino, morpholino, N- (leaving) alkyl) piperazino-, N- (hydroxyalkyl) piperazino- or nitroguanidinogroup, with the addition of A and B to the same or more valentic derivatives and X and Y are methylphenyl, beta-dimethylaminoethyl, diethylaminoethyl or morpholylamino are (Z) -isomers, and stereoisomers and isom A particular mixture of compounds and compounds of the formula (I), which is -netecked with phenoxyalkyl halides or -sulfonates of the compounds of formula (III)