The method of obtaining e-1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'- hydroxyphenyl)-2-phenylbutane-1

 

(57) Abstract:

The invention relates to a method for E-1-[41-(2 dimethylaminoethoxy)phenyl] -1-(31-hydroxyphenyl)-2 - phenylbutane-1 of formula (I), which involves the heating of the compounds of formula (II) in the presence of an organic solvent and gaseous Hcl, cooling the reaction medium to obtain the compounds of formula (IIIa) and then heating the selected compound of formula IIIA in the presence of sulfuric acid or hydrochloric acid to obtain the compounds of formula (I).

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where R denotes easily gidrolizuyutza protective group. The method allows to obtain the compound of formula I with an exceptionally high yield and purity. The connection I have valuable therapeutic properties, showing visible antiestrogenic action, and can be used to treat breast cancers that depend on hormones. 11 C.p. f-crystals.

The invention relates to a new method of obtaining E-1-/4'- (2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1 (Droloxifene/1NN) with an exceptionally high yield and purity. This connection has valuable therapeutic properties, reflected in the fact that it has been quite antiestrogen

Background of the invention

The compound corresponding to the formula (I):

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disclosed in U.S. patent 5047431. In U.S. patent 5047431 also describes a method of obtaining. E-1-/ 4'-(2-dimethylaminoethoxy) phenyl/-1- (3'-hydroxyphenyl)-2 - phenylbutane-1, according to which a mixture of E/Z stereoisomers of formula (III):

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in the form of the free base is obtained by dehydration of compounds of General formula (II):

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where

R denotes easily gidrolizuyutza protective group,

in the presence of dilute hydrochloric acid. The output is a mixture of E/Z - isomers of the formula (III) in this way is 90%. Mixture of E/Z - isomers of the formula (III) then allocate, refluxed in concentrated hydrochloric acid and the hydrochloride E-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl) -2-phenyl-butene-1 allocate by crystallization to yield 48%. Hydrochloride E-isomer then transformed into E.-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'- hydroxyphenyl)-2 - phenylbutane-1 by crystallization (yield=96%). The full transition from the compounds of formula (II) to the compound of formula (I) gives the output 41% of theoretical, and generally includes two stages of synthesis and the three stages of crystallization. The above method is unsatisfactory is nibutani-1.

In the European patent EP-0313799 disclosed is a method of obtaining E-1-/4'-(2- dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1 of formula (I), according to which the carbinol of the formula (IV):

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enter into interaction with either sulfuric acid or hydrochloric acid, and then kristallisera with getting E-1-/4'-(2- dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1 with outputs in the range of 90-96% and a purity of the order of 99.4-99.7 per cent. The method disclosed in the European patent EP-0313799, has drawbacks, namely, that the original connection, the carbinol of the formula (IV), receive only with the release of 90% of the compounds of formula (II) described previously in U.S. patent 5047431. Thus, the total yield of the process of conversion of compounds of formula (II) in E.-1-/4'-(2-dimethylaminoethoxy) phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1 in the best case is only 81-86%, and the method includes two stages of synthesis and the three stages of crystallization. In addition, the purity E-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'- hydroxyphenyl)-2-phenylbutane-1 obtained by the above methods is unsatisfactory in order to allow direct conversion E-1-/4'-(2- dimethylaminoethoxy)-phenyl/-1-(3'-hydroxyphenyl)-2 - phenylbutane the pure form E-1-/4'-(2- dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2 - phenylbutane-1 for use for the preparation of a medicinal product.

The object of the present invention is to develop a method that includes fewer stages than in the above-described methods, to obtain E-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)- 2-phenylbutane-1 of compounds of General formula (II), which gives in General with excellent yield and excellent purity E-1-/4'- (2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2 - phenylbutane-1, suitable for direct use in the preparation of a pharmaceutical preparation.

Summary of the invention

It has been unexpectedly found that carbinole General formula (II) can be directly converted into a mixture of E/Z stereoisomers of formula (III) with a surprisingly high yield, and that the isolated mixture of E/Z stereoisomers can be converted into biologically active E-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)- 2-phenylbutane-1 with high yield and excellent purity. The purity of the obtained product according to the present invention can be used for direct production of pharmaceutical preparations, thus, exclude (bypass) still need further cleaning E-1- /4'-(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1 for its application in the preparation of Pharm the person receiving the E-1-/4'-(2- dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1 of formula (I):

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which involves the following stages:

a) heating the compounds of formula (II):

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where

R denotes easily gidrolizuyutza protective group, preferably tetrahydropyranyloxy group

at a temperature in the range of 70-80oC over time within 4-6 hours, in the presence of an organic solvent, preferably propane-2-ol, and gaseous HCl, and then cooling the reaction medium at a temperature in the range from -5oC to 5oC, preferably 0oC, during the time within 4-6 hours, preferably 5.5 hours, to obtain the E/Z-1-/4'-(2- dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl) -2-phenylbutane-1-hydrochloride of the formula (IIIa):

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and b) heating the compounds of formula (IIIa) at a temperature in the range of 50-60oC over time within 10-24 hours, in the absence of an organic solvent and in the presence of 40-50 vol.% sulfuric acid, preferably about 50. % sulfuric acid, or 32-34% hydrochloric acid, preferably 37% hydrochloric acid. When in stage b) uses sulfuric acid, obtained in stage a) mixture of E/Z-stereoisomers of the formula (IIIa) is heated at a temperature preferably in the range of 55-60oC for the time prefer the ormula (IIIa) is heated at a temperature preferably in the range of 50-55oC in the course of time, preferably 16 hours. When the ratio Z-stereoisomer E - stereoisomer of the compounds of formula (IIIa) obtained in stage a), more than 3:7, and preferably greater than 5:1 mixture of E/Z - stereoisomers of the formula (IIIa) is heated preferably at a temperature in the range of 55-60oC in the course of time, preferably 22 to 24 hours. After that the reaction mixture is alkalinized preferably using 25% ammonia solution in an organic solvent, such as dichloromethane.

The following examples are given hereinafter referred to as typical and preferred implementations of the present invention. These examples should not be seen as organic in any way the scope of protection of the invention. It should be clear that there may be variations and modifications, while remain within the framework of the invention, and of preserving its essence.

Example 1

a) 25 parts of 1-/4'-(2-dimethylaminoethoxy)phenyl/-2 - phenyl-1-/3'-(2-tetrahydropyranyloxy)phenyl/-n-butanol-1 in 150 parts of propane-2-ol is stirred and heated at a temperature of 70-80oC and injected (miss) gaseous hydrogen chloride. Later premenstrual in vacuum and washed with 25 parts of propane-2-ol. After drying, get 21 part (output from theoretical =96%) E/Z-1-/4' -(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl) -2-phenyl-butene-1-hydrochloride with a content of more than 70%, S-stereoisomer (1H-NMR); so pl. = 215 - 217oC.

1H-NMR spectrum (CDCl3/DMSO-d6) (100 MHz, chemical shift are given in M. D. (ppm); TMS [ = 0.0]; s = singlet; so = triplet; K. = Quartet; m = multiplet):

of 0.9(3H, T. , CH2CH3); 2,4(K., 2H, CH2CH3); 2,88(SD, N(CH3)2, E-isomer); 2,95(SD, N(CH3)2, Z-isomer); 3,4(t, 2H, CH2N); 4,3(so, OCH2, E-isomer); 4,5 (So , OCH2, Z-isomer); and 6.2, and 7.1(m , 13H, aromatic protons); 6,9 and 12.0(broad, OH, NH+).

b) 3 part E/Z-1-/4'-(2-dimethylaminoethoxy)-phenyl/-1-(3'-hydroxyphenyl)-2-phenylbutane-1-hydrochloride (mixture of isomers) is stirred in 25 parts of 37% hydrochloric acid and the suspension is heated at 50oC for 16 hours under vigorous stirring. Then the suspension is cooled and alkalinized by adding 15 parts of ice and 50 parts of dichloromethane with 25% ammonia. The organic phase is washed several times with water. After removal of the organic solvent, 2,6 get parts (output from theoretical =95%) E-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'- hydroxyphenyl is lly from acetone have a melting point 164oC.

Example 2

a) 25 parts of 1-/4'-(2-dimethylaminoethoxy)phenyl/-2 - phenyl-1-(3'-(2-tetrahydropyranyloxy)phenyl/n-butanol-1 in 150 parts of propane-2-ol is stirred and heated at a temperature of 70-80oC and introducing gaseous hydrogen chloride. After about 5.5 hours, the suspension is cooled to 0oC and kept at this temperature for 12 hours. The precipitate is filtered under vacuum and washed with 25 parts of propane-2-ol. After drying receive 21 parts (96% of theoretical yield) of E/Z-1-/4'-(2-dimethylaminoethoxy) phenyl/-1-(3'-hydroxyphenyl)-2 - phenylbutane-1-hydrochloride with the content of the E-stereoisomer (1H-NMR) more than 70%; so pl. = 215-217oC.

1H-NMR spectrum (CDCl3/DMSO-d6) (100 MHz, chemical shift are given in M. D.; TMS /trimethylsilane/ ( = 0.0); C. = singlet; so = triplet; K = Quartet; m = multiplet): 0,9 (t, 3H, CH2CH3); 2,4 (K., 2H, CH2CH3); 2,88 (SD, N(CH3)2, E-isomer); 2,95 (SD, N(CH3)2, Z-isomer); 3,4 (t, 2H, CH2N); 4,3 (so, OCH2, E-isomer); 4,5 (so, OCH2Z-isomer); and 6.2, and 7.1 (m, 13H, aromatic protons); 6,9 and 12.0 (broad, OH, NH+).

b) 6 parts (E/Z- -1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'- hydroxyphenyl)-2-phenylbutane-1-hydrochloride (mixture of isomers) premesis the Institute. After adding 10 parts of water and 80 parts of toluene, the reaction mixture is alkalinized with 25% aqueous ammonia. After washing with water, the organic phase is concentrated by vacuum distillation and the resulting suspension is crystallized from toluene. The precipitate is filtered under vacuum and washed with 6 parts of toluene. After drying, remain to 5.3 parts (97% of theoretical yield) E-1/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl) -2-phenylbutane-1 with the content of the E-stereoisomer 100%. (HPLC). Crystals of ethyl acetate are so pl. = 164oC.

Example 3

3 part E/Z-1-/4'-(2-dimethylaminoethoxy)phenyl/-1- (3' - hydroxyphenyl)-2-phenylbutane-1-hydrochloride with the contents of the Z - stereoisomer more than 90%, is stirred in 30 parts of 50% vol. -sulfuric acid and heated at a temperature of 55-60oC for 24 hours with vigorous shaking. Then the reaction mixture is cooled and alkalinized by adding 8 parts of water and 20 parts of dichloromethane with 25% ammonia. The organic phase is washed with water. After removal of the organic solvent by vacuum distillation, remain to 2.3 parts (83% of theoretical yield) E-1/4'- (2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl) -2-phenylbutane-1 with the content of the E-stereoisomer (HPLC) and 99.8%. KRI'-(2 - dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2 - phenylbutane-1, can be obtained by mixture of 111 g of mannitol, 15 g of corn starch and 6 g of alginic acid and 20.0 g of fine powder E-1-/4'-(2-dimethylaminoethoxy)phenyl/-1-(3'-hydroxyphenyl)-2 - phenylbutane-1, granulating the mixture and drying of the granulate. After that, the pellets gently mixed with 0.75 g of methyl cellulose and 1.5 g of magnesium stearate, the mixture is pressed into 1000 tablets, each contains 20 mg of the active ingredient.

1. The method of obtaining E-1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbutane-1 of the formula I

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of the compounds of formula II

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where R denotes easily gidrolizuyutza protective group, characterized in that a) a compound of formula II is heated at 70-80oC for 4-6 h in the presence of an organic solvent and gaseous HCl and then carry out the cooling of the reaction medium at a temperature of from -5 to 5oC for 10-24 h with obtaining E/Z-1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbutane-1 hydrochloride of the formula IIIa

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and b) a compound of formula IIIa is heated at 50-60oC for 10-24 h in the absence of organic solvent and in the presence of 40-50 vol.% sulfuric acid or 32-37% hydrochloric acid and alkalinized reaction smartvoltage in stage a) is propan-2-ol.

3. The method according to p. 1, characterized in that the reaction mixture of stage a) is cooled at 0oC.

4. The method according to p. 1, characterized in that the reaction mixture of stage a) is cooled within 12 hours.

5. The method according to p. 1, characterized in that the protective group in formula II is tetrahydropyranyl group.

6. The method according to p. 1, characterized in that the reaction mixture of stage (b) heated for 14-16 hours

7. The method according to p. 1, characterized in that the reaction mixture of stage (b) is sulfuric acid in the form of 48-50% acid.

8. The method according to p. 7, characterized in that the reaction mixture of stage (b) is heated at 55-60oC.

9. The method according to p. 7, characterized in that the reaction mixture of stage (b) is heated for 22-24 h

10. The method according to p. 1, wherein the hydrochloric acid is present in the reaction mixture of stage (b) in the form of 35-37% acid.

11. The method according to p. 10, characterized in that, when the ratio of the Z-stereoisomer E-stereoisomer of the compounds of formula IIIa obtained in stage a), more than 3:7, the reaction mixture in stage (b) heated for 14-24 h

12. The method according to p. 10, characterized in that, when the ratio of the Z-stereoisomer to E-stereo the increase 22-24 PM

 

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1 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of general formula (A), their stereoisomers or pharmaceutically acceptable salts, possessing ability to inhibit activity of isomerase, taking part in visual cycle. Compounds can be applied for treatment of ophthalmological disease or disorder, such as age-related macular degeneration or Stargardt's macular dystrophy. In general formula (A) Z represents-C(R9)(R10)-C(R1)(R2)-; R1 and R2 each, independently on each other, are selected from hydrogen, halogen, C1-C5alkyl, or -OR6; or R1 and R2 together from oxo; R3 and R4 each, independently on each other, are selected from hydrogen; R6 is selected from a) C5-C15alkyl, optionally substituted with hydroxy, C1-C8alkoxy; or b) C5-C10carbocyclylalkyl, in which carbocycle is 4-, 5-, 6-, 7- or 8-member non-aromatic carbocycle, optionally substituted with hydroxy, halogen or R6CO2-; R9 and R10 each, independently on each other, is selected from hydrogen, halogen, C1-C5alkyl, optionally substituted with hydroxy, or -OR19; or R9 and R10 form oxo; or optionally, R9 and R1 together form direct bond to provide double bond; or optionally, R9 and R1 together form direct bond, and R10 and R2 together form direct bond to provide triple bond; R11 and R12 each, independently on each other, is selected from hydrogen, -C(=O)R23 or -C(NH)NH2, R23 is selected from C1-C8alkyl; R6, R19 and R34 are independently on each other are hydrogen or C1-C8alkyl; each R33 is independently selected from halogen, hydroxyl, C1-C5carboalkoxy, C1-C8alkyl, optionally substituted with hydroxy; and n equals 0 or 1.

EFFECT: compounds inhibit degeneration of retinal cell, in particular neuronal cell, such as photoreceptor cell, in patient's retina.

45 cl, 11 dwg, 11 tbl, 206 ex

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