CS241030B2 - Method of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene's new derivatives production - Google Patents

Abstract

New 1,1,2-triphenylpropane and -propene derivatives of the general formula (I), <IMAGE> wherein A and B each stand for hydrogen or they form together a valence bond, X and Y are identical or different and stand for phenyl group or a phenyl group having a halogen, hydroxy methoxymethoxy, C1-6 alkoxy or benzyloxy substituent in the para position, R1 is a C1-6 alkyl, epoxyalkyl, azidoalkyl, methoxymethyl or benzyl group or a group of the general formula (II), <IMAGE> wherein R2 and R3 each represent hydrogen or a C1-6 alkyl, hydroxyalkyl or haloalkyl group, or R2 and R3 form together with the adjacent nitrogen atom an up to 8-membered heterocyclic group, an up to 6-membered heterocyclic group optionally containing further hetero atom(s), which heterocyclic groups optionally have a lower alkyl or hydroxyalkyl substituent, a guanidino group, an aminoguanidino group or a nitroguanidino group, with the proviso that if A and B form together a valence bond and X and Y each stand for phenyl or X is phenyl and Y is p-methoxyphenyl, R1 may not stand for a dimethylaminoethyl, diethylaminoethyl, pyrrolidinoethyl, a piperidinoethyl or morpholinoethyl group in the (Z) isomers, stereoisomers and isomeric mixtures thereof, and acid addition salts of the basic compounds of the general formula (I) exert oestrogenic or antioestrogenic effects and furthermore inhibit the growth of the mammary tumor induced by 7,12-dimethyl-benz(a)anthracene.

Description

Process for the preparation of the novel derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene of the general formula I

O

CRA-CC ³ IIXY is performed so that the appropriate phenoxyalkyl halide or phenoxyalkylsulfonates, substituted at the R group Z denoting a halogen atom or a sulfonyloxy group, is reacted with an amine R2R5NH, or with an alkali metal azide and the resulting azide derivative is optionally reduced and converted into the corresponding ' aminoguanidine or nitroguanidine. the derivative and optionally the individual stereoisomers are separated from the isomer mixture and optionally the basic compound. is converted into an acid addition salt.

X and Y are the same or different phenyl group substituents optionally substituted with a halogen atom in the para position,

R 1 is azidoethyl or a group of formula II

The present invention relates to a process for the preparation of novel 1,1,2-triphenylpropane and -propene derivatives.

It is known that some triphenylalkene derivatives have estrogenic properties (J. Grundy: Chem. Rev. 57, 281, 1957; PR Carter et al.: J. Chem. Soc. 1948, 150; N. P Buu-Hoi et al. : Chim. Ther. 1969, 327; WJ Middleton et al., J. Med. Chem., 14, 1193, 1971; U.S. Pat. No. 3,712,929). Analogous derivatives with a basic substituent on the phenyl core have primarily antiestrogenic effects (D. J. Collins et al., J. Med. Chem. 14, 952, 1971). The two most important representatives of these compounds are 1- [4- (2-diethylaininoethoxy) phenyl] -1,2-diphenyl-2-chloroethylene (clomifene) and (Z) -1- (4- (2-dimethylaminoethoxy) phenyl] -1 2-diphenyl-1-butene (tamoxifen) FP Palopolí sp .: J. Med. Chem. 10, 84, 1966; GR Bedford sp .: Nature 212, 733,

1966). Although both compounds exhibit antiestrogenic activity (estrogen antagonizing and weakly agonizing activity), the first is mainly used to induce ovulation (M. Muray et al., J. Obstet. Gynaec. Br. Commonw. 78, 1,108, 1971); for the treatment of oligospermia (FJ Potts: J. Am. Med. Aass. 231, 907, 1975), while the main field of use of tamoxifen is the treatment of breast tumors (P. P. Cole et al .: Brit. J. Cancer 1971, 270) . However, both compounds have the disadvantage that undesirable side effects such as visual disturbances occur during long-term treatment (H. J. Silverman: Am. J. Optom. 49, 335, 1972; L.

M. Roch et al.: Arch. Ophtalm. 77, 14 [1967]; M. J, Kalser-Kupfei; Ltd.: Cancer Treatment Rep. 62, 315, 1978), liver damage (Martindale: The Extra Pharmacopoeia XXVII, 1392, 1977; The Pharmaceutical Press, London) and thrombosis (K. Nevasaari et al., Lancet, 946, 1978).

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds which are more effective than known compounds, which exhibit more specific effects and which cause only a few undesirable side effects.

New compounds prepared. according to the invention exhibit various effects on the endocrine system and greatly inhibit the growth of breast tumors induced experimentally by 7,12-dlmethylbenz (a) anthracene (DMBA).

Summary of the novel derivatives of 1,1,2-and 1,1,2-trifenylpropanu trífenylpropenu formula I R- ^B \

CF ₄ C-C - ^<0R ^ y 1 | I> - '

R2 / CH2-CH2-N1

R3

in which

R 1 and R 3 are each hydrogen, C _1-6 alkyl or C 1-6 hydroxyalkyl or together with the adjacent nitrogen atom form an aminoguanidine or nitroguanidine group or a heptamethylenimine, N-methylpiperazine, N- (2-hydroxyethyl) piperazine or morpholine group, with the proviso that when A and V together form a valency bond and X and Y are each phenyl, R 1 is other than dimethylaminoethyl, diethylaminoethyl or morpholinoethyl in the (Z) -isomers, and their stereoisomeric and isomeric mixtures and addition salts of basic compounds of formula I, The process according to the invention is characterized in that the phenoxyalkyl halide or phenoxyalkyl sulfonate of the general formula III

А В c $ -č- c-0-oh _{ž 2} -z

X Ϊ (III) in which

A, V, X and Y are as defined above and

Z represents a halogen atom or a sulfonyloxy group, reacted with an amine of the formula R 2 R 3 NH, in which R 2 and R 5 are as defined above, or with an alkali metal azide and the resulting azide derivative optionally reduced and converted to the corresponding aminoguanidine or is separated from the resulting isomeric mixture and optionally the basic compound of formula I is converted into its acid addition salt.

The term "alkyl" used alone or in combination (for example, as alkoxy, azidoalkyl, epoxyalkyl, hydroxyalkyl or haloalkyl) refers to a straight or branched saturated aliphatic hydrocarbon group having 1 to 6, preferably 1 to 4, carbon atoms (such as methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl and the like, preferably methyl, in which

A and V are hydrogen or form a valence bond, or ethyl). The term "halogen atom" includes all. four halogens, i.e. fluorine, chlorine, bromine and iodine. When R 1 and R 5 form together with the nitrogen atom to which. are bound, a heterocyclic group, optionally substituted. an alkyl or hydroxyalkyl group, preferably a pyrrolidine, piperazine or N-methylpiperazine group.

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

Also preferred are those compounds of formula I wherein A and B represent a hydrogen atom or are taken together to form a valence bond, X and Y are the same or different and represent a phenyl or p-methoxyphenyl group and Rt represents a C1-aazidoalkyl group or group of formula (II) in which R 2 and R 3 are hydrogen, C _1-4 alkyl or C 1-4 hydroxyalkyl or form, with the nitrogen atom to which they are attached, a piperazine, pyrrolidine, piperidine or morpholine group, which is optionally substituted by C. . A 4alkyl group.

Particularly preferred compounds of formula I are:

(E) -1,2-diphenyl-3,3,3-difluoro-1- (4- (2- (4-methylpiperazino / ethoxy) phenyl) propene), (E) -1,2-diphenyl-3 1,3,1-trifluoro-1- [4- (2- / 2-hydroxyethylamino / ethoxy) phenyl] propene, (E) -1- [4- (2-azidoethoxy) phenyl] -1,2- diphenyl-3,3,3-trifluoropropene and their pharmaceutically acceptable acid addition salts.

The basic compounds of formula I form addition salts with mineral or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, maleic, fumaric, lactic, methanesulfonic, p-toluenesulfonic, citric and the like.

The compounds of formula I may exist in the form of various stereoisomers, for example the (Z) - and (E) -isomers, the threo- and erythroisomers. All of these isomers and mixtures thereof, as well as preparations thereof, and pharmaceutical compositions containing these isomers or mixtures of isomers are included within the scope of the invention.

The process according to the invention is preferably carried out by:. the starting material of formula III is heated with an amine of formula R 2 R 3 NH in an inert solvent or diluent (such as an alcohol, an aqueous alcohol, acetone, etc.). in the presence of an acid scavenger (e.g. potassium carbonate or excess reacting amine) or reacted with an alkali metal azide in dimethylformamide or preferably in aqueous 2-ethoxyethanol. If desired, the resulting azidoderivate may be reduced in a manner known per se, for example with an alkali metal hydride or hydrogen in the presence of palladium on carbon. as a catalyst.

In the starting compound. of Z (III) is preferably Z (halogen, fluorine, chlorine, bromine or iodine), alkylsulfonyloxy (e.g. methylsulfonyloxy) or arylsulfonyloxy. (for example phenylsulfonyloxy optionally substituted, such as phenylsulfonyloxy, p-toluenesulfonyloxy or p-bromophenylsulfonyloxy).

The individual stereoisomers may be isolated from their mixtures by methods known per se, for example, fractional crystallization.

The basic compounds of formula (I) may be converted into the appropriate compounds. acid addition salts by reaction with a suitable acid in an inert solvent. Of the acid addition salts, those formed by reaction with pharmaceutically acceptable acids are preferred. The base may be liberated from the appropriate acid addition salts by treatment with a strong base.

The starting materials of formulas III, IV and V are novel compounds and their preparation is described in detail in the Examples.

The endocrinological and carcinostatic effects of the novel compounds of the invention are demonstrated by the following tests. Test compounds are listed below:

- (E) -1,2-Diphenyl-3,3,3-trifluoro-1-

- {4- [2- (bis- (2-hydroxyethyl) -amino] -ethoxy] phenyl] propene,.

- (E) -1,2-diphenyl-3,3,3-trifluoro-1- [4- (2- (4-methylpiperazino / ethoxy) phenyl] propene, -1- [4- (2-dimethylaminoethoxy) phenyl] -2-phenyl-3,3,3-trifluoro-1-

- (4-methoxyphenyl) propene, = (E) -12-diphenyl-3,3,3-trifluoro-1-

- [2- (2t / 2-hydroxyethylamino / ethoxy) phenyl] propene, = (E) -1,2-diphenyl-3,3,3-trifluoro-2-

- (4- (2-pyrrolidinoethoxy) phenyl) propene, (E) -1,2-diphenyl-3,3,3,4-trifluoro-1H-2-carboxylic acid;

- [4- (2-morpholinoethoxy) phenyl] propene, - (E) -1- [4- (2-diethylaminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene, == ( E) -1- [4- (2-Aaidoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene, = - (E) -1L-2'-diphenyl-3,3,3'-dd ' ifluor-l ^ - '

- 4- [2- (bis- (2-chloroethyl / amino) ethoxy] phenyl] propene, ⁴ -l-phenyl-2- (4-methoxyphenyl) -

-1- (4- (2-dimethylaminoethoxy) phenyl) -3,3,3-trifluoropropene;

- (E) -1,2-diphenyl-3,3,3-trifluoro-1-

- (4- (2- (nitroguanidino / ethoxy) phenyl) propene).

The antiestrogenic effect was determined by the method of M. J. K. Harper et al. (J. Reprod. Fert. 13, 101, 1967); 24 day old infantile female rats were premedicated with daily doses of 5 µg / kg estradiol for 3 days. . Test compounds were also administered once daily orally for 3 days.

On day four, the animals were sacrificed, their uterus removed and weighed. The data characterizing the anti-estrogenic activity (inhibition of the uterotropic effect of estradiol) of some of the compounds of the invention are shown in Table 1.

The anti-estrogenic activity of some of the compounds listed in Table 1 achieves the activity of clomifene or tamoxifen used as reference. Compound # 1 induces only slight inhibition when administered at a 1 mg / kg cral dose. The degree of inhibition remains low (39%), although the dosage is increased to 10 mg / kg.

Table 1

Determination of antiestrogenic effect in infantile female rats

Test substance 0.1 0.3 Dose mg / kg / day 1.0 3.0 10.0 Clomifen —37.1 —67.7 -7 7-, 3 Tamoxifen —45.6 + 6.85 —55.2 + 2.5 —60.9 + 4.04 —70.3 + 4.52 —68.61-4.83 3 —14 —53 —59 -67 —73 4 —65.2 + 3.93 —71.9 + 1.81 —71.8 + 5.0 —72.2 + 5.5 5 —52.8 + 4.2 —222 + 6.12 60, ^{J =} 2.13 —68.2-1-3.32 -63, + - 3.68 7 —26.5 + 2.98 -49.2 + 2.1 —68.5 + 5.14 —60.4 + 2.5 -51.0 + 8.1

Note: the antiestrogenic effects (decrease in uterine weight) of the compounds are given, in percentages. Tests were performed with groups of 5 to 10 animals. .

The estrogenic (uterotropic) effect was determined by the method of R. J. Dorfman (Endocrinolcgy 55, 65, 1954). 24 day old female rats were premedicated with a single daily oral dose of test compounds. On day 4, the animals were sacrificed, their uterus removed and weighed. The data characterizing the estrogenic (uterotropic) effects of some of the compounds of the invention are summarized in Table 2. Ethinylestrradiol, a highly active estrogenic substance, as well as clomifene and tamoxifen, two known antiestrogenic active substances, have also been tested and their activity data are also listed.

The compounds listed in Table '2 generally have weak estrogenic properties. Or in a dosage range from 0.1 · 1.0 mg / kg, their activity _ч slightly less than' the moxifenu activity. The dose-response curve is different from the previously known compounds, since it is somewhat steeper. In the dosage range used (0.01 to 0.3 mg / kg per · os), the estrogenic effect is even less than the weak agonist effect of the antiestrogenic agents, while the maximum achievable uterine weight increase exceeds the maximum effect achievable use of antiestrogenic agents. '

Table 2

Determination of uterotropic (estrogenic) effect in female infantile rats

Test Dose mg / kg / day p.o.

Compound 0 0.01 0.03 0.1 0.3 1.0 3.0 10.0 20.0

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The stimulating effect on luteotropic hormone (LH) secretion was determined as follows: 24 and 25 day old infantile female rats were injected subcutaneously for two consecutive days of test compound. Two hours after the second dose, animals were euthanized by bleeding and the plasma luteotropic hormone (LH) level was determined by radioimmunoassay. At a subcutaneous dose of 1 mg / kg, the compounds produced a marked increase in plasma LH levels. The results are summarized in Table 3.

Table 3 according to V. C. Jordan sp. (Europ. J. Cancer 12, 419, 1976), by caliper. Tumor volume was determined by the Griswold method. The animals were observed for another two months after the end of the treatment period and the tumors were measured during this period.

A relative potency index was determined to characterize the potency of the test compounds. In order to calculate the relative efficacy index, the number of animals showing permanent transient cure or remission of varying duration was determined and compiled in the following table:

or time

Effect of increasing LH level in female infantile rats

Tested Percentage Change of Compound LH Compared to Permanent Cure Control10 Temporary Cure8 Permanent Remission6 Short Remission or Unchanged State Points.

points points points tamoxifen117

3134

4106

739

953

The changes in mean tumor size that occurred during the treatment period were evaluated according to the following niceness:

note: tests were performed on groups of 4-5 animals; dosage: 2X1 mg / kg s. c.

tumor unchanged double increase in average tumor size multiple increase in average tumor size points points.

The effects of the novel compounds manifesting in hormone-dependent tumors were tested by the method of P. Griswold et al. (Cancer Research 26, 2169, 1966) 4ia 7,12-dimethylbenz (a) anthracenene-induced mammary tumor (DMBA). Treatment was initiated when the tumor weight reached about 500 mg and the animals were treated for 3 months with oral doses of 20 mg / kg of active ingredient administered three times a week. Veli-. Tumor bone was measured by the method described by the above authors, as well as the meta-numbers found in each animal using both of the above scales were summed and expressed as a percentage relative to the sum of numbers corresponding to the maximum activity (sustained cure). This percentage represents the relative efficiency index.

The results are included in Table 4, in which the numbers in brackets have the following meaning: (1) permanent cure; (2) temporary cure; (3) permanent remission; (4) short remission; (5) unchanged.

Table 4

Effect on mammary tumor induced in DMBA rat

Test substance (and) (2) Efficiency (3) (4) (5) Index of relative efficiency Untreated controls - - - - 25/25 0 Tamoxifen 2/5 1/5 - 1/5 1/5 70 3 1/5 1/5 - 3/5 - 65 4 - -  3/4 1/4 - 60 7 2/5 1/5 1/5 - 1/5 78 10 4/5 .— -. - 1/5 90 11 1/5 - 3/5 - 1/5 72 12 2/5 2/5 1/5 - 85 13 1/5 1/5 1/5 2/5 - 67 15 Dec 2/5 - 2/5 - · 1/5 70 16 - 1/4 3/4 - - 73

The invention also relates to pharmaceutical compositions comprising as active ingredient one or more compounds of formula I in the form of individual isomers or mixtures of isomers, or acid addition salts of basic compounds of formula I, together with a conventional inert, solid or liquid pharmaceutical carrier. These pharmaceutical compositions can be administered both in human therapy and for veterinary purposes to act on the endocrine system. Some of the compounds of formula (I) may also be applied in the treatment of tumors, since they significantly inhibit the growth of tumors experimentally induced by DMBA. The pharmaceutical compositions may conveniently be in the form of orally administrable preparations (such as tablets, capsules, powder mixes, solutions, suspensions, emulsions, elixirs, etc.) or as compositions for parenteral administration (for example, injectable solutions or suspensions). These compositions may contain conventional inert, solid or liquid carriers (for example, starch, lactose, magnesium stearate, silica, magnesium carbonate, polyvinylpyrrolidone, water, and the like). The content of active ingredient in the composition can generally vary from 0.05 to 98% by weight. The pharmaceutical compositions may also contain conventional pharmaceutical additives or excipients such as emulsifying, dispersing, wetting or disintegrating agents, buffers, etc.

The pharmaceutical compositions can be prepared by methods conventional in the pharmaceutical industry.

The daily dosage of the compounds of the invention depends on various 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 may generally vary from 0.01 to 10 mg / kg body weight.

However, the above data is of an informative nature only, as higher or lower doses may be applied if necessary.

The invention is illustrated in further detail by the following non-limiting 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 of morpholine was heated to boiling. The mixture was then cooled, diluted with 50 ml of ether and washed with water to neutrality. The ether solution was dried, evaporated to dryness and the residue crystallized from hexane. 1.02 g (83.6 percent of theory) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- [4- (2-morpholinoethoxy) phenyl] propane are obtained; mp 112-115 ° C.

Analysis:

calculated for CsrltoFsNOz:

C 71.19%, II 6.20%, F 11.5.1%, 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 boiling and then heated to reflux. proceeds as described above. The resulting product was recrystallized 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:

calculated for C18H18F3NO2:

C 71.19%, H 6.20%, F 12.51%, N 3.08%, found:

C 71.24%, II 6.44%, F 12.45%, N 3.03%.

Starting materials, i.e. erythro- and threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane, were prepared as follows: a solution of 456 g (1.17 mol) of benzyl- triphenylphosphonium chloride (G. Wittig: Chem. Ber. 87, 1318, 1954), in 1500 ml of anhydrous ethanol, is added to a solution of 27 g (1.17 gatom) of sodium in 500 ml of anhydrous ethanol at 0-2 ^° C. This was combined with a solution of 204 g (1.17 mol) of 2,2,2-trifluoroacetophenone in 100 ml of anhydrous ethanol and allowed to stand overnight. The solution is evaporated, the residue is stirred with 800 ml of petroleum ether, filtered and the filter cake is washed. The filtrate was evaporated and the residue distilled in vacuo. 268 g (92.5% of theory) of 1,2-diphenyl-3,3,3-trifluoropropene are obtained; boiling point 107-109 ° C) 27 Pa, mp 58-61 ° C.

Analysis:

calculated for C15H11F3:

C 72.57%, H 4.47%, F 22.96%,

C 72.49%, H 4.23%, F 23.20%.

268 g (1.08 mol) of the above product are hydrogenated at 20 ⁰ С for 6-8 hours in 4000 ml of acetic acid in the presence of 20 g of 10% palladium on charcoal as catalyst. The solution was evaporated and the residue distilled in vacuo. 252 g (93.3% of theory) of 1,2-diphenyl-3,3,3-trifluoropropane are obtained;

boiling point 94 to 96 O / 13.3 Pa, n _D ²⁰ -

- = 1.5100.

alcohol. Yield: 109 g (37%) of threo-l, 2-diphenyl-3,3,3-trifluoro-l- (4-inethoxyfenyljpropanu; mp 129-131 ^C C.

Analysis:

Analysis:

calculated for C15H13F3:

C 71.98%, H 5.26%, F 22.75%, found:

C 72.12%, H 5.44%. F 22.50%.

g (0.02 mol) of benzoyl peroxide is added to a solution of 250 g (1 mol) of the preceding product in 2500 ml of carbon tetrachloride and a solution of 176 g (1.1 mol) of bromine in 500 ml of carbon tetrachloride is added thereto at 50 ^Q C in 30 minutes. The resulting solution was heated to boiling for 2 hours, then cooled, washed with sodium thiosulphate solution, sodium bicarbonate solution and then water, dried and evaporated. The residue was crystallized from 1260 ml of ethanol to give 140 g (42.6% of theory) of erythro-1-bromo-1,2-diphenyl-3,3,3-trifluoropropane; mp 164-165 ° C.

Analysis:

calculated for C 18 H 25 BrF 5:

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 the original volume. 130 g (39.5% of theory) of threo-1-bromo-1,2-diphenyl-3,3,3-trifluoropropane are precipitated; mp 91-94 ° C.

Analysis:

calculated for C 18 H 30 BrFs:

C 54.83%, H 3.67%, Br 24.28%,

F 17.32%, found:

C 54.86%, H 3.82%, Br 24.01%,

F, 17.27%.

NMR spectra of the compounds confirm the proposed structure.

270 g (0.82 mol) of the erythro-threo-isomer mixture obtained as described above are dissolved in 2500 ml of anisole and 110 g (0.83 mol) of anhydrous aluminum chloride are added to the solution while stirring at 6 ^° C. and allowed to stand at room temperature overnight. The reaction mixture is poured onto a mixture of 4 kg of crushed ice and 600 ml of aqueous 36% hydrochloric acid and extracted with 3 liters of chloroform. The organic solution was washed with aqueous sodium bicarbonate and then with water, dried and evaporated. The dry residue was crystallized from 750 ml of isopropanol and the crude product obtained (162 g, 55% of theory, mp 121-126 [deg.] C.) was recrystallized again from 1500 ml of isopropyl calculated for C18H18F5O:

C 74.14%, H. 5.37%, F 16.00%, found:

C 74.08%, H 5.47%, F 15.75%.

Spectral values:

kCH 3,050, 3,025, 2,995, 2,950, 2,925, 2,900, 2,830 in C — C 1 605, 1 580, 1 508 / Ar 808, 786, 758, 702

ICH (Arh = 4.60 (d), 1H < N (R)) = 4.23 (m), 1H dOCH3 3.60 (s), 1H < 5Ar = 6.7-7.3 (m), E4H.

The mother liquor obtained in the first crystallization is evaporated to dryness, the residue is stirred with 300 ml of hexane and filtered. The crude product obtained (96 g, 27% of theory, mp 89-101 DEG C.) is recrystallized again from 960 ml of isopropyl alcohol to give 41.4 g (14% of theory) of erythro-1,2-diphenyl-3,3 3-trifluoro-1- (4-methoxyphenyl) propane; mp 108 DEG C. III ^1.

Analysis:

calculated for C22H; f.F3O:

C 74.14%, Ή 5.37%, F 16.00%, found:

C 74.23%, H 5.18%, F 16.17%.

Spectral values:

> CH 3 090, 3 060, 3 025, 3 010, 2 960, 2 940, 2 915, 2 840 uC = C 1 658, 1612, 1 590, 1513, 1 500 / Ar 808, 790, 762, 708, 702 OCH (Ar) 2 = 4.60 (d), 1 H 5CH (CF 3) = 4.23 (m), 1 H <5ОСНз = 3.60 (s), 3 H <5Ar = 6.4-7.6 ( m), 14H.

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 at 200 to 220 ° C for 3 hours. . The reaction mixture is cooled, diluted with 700 ml of chloroform, washed with water to neutrality, dried and evaporated. The residue was crystallized from chloroform / hexane (1; 2) to give

85.7 g (90% of theory) of threo-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane; mp 123-125 ° C.

Analysis:

calculated for C21H17F3O:

C 73.67%, H 5.01%, E 16.65%., I

1δ found:

C 73.56%, H 4.92%, F 16.78%.

g (0.11 mol) of erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-methoxyphenyl) propane was treated with 120 g of hydrochloride. pyridine as described above. The resulting erythro-1,2-diphenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane is crystallized from chloroform / hexane (1: 2) to give 32.5 g (84%). 5% of theory) of the product; Mp 114-117 ° C.

Analysis:

calculated for C21H17F3O:

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) threo-1,2-diphenyl-3,3,3-rifluoro-1- (4-hydroxyphenyl) propane, 400 ml 1,2-dibromoethane and 18.5 g Powdered potassium hydroxide (0.33 mol) was heated to boiling with stirring. The reaction mixture was diluted with 1.5 liters of dichloromethane, washed with 10% aqueous hydrochloric acid and water, dried, and the solvent and excess 1,2-dibromoethane were distilled off in vacuo. The residue is crystallized from benzene to give 97.7 g (87% of theory) of threo-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane; mp 144-111 ° C.

Analysis:

calculated for C 13 H 10 BrF 5 O:

C 61.48%, H 4.49%, Br 17.78%,

F 12,68¾ found: ·

C 61.55%, H 4.57%, Br 17.63%,

F, 12.71%.

g (87.6 mmol) of erythvo-1,2-d: phenyl-3,3,3-trifluoro-1- (4-hydroxyphenyl) propane was reacted with 1,2-dibromoethane as described above. The resulting erythro-1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-1,3,3,3-trifluoropropane was recrystallized from benzene and recovered from 27.9. g (71% - theory) · product; Mp: 130-133 ° C.

Analysis:.

calculated for Cr3H’oBrFgO:

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-tetrahydro-1,3,34-fluoropropane, prepared as described in Example 1, 9.15 g (150 mmol) of 2-aminoethanol and 15 ml of 2-methoxyethanol are heated to boiling for 1/2 hour The reaction mixture is cooled, diluted with 200 ml of chloroform, washed with water, dried and evaporated. benzene with hexane (1: 1) to give 4.32 g (67% of theory) of the title compound, mp 120-122 ° C.

Analysis:

calculated for C25H23F3NO2:

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 Ethylthiol 1,2-diphenyl-33,3-trifluorofluoro-4- [2- (bis- (2-hydroxyethyl) amine 3) ethoxy] phenylpropane hydrochloride

8.98 g (20 mmol) of erythro-1- [4- (2-bromoethoxyphenyl) -1,2-diphenyl-3,3,3-trifluoropropane, prepared as described in Example 1, are dissolved in g (400 mmol) of diethanolamine and the solution is heated at 100-120 ° C for 1/2 hour The reaction mixture is treated as described in Example 2 and the residue is crystallized from a mixture of a solution of hydrogen chloride in isopropyl alcohol and ether (1: 2) to give · 5.98 · g (58.7%) of the title compound, mp 190-195 ° C.

Analysis:

calculated for CZ7H31CIF3NO3:

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-alaidoethoxy-) phenyl] -1,2-diphenyl-3,3,3-trifluoropropane

A solution of 3.25 g (50 mmol) of sodium azide in 11 mL of water was added to a solution of 11.2 g · (25 mmol) of erythro-1- [4- (2-biOmethoxy) phenyl] -1.2 diphenyl-3,3,3-trifluoropropane; prepared as described in the example. 1 ,. in 112 ml of 2-methoxyethanol and the mixture is heated to boiling for 1 hour. The reaction mixture is evaporated to dryness, 30 ml of toluene are added and the mixture is evaporated once more to remove the last residue.

2-methoxyethanol. The solid residue is triturated with water, filtered and washed with water. The crude product was recrystallized twice from ethanol. 7.83 g (76%) of the title compound are obtained; mp 144-148 ° C.

Analysis:

calculated for C23H20F3N5O:

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-1,3,3,3-trifluoropropane

5.15 g (12.5 mmol) of erythro-1- (4- (2-azidoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropane, prepared as described in Example 1, is hydrogenated after for about 1 hour in a mixture of 100 ml of methanol with 40 ml of tetrahydrofuran in the presence of 0.6 g of 5% palladium on carbon catalyst, the solution is evaporated and the residue is recrystallized from hexane to give 3.86 g (80.2% of theory). mp 125-127 ^° C.

Analysis:

calculated for C 23 H 22 F 3 NO:

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- (2-bromoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropene are dissolved in 100 ml of 1-methoxyethanol, k A solution of 2.86 g (44 mmol) of sodium azide in 10 ml of water is added and the mixture is heated to boiling for 1 hour, the reaction mixture is worked up as described in Example 4 and the product is recrystallized twice from ethanol. 40 g (82% of theory) of the desired product, mp 73-75 [deg.] C.

Analysis:

Calculated for C25H18F5N3O:

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 compound, (E) -1- (4- (2-bromoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropene, was prepared as follows:

45.4 g (0.2 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (D.Walker et al .: J. Or. Chem. 30, 3 240, 1965) add to solution

44.7 g (0.1 mol) of threo-1- (4- (2-bromoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropane, prepared as described in Example 1, in 225 ml of anhydrous The reaction mixture is cooled and the precipitated 2,3-dichloro-5,6-dicyano-1,4-hydroquinone is filtered off. The filtrate is evaporated to dryness and the residue is stirred. The filtrate was diluted with 400 ml of chloroform, washed with 10% aqueous sodium bicarbonate solution and then with water, dried and evaporated. The residue was filtered off with 100 ml of chloroform and the precipitated 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was filtered off. The residue is recrystallized from 220 ml of ethanol to give 34.4 g (77% of theory) of the crude product, which melts at 110 DEG-118 DEG C. This crude product, which is a 4: 1 mixture of E and Z isomers, is recrystallized. from 200 ml of ethanol to give 29.5 g (66% of theory) of Isomer E; mp 118-120 ^° C.

Analysis:

calculated for С2зН1бВ1ТзО:

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:

vCH 3 060, 3 020, 2 920, 2 900, 2 850> C — C 1 590, 1 495 yAr 815, 822, 758, 705 ЙОСН2 = 4.08 (t), 2H А'ВгСНг = 3.46 ( t), 2H 6Ar = 6.4-7.4 (m), 14 H.

The mother liquor is evaporated and the residue is recrystallized several times from ethanol. Yield: 2.14 g (4.8% of theory) of (Z) -1- (4- (2-bromoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropene, mp 135-138 ° C .

Spectral values:

vCH 3,080, 3,060, 3,030, 2,935, 2,870 i> C = C 1,610, 1,510 yAr 832, 770, 760, 715 OCH2 - -4.28 (t), 2H + BrCH3 - 3.59 (t), 2H < 5Ar = 6.8-7.4 (m), 14H.

Example 7

Preparation of (E) -1- [4- (2-aminoethoxy) phenyl] -1,2-diphenyl-1,3,3-fluoro-propene

7.40 g (18 mmol) of (E1-1H-aaiddeethoxy) phenyl] 1,2-diphenyl-3,3,3-trifluoropropene, prepared as described in Example 6, are dissolved in 100 ml of methanol, 0, 70 g of 5% palladium on carbon catalyst and the mixture is hydrogenated for about 1 hour, the catalyst is filtered off, the filtrate is evaporated and the residue is recrystallized from hexane to give 3.63 g (5 (3% of theory) of the title compound); Mp 71-76 ° C.

Analysis:

calculated for C23H20F3NO:

C 72.05%, H 5.26%, F 14.17%, N 3.65%, found:

C 72.36%, H 5.30%, F 14.11%, N 3.52%.

Example

Preparation of (E) -1,2-diphenyl-3,3,3-trienyl-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 as described in Example 6, and 13 g of morpholine are heated to boiling for 1 hour. The reaction mixture was worked up as described in Example 1 and the crude product was recrystallized from hexane. 2.10 g (12.4% of theory) of the title compound are obtained; mp 14-19 ° C.

Analysis:

calculated for CazHzuFoNO ?:

C 71.51%, H 5.71%, F 12.57%, N 3.09%, found:

C 71.10%, H 5.91%, F 12.70%, N 3.21%.

Example 1 9

Preparation of (E) -1,2-Diphenyl-3,3,3-

-trifluoro-1,4-2- (4-methylpiperazino / ethoxy) phenyl] propene

4.0 g of N-methylpiperazine is added to a solution of 4.47 g (10 mmol) of (E) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropro - _ч foam, prepared as described in Example. 7, in δ0 ml of anhydrous ethanol and the reaction mixture is heated to boiling for 6 hours. The reaction mixture was evaporated to dryness and then proceeded as described in Example 1. The product was recrystallized from hexane. 3.45 g (74% of theory) of the title compound are obtained; mp 94-97 ° C.

Analysis:

calculated for C23H29F3N2O:

C 72.0δ ·%, H 6.27%, F 12.22%, N 6.00%, found:

C 72.27%, H 6.32%, F 12.21%, N 5.77%.

Example 10

Preparation of (E) -17-dH-r-thiyl-1,3,3-trifluoro-1- [4- [2- (4- / 2-hydroxyethyl / piperazino) ethoxy] phenyl] propene

A mixture of 1.79 g (4 mmol) of (E) -1- [1- (2-bromoethoxy) phenyl] -1,1,6-thieno-1,3-trifluoropropene, prepared as described in Example 6, and 10.4 g of Li (2-hydroxyethyl) piperazine was heated for 1 hour. The mixture was worked up as described in Example 1 and the product was recrystallized from hexane. 1.35 g (68% of theory) of the title compound are obtained; t. tt. 79 to H ’C.

Analysis:

calculated for CL9H31F..N .. Oz:

C 70.14%, H 6.29%, F 11.41%, M 5.64%, found:

C 70.15%, H 5.65%, F 1 → 1.36%, N 5.41%.

Example 11

Preparation of (E) 11,2-0,0-β-3,3,3-trifluoro-1H-4- (4-hydroxyethylamino / ethoxy) phenyl] propene

6.71 g (15 mmol) (E) of [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene, prepared as described in Example 6, are dissolved in a mixture of 9.15 g. Of 2-aminoethanol and 15 ml of methoxyethanol. The solution was heated to boiling for 30 minutes, then the mixture was worked up as described in Example 2. The product was recrystallized from 1: 1 ethyl acetate: hexane to give 5.29 g (13%) of the title compound; mp 96-91 ° C.

Analysis:

calculated for C25H24F3NO2:

C 70.24%, H 5.66%, F 13.33%, N 3.21%, found:

C 70.42%, H 5.10%, F 13.39%, N 3.23%.

Example 1 a d 12

Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- {4- [2- (bis / 2-hydroxyethyl / amino) ethoxy] phenyl] propene

A solution of 7.15 g (16 mmol) of (E) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-3,3,3-tritluoropropene, prepared as described in Example 6, at 16, Heat 8 g of diethanolamine at 120-140 ° C for 1/2 hour and then proceed as described in Example 2. The product was recrystallized from ethyl acetate-hexane (1: 1) to give 5.66 g (75%). mp 113.5-116 ° C.

Analysis:

calculated for C27H23F3NO.l:

C 68.78%, H 5.99%, F 12.09%, found:

C 63.75%, H 5.78%, F 12.13%.

Example 13

Preparation of 1- [1- (2-azidoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene

11.63 g (25 min) of 1- [4- (2-bromoethoxy) phenyl; -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene was converted to the azide derivative as described in Example 4. The product Recrystallization from ethanol gave 8.54 g (80% of theory) of the title compound, mp 62-64 ° C.

Analysis:

calculated for C20H18FN5O:

C 64.63%, II 4.01%, F 17.78%, N 9.82%, found:

C 64.71%, H 4.13%, F 17.74%, N 9.63%.

1- | The C- (2-bromoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenylpropene) used as starting material was prepared as described in Examples 1 and 6 as follows:

4‘-Fluoro-2,2,2-trifluoroacetophenone (F.E.

Herkes et al., J. Org. Chem. 32, 1 311—18.

1967) was reacted with benzyl-triphenylphosphonium chloride in the presence of an ethanolic solution of sodium ethylate. 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene is obtained in a yield of 91% of theory; boiling point 110-114 ° C / 27 Pa, m.p. 43-45 ° C.

Analysis:

calculated for CtsHjdFi:

C 67.67%, H 3.79%, F 28.54%, found:

67.83%, H 3.90%, F 28.33%.

This compound is hydrogenated in the presence. palladium-on-carbon catalyst to give 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -propane in 91.7% yield, bp 100-104 ° C / 27 Pa; n _D ²⁰ == 1 , 4980.

Analysis:

calculated for C15H12F4:

C 67.16%, H 4.51%, F 28.33%, found:

C 67.30%, H 4.68%, F 28.18%.

The product obtained is brominated in carbon tetrachloride and the accumulated compound is recrystallized from ethanol. 1-bromo-1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propane is obtained in a yield of 48.2% of theory; mp 144-146 ^° C.

Analysis:

Calcd.

C 51.90%, H 3.19%, Br 23.02%,

F 21.98%, found:

C 51.70%, H 3.18%, Br 23.06%,

F, 22.03.

The brominated compound is reacted with anisole in the presence of aluminum chloride. The obtained 1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) -1- (4-methoxyphenylpropane (isomeric mixture) is recrystallized from isopropyl alcohol (yield: 79.8% of theory, mp 152-167 ° C). C.

Analysis:

calculated for CszHr-FiO:

C 70.58%, H 4.85%, F 20.30%, found:

C 70.30%, II 4.73%, F 20.40%.

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

Analysis:

Calcd. for C 23 H 9 BrF: O:

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 was evaporated to dryness and the solid was recrystallized from benzene. 5 ml of benzene was used per 1 g of solid. The second fraction, which is a mixture of isomers, melts at 100-110 ° C.

Analysis:

calculated for C 14 H 10 BrF 3 O:

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 were combined and heated to boiling with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone for 25 hours as described in Example 6. The product was recrystallized from ethanol. 1- (4- (2-bromoethoxy) phenyl) -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene is obtained in a yield of 66.5% of theory, mp 115-118 ° C.

Analysis:

calculated for C28HnBrF3O:

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

A solution of 8.54 g (20 mmol) of 1- [4- (2-azidoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene, prepared as described in Example 13, in 170 ml of methanol is hydrogenated for about 1 hour in the presence of 0.9 g of 5% palladium on carbon catalyst. The solution was evaporated and the product was recrystallized from hexane. Thus, 4.51 g (56.4% of theory) of the title compound are obtained; mp 83-89 ° C.

Analysis:

calculated for G23H19F4NO:

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-

morpholinoethoxyphenyl Jpropene

3.25 g (7 mmol) of 1- [4- (2-bromoethoxy) phenyl] -1-phenyl-3,3,3-trifluoro-2- (4-fluorophenyl) propene, prepared by as described in Example 13, was reacted with morpholine as described in Example 1.

The product was recrystallized from hexane. 2.5 g (75.7% of theory) of the desired product are obtained; t. Mp 67-69 ° C.

Analysis:

calculated for C27H25F4NO:

C 68.78%, H 5.35%, F 16.12%, N 2.97%, found:

C 68.62%, H 5.91%, F 16.40%, N 3.14%.

Example 1 a d 16

Preparation of 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -1- (4- (2-morpholinoethoxy) phenyl) -propene

3.25 g (7 mmol) of 1- [4- (2-bromoethoxy) phenyl! The 2-phenyl-3,3,3-trifluoro-1- (-1-fluorophenyl) propene was reacted with morpholine as described in Example 1. The product was recrystallized from hexane. 3.03 g (92% of theory) of the title compound are obtained; mp 95-96 ° C.

Analysis:

calculated for C27H2-F1NO:

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 1- (4- (2-bromoethoxyphenyl) -2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propene used as starting material was prepared as described in Example 1 as follows:

2,2,2-trifluoroacetophenone is reacted with triphenyl- (4-fluorobenzyl) phosphonlumyl chloride (RA Jones: Australian J. Chem. 18, 903-6, 1965) in ethanol in the presence of sodium ethylate; 2-phenyl-3,3,3-trifluoro-l- (4fluorfenyll propene Yield. 90 percent of theory; boiling point 105 to 107 ^Q C / / 27 mm Hg, mp 35-41 ° C.

Analysis:

calculated for C15H10F4:

C 67.67%, H 3.79%, F 28.54%,

ΤΊ O 1 P * 7 *

C 67.58%, H 3.95%, F 28.50.

The above product was hydrogenated using palladium on carbon catalyst to give 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propane in 94% yield; boiling point 95-100 ° C / 40 Pa.

Analysis:

calculated for C15H12F4:

C 67.16%, H 4.51%, F 28.33%, found:

С 67.22%, Η 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 recrystallized from ethanol. Use 3.5 ml of ethanol per g of solid. The obtained first fraction, which is a mixture of isomers, melts at 143-145 ° C.

Analysis:

calculated for C18H18BrFa:

C 51.90%, H 3.19%, Br 23.02%,

F, 21.89%, found:

C 51.91%, I-I 3.13%, Br 22.92%,

F, 22.06%.

The mother liquor evaporates to about one third of its original volume. The second fraction obtained, a mixture of isomers, melts at 69-76 °. Celsius.

Analysis:

calculated for C 18 H 18 BrF:

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 total yield is 76% of theory.

The above fractions were combined and reacted with anisole in the presence of aluminum chloride. The obtained 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -1- (4-methoxyphenyl) propane was recrystallized from ethanol. Use 4 ml of ethanol per g of solid. The first fraction, a mixture of isomers, melts at 120-127 ^° C.

Analysis:

calculated for C22H18F4O:

C 70.58%, H 4.85%, F 20.30%, found:

C 70.81%, I 5.01%, F 20.35%.

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

Analysis:

calculated for C18H18N2O:

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% of theory.

The above fractions (mixtures of isomers) were combined and heated with pyridine hydrochloride.

The obtained crude 2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) -1- (4-hydroxyphenyl) propane is directly reacted, without purification, with 1,2-dibromoethane in presence of potassium hydroxide. The resulting 1- [4- (2-bromoethoxy) phenyl] -2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propane was recrystallized from ethanol. Use 4 ml of ethanol per g of solid. The first fraction, a mixture of isomers, melts at 119-123 ° C.

Analysis:

calculated for C18H18BrFiO:

C 59.11%, H 4.10%, Br 17.10%,

F 12.26%, found:

C 59.30%, H 4.16%, Br 17.03%, F 16.26%.

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

Analysis:

calculated for C18H18BrFiO:

C 59.1.1%, 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) were combined and reacted with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in benzene at boiling as described in Example 6. The reaction mixture was worked up as described in of Example 6 and the product is recrystallized from isopropyl alcohol. 1- [4- (2-bromoethoxy) phenyl] -2-phenyl-3,3,3-trifluoro-1- (4-fluorophenyl) propene is obtained in a yield of 58.4% of theory; Deň: 32 ° C.

Analysis:

calculated for C 25 H 25 BrFiO:

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-1- [4- (2-heptamethyleniminoethoxy) phenyl] propene

2.32 g (20 mmol) of heptamethylenimine was added to a solution of 4.47 g (10 mmol) of (E) -1- [4241030]

[2-Bromoethoxy] -phenyl] -1,2-diphenyl-3,3,3-trifluoropropene, prepared as described in Example 6, in 30 ml of ethanol and heated to boiling for 5 hours. The reaction mixture was evaporated to dryness. Then proceed as it is. as described in Example 1 and the product was recrystallized from hexane. 3.22 g (67% of theory) of the desired product are obtained; mp 73-77 ° C.

Analysis:

calculated for C3 <> H.uF3NO:

C 75.13%, H 6.73%, F 11.88. %, Ň 2.92%, found:

C 75.11%, H 6.75%, F 11.88%, N 2.98%.

Example 18

Preparation of (E) -1- [4- (2-diethylamino-ethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene

5.37 g (12 mmol) of (E) -1- [4 ((2-bromoelkoxy) phenyl 11,2-diphenyl-3,3,3-trifluoropropene), prepared as described in Example 6, were heated to boiling with 8.8 g of diethylamine for 5 hours The reaction mixture was diluted with 50 ml of benzene, washed with water to neutrality, dried and evaporated.The residue was dissolved in 20 ml of 95% ethanol and a solution of 3.22 g (14 mmol) was added. of picric acid in 32 ml of 95% ethanol The precipitated crystals are filtered, washed with ethanol and ether to give 6.46 g (80.4% of theory) of the title compound, mp 131-135 ° C.

Analysis:

calculated for C35H51F3N1O):

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

0.03 ml (0.55 mmol) of 98% sulfuric acid was added to the solution of 0.205. g (0.5 mmol) of (Ej-1- [4- (2-dimethylaminoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene in 1.5 ml of isopropanol. The product was recrystallized from isopropyl alcohol to give 0.22 g (84.6% of theory) of the title compound, mp 150-153 ° C.

Analysis:

calculated for C25H26F3NO5S:

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 6.46%.

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

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

Analysis:

calculated for C8 -HnFsNO:

C, 72.98%, H 5.88%, F 13.85%, N 3.49%, found:

C 72.80%, H 5.51%, F 14.01%, N 3.53%. Example 20

Preparation of mesylate (E) -1,2-di-phenyl-.

-3,3,3-Trifluoro-1- (4- [2- (4- / 2-hydroxyethylpiperazino) ethoxy] phenyl'propene

A solution of 0.2 g (2 mmol) of methanesulfonic acid in 2 ml of isopropyl alcohol was added to a solution of 0.50 g (1 mmol) of (E) -1,2-diphenyl-3,3,3-trifluoro-1- {4 - [2- (4- (2-hydroxyethyl) piperazino) ethoxy Ifenylpropene, prepared as described in Example 10, in 1 ml of isopropyl alcohol. The precipitated crystals are filtered off and washed with ether. 0.58 g (96.7% of theory) of the title compound is obtained; mp 203-209 ° C.

Analysis:

calculated for C31H39F3N200S2:

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- (4- (2-aminoethoxy) phenyl) -1,2-diphenyl-3,3,3, -trifluoropropene tosylate

A solution of 0.20 g (1 mmol) of p-toluenesulfonic acid in 1 ml of isopropyl alcohol was added

4 1 О 3 Π add to the solution 0,30 g [0,8 ml] of (E) -1- [4- (2-aminoethoxy) phenyl (-1,2-diphenyl-3,3,3-trifluoropropene), prepared by the method of Example 7 in 0.5 ml of isopropanol The precipitated crystals were collected by filtration and washed with ether to give 0.37 g (84% of theory) of the title compound, mp 162-163 ° C.

Analysis:

calculated for C30H28F3NO1S:

C 6: 1.85%, 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- [4- (2- / 2-hydroxyethylamino / ethoxy) phenyl] propencitrate

A solution of 0.13 g (0.6 mmol) of citric acid hydrate in 0.8 mL of acetone was added to a solution of 0.21 g (0.5 mmol) of (E) -1,2-diphenyl-3,3,3- trifluoro-1- [4- (2- (2-hydroxyethylamino) ethoxy) phenyl] propene, prepared as described in Example 11, in 0.2 mL acetone. The mixture was cooled, the precipitated crystals were filtered off and washed with acetone. 0.18 g (58% of theory) of the title compound is obtained; mp 127-129 ^J C.

Analysis:

calculated for C8H8F5NO3:

C 69.09%, 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-hexylaminoethoxy) phenyl) propene tosylate

2.23 g (5 mmol) of (E) -1- (4- (2-bromoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropene, prepared as described in Example 6, are dissolved in A mixture of 5.0 g (50 mmol) of n-hexylamine and 10 ml of 2-methoxyethanol is heated to boiling for 30 minutes, then evaporated and the residue chromatographed on a column of 50 g of silica gel. The mixture is chromatographically uniform, combined and evaporated, the residue is dissolved in 5 ml of isopropanol, and a solution of 1.20 g (6 mmol) of p-toluenesulfonic acid in 6 ml of isopropanol is added. 14 g (91.8% of theory) of the title compound, mp 151-153 ° C.

Analysis:

calculated for C36H10F3NO1S:

C 67.58%, Ή 6.30%, F 8.91%, N 2.19%,

S 5.01%, found:

C 67.61%, H 6.55%, F 9.08%, N 2.39%, S 5.15%.

Example 1 a d 24

Preparation of (E) -1,2-diphenyl-3,3,3-trifluoro-1- (4- (2- / 3-hydroxypropylamino / ethoxy) phenyl) propene

2.23 g (5 mmol) of (E) -1- (4- (2-bromoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropene, prepared as described in Example 6, are dissolved in a mixture of: 3.80 g of 1-amino-3-propanol and 10 ml of 2-methoxyethanol. The mixture was heated to boiling for 30 minutes and then worked up as described in Example 2. The mixture was recrystallized from ethyl acetate-hexane (1: 1). 1.77 g (80.5% of theory) of the title compound are obtained; mp 97-99 ° C.

Analysis:

calculated for C20H22F20NO2:

C 70.73%, H 5.94%, F 12.91%, N 3.17%, found:

C 70.71%, H 5.94%, F 12.83%, N 3.23%.

Example 25

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

A solution of 3.83 g (10 mmol) of (E) -1- (4- (2-aminoethoxy) phenyl) -1,2-diphenyl-3,3,3-trifluoropropene, prepared as described in Example 7 , and 1.22 g (9 mmol) of 2-methyl-1-nitro-2-isothiourea (L. Fishbein et al., J. Am. Chem. Soc. 76, 1877, 1954) in 25 ml of ethanol are added. The reaction mixture was evaporated and the residue was recrystallized from methanol to give 2.78 g (66%) of the title compound, mp 112-116 ° C (dec.).

Analysis:

calculated for C ^ ^HziFFsNdOs:

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 26

Preparation of (Z) -1,2-diphenyl-3,3,34г1Piog-1- [4- (2- / 2-hydroxyethylaminoethoxy) phenyl] propene fumarate

0.59 g (1.17 mmol) of (Z) -1- [4- (2-bromoethoxy) phenyl] -1,2-diphenyl-1,3,3-trifluoropropene, prepared as described in Example 6, was treated with Dissolve in a mixture of 1.34 g of 2-aminoethanol and 1.5 ml of 2-methoxyethanol. The solution was heated to boiling for 30 minutes and then proceeded as described in Example 2. The crude product was recrystallized from ethyl acetate-hexane (1: 3). 0.35 g (70% of theory) of the title compound is obtained in base form; 81 to 83 ° C. The free base was dissolved in 1.5 mL of ethanol, and an ethanolic solution of 0.12 g (1 mmol) of fumaric acid was added. The precipitated crystals are filtered off with suction and washed with ether. 0.28 g (62.2% of theory) of the title compound is obtained; mp 168-172 ° C.

Analysis:

Calcd for C 15 H 16 F 3 NO 2:

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 27

Preparation of (E) -1- [4- (2- / aminoguanidinoethoxy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene hydroiodide

To a solution of 3.85 g (10 mmol) of (E) -1- (4- (2-bromoethoxyphenyl) -1,2-diphenyl-3,3,3-trfluoropropene (Example 6) in 25 ml). S-methylisothiuronium iodide (2.3 g, 10 mmol) was added in methanol (ml) and the mixture heated to boiling for 2 hours, then evaporated to dryness and the residue washed with plenty of water and ether to give 3.44 g. (60.61%) of the desired product, m.p. 190-193 ° C.

Analysis:

calculated for C24H21F3JN4P:

C 50.72%, H 4.26%, F 10.03%,

J 22.33%, N 9.86%,

ΎΛ O 1 O ·

C 50.91%, H 4.54%, F 10.22%,

J 22.60%, N 9.86%.

Example 28

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

3.58 g (8 mmol).

xy) phenyl] -1,2-diphenyl-3,3,3-trifluoropropene (Example 6) and 6 g (80 mmol) of N-methylaminoethanol in 10 ml of isopropanol were heated to boiling for 30 minutes and the obtained The reaction mixture is worked up as described in the example. The crude product is crystallized from hexane to give 3.05 g (86.4%) of the desired product; mp 66-68 ° C. '

Analysis:

calculated for CuH2-3F3NO ?:

No 70.73% o. H 5.94%, F 12.91%, xN 3.17%, found:

C 70.67%, H 5.94%, F 13.04%, N 3.00%.

Example 29

Preparation of pharmaceutical preparations

(a) Tablets

Oral tablets containing 10 mg of active ingredient are prepared in a manner known per se. The composition of one tablet is as follows (in mg):

(E) -1,2-Diphenyl-3,3,3-trifluoro-1- [4- (2- / 2-hydroxyethylaminoZethoxy) phenyl] propene

calculated as free base) 10.0 cornstarch 49.6 lactose 109.0 polyvinylpyrrolidone 5.4 magnesium stearate 1.0 colloidal silicon dioxide 5.0

average weight 180.0

(h) Capsules

Hard gelatin capsules containing 10 milligrams of active ingredient are prepared in a manner known per se. The composition of one capsule is as follows (in mg):

thr eo-1- [4- (2,3-epoxypropoxy) ienyl] -1,2-dienyl-3,3,3t

-trifluoropropane10.0 maize starch) b81.0 magnesium stearate1.0 colloidal silica5.0

Example 30

Preparation of (E) -1,2-Methoxy-3,3,3-methyl-1- [4- (2- / 4-methyl-piperazino / ethoxy) phenyl] propene

Solution. 4.62 g (10 mmol) of (Epi) -diphenyl-3,3,34-fluoro-1- [4- (2-mesyloxy-ethoxy) -phenyl] -propene (m.p. 71-73 ° C) in 80 mL of e241030

Analysis:

calculated for C C HaHFFjNzO:

, C 72.08%, H 6.27%, F 12.22%, N 6.00%, found:

C 71.94%, H 6.45%, F 12.34%, N 5.83%.

of thyl alcohol was heated with 4.0 g (40 mmol) of N-methylpiperazine for 5 hours.

The reaction mixture was evaporated to dryness and worked up as outlined in the example

1. Crystallize from hexane, 3.16 g (68%), m.p. 96-99 ° C.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of the novel derivatives of 1,1,2-triphenylpropane and 1,1,2-triphenylpropene of the general formula I X Y (I) wherein А а В stand for a hydrogen atom or form a rolling bond together, X and Y are the same or different phenyl group substituents optionally substituted with a halogen atom in the para position, R 1 is azidoethyl or a group of formula II Rz / -CH 2 -CH 2 -N 1 R 3 (II) wherein R2 and R3 are each hydrogen, Ci_6alkyl or _C2 -4hydroxyalkyl or form together with the adjacent nitrogen atom, or aminoguanidine nitroguanidinovou heptamethyleniminovou group or N-methylpiperazine, N- (2-hydroxyethyljpiperazinovou or morpholino. With the proviso that when A and V together form a valency bond and X and Y are each phenyl, R 1 is other than dimethylaminoethyl, diethylaminoethyl or morpholinoethyl in the (Z) -somers, and their stereoisomeric and isomeric mixtures and addition salts of basic compounds of formula I, characterized in that wherein the phenoxyalkyl halide or phenoxyalkylsulfonate of formula III (III) wherein: A, V, X and Y are as defined above and Z is halogen or sulfonyloxy, reacted with an amine of the formula R 2 R 5 NH, wherein R 2 and R 5 are as defined above, or an alkali metal azide and the azide derivative obtained is optionally reduced and and the individual stereoisomers are separated from the resulting isomeric mixture and optionally the basic compound of formula 1 is converted into its acid addition salt.