CA2180341A1 - Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene - Google Patents
Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-buteneInfo
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- CA2180341A1 CA2180341A1 CA002180341A CA2180341A CA2180341A1 CA 2180341 A1 CA2180341 A1 CA 2180341A1 CA 002180341 A CA002180341 A CA 002180341A CA 2180341 A CA2180341 A CA 2180341A CA 2180341 A1 CA2180341 A1 CA 2180341A1
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- phenyl
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- dimethylaminoethoxy
- hydroxyphenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Chemistry (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to methods for the production of E-1-¢4'-(2-dimethylaminoethoxy)-phenyl!-1-(3'-hydroxyphenyl)-2-phenyl-1-butene of formula (I) which comprises heating the compound of formula (II) (where R is an easily hydrolyzable protecting group) in the presence of an organic solvent and HCl gas and cooling the reaction to obtain the compound of formula (IIIa), and then heating the isolated compound of formula (IIIa) in the presence of sulfuric acid or hydrochloric acid to obtain the compound according to formula (I).
Description
~ -- WO95/18786 PCT~P94/0000l Method for the Production of E-1-[4 -(2- Dimethylaminoethoxy) -Phenyl]-1-(3~-Hydroxyphenyl) -2-Phenyl-1-sutene Field of the Invention The present invention relates to novel methods for the production of E-1-[4 -(2- dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phenyl-1-butene (Droloxifene/INN) in exceptionally high yield and purity. This compound possesses valuable therapeutic properties in that it exhibits marked anti-estrogen effects and is useful in the treatment of hormone-dependent m~mm~ry tumors.
sackground Art The compound having the formula (I) o~N(cH3)2 Ih OH
is disclosed in US 5,047,431. A method for the production of E-;-[4 -(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene is also described in US 5,047,431 in which the E/Z-stereoisomer mixture of formula (III) as a free base ~ W095/18786 PCT~P94/00001 o~N(C H3)2 OH
is obtained by dehydrating compounds of the general formula (II) o ~N(C H3)2 '. 1~11 R/O
where R is an easily hydrolyzable protecting group in the presence of dilute hydrochloric acid.- The yield of the E/Z-isomer mixture of formula (III) in this process is 90%.
The E/Z-isomer mixture of formula (III) is subsequently isolated, refluxed in concentrated hydrochloric acid, and the hydrochloride of E-1-[4'-(2- dimethylaminoethoxy) -phenyl]
(3 -hydroxyphenyl) -2-phenyl-1-butene is isolated by crystallization with a yield of 48~. The E-isomer hyarochloride is then converted to E-1-[4'-(2-di~ethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene by crystallization (yield 96~). The entire process from cc~pound (II) to compound (I) has a theoretical yield of 41~
and involves a total of two synthetic and three crystallization steps. The afore-mentioned method is unsatisfactory due to the ^ WO95/18786 PCT~P94/00001 low yield of therapeutically active E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phen butene.
In EP 0313799, the process for the production of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phen butene of formula (I) is disclosed in which the carbinol of formula (IV) o--~N(CH3)2 is reacted with either sulfuric acid or hydrochloric acid, and subsequently crystallized to give E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene with yields ranging from 90-96% and purities ranging from 59.4-99.7%. The procedure disclosed in EP 0313799 has the disadvantages that the starting compound, the carbinol of formula (IV) is only obtained with a yield of 90% from the compound of formula (II) previously described in US 5,047,431.
Thus, the overall yield of the conversion of the compound of formula (II) to E-1-[4 -(2- dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phenyl-1-butene is only at-best between 81 and 86%, and the total process involves two synthetic and three crystallization steps. Furthermore, the purity of E-1-[4'-(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene obtained by the afore-mentioned methods is insufficient to allow for direct formulation of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene into pharmaceutical `~ W095/18786 PCT~P94/00001 preparations. Therefore, additional purification steps are necessary to obtain E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phenyl-l-butene in a form sufficiently pure to use for the production of a medicinal preparation. The object of the present invention is to provide methods involving fewer steps than previously described methods for the production of E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3~-hydroxyphenyl) -2-phenyl-l-butene from compounds of the general formula (II) which result in an excellent overall yield and exceptional purity of E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-phenyl-l-butene suitable for direct use in the formulation of pharmaceutical preparation.
Brief Summary of the Invention Surprisingly, it has been found that the carbinols of the general formula (II) can be directly converted to the E/Z-stereoisomer mixtures of formula (III) with remarkably high yield, and that the isolated E/Z-stereoisomer mixture can be ccnverted to the biologically active E-l-[4'-(2-dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-phenyl-l-butene with high yield and exceptional purity. The purity of the resulting products of the present invention allow for the direct formulation of pharmaceutical preparations, thereby circumventing the previous need to further purify E-l-[4'-(2-dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-phenyl-l-bu;ene for use in manufacturing pharmaceuticals.
Detailed Description of the Invention Tr.e present invention provides methods for the production of E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-~henyl-l-butene of formula I
- ~voss/18786 PCT~P94/00001 -o--~N(cH3)2 ,b f 11 OH
which comprises the steps of a) heating the compound of formula (II) O - ~N(cH3)2 ,b where R is an easily hydrolyzable protecting group, preferably a tetrahydropyranyl group, at a temperature within the range of 70-80C for a time within the range of 4-6 hours in the presence of an organic solvent, preferably 2-propanol, and HCl gas, and then cooling the reaction to a temperature within a range of -5 to 5C, preferably 0C, for a time within the range of 4-6 hours, preferably 5.5 hours, to obtain E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl~-1-(3 -hydroxyphenyl) -2-phenyl-l-butene x hydrochloride of formula (IIIa) 95/l8786 PCT~P94/00001 o~N(cH3)2 (IIIa) 1~, 1 )I XHCI
OH
and b) heating the compound of formula(IIIa) at a temperature within the range of 50-60C for a time within the range of 10-24 hours in the absence of an organic solvent and in the presence of 40-S0~ by volume sulfuric acid, preferably S0~ by volume sulfuric acid, or 32-37~
hydrochloric acid, preferably 37~ hydrochloric acid. When sulfuric acid is used in step b, the E/Z-stereoisomer mixture of formula (IIIa) obtained by step a is heated at a temperature, preferably within the range of 55-60~C for a time of preferably 14 hours. When hydrochloric acid is used in step b, the E/Z-stereoisomer mixture of formula (IIIa) obtained by step a is heated at a temperature, preferably within the range of 50-55C for a time of preferably 16 hours. When the ratio of the Z- to the E-stereoisomer of formula (IIIa) obtained by step a is greater than 3:7, and preferably greater than 5:1, the E/Z-stereoisomer mixture of formula (IIIa) is heated at a temperature preferably within the range of 55-60~C for a time of preferably 22-24 hours. Thereafter, the reaction mixture is alkalinized, preferably with a 25~ solution of ammonia in an organic solvent, such as dichloromethane.
The following examples are set forth as representative and preferred embodiments of the present invention. These examples are not to be construed as limiting the scope of the invention - -- WO95/18786 PCT~P94/00001 in any manner. It should be understood that variations and modifications can be made while remaining within the spirit and scope of the invention.
Example 1 a) 25 parts of 1-[4~-(2-dimethylaminoethoxy)-phenyl] -2-phenyl-1- [3 -(2-tetrahydropyranyloxy)-phenyl]-n-butan-1-ol in 150 parts 2-propanol are stirred and heated at a temperature of 70-80C and hydrochloric gas is introduced.
After ca. 5.5 hours, the suspension is cooled to 0C and kept at this temperature for 12 hours. The precipitate is filtered by vacuum and washed with 25 parts 2-propanol.
After drying, 21 parts (96~ theoretical yield) E/Z -1-(4 -2-dimethylaminoethoxy)-phenyl]-1-(3 -hydroxyphenyl)-2-phenyl-1-butene x HCl having a content of greater than 70 of the E-stereoisomer (lH-NMR) are obtained; melting point 215-217C.
lH-NMR- spectrum (CDCl3/DMSO-d6) (100 MHz, chemical shifts are given in ppm. TMS (~ = 0.0) s = singlet, t = triplet, q = quartet, m = multiplet):
0.9 (3H, t) CH2C~3 2.4 (2H, q) C~2CH3 2.88 s N(C~3)2/ E-isomer, 2.95 s N(C~3)2/ Z-isomer 3.4 (2H, t) C_2N
sackground Art The compound having the formula (I) o~N(cH3)2 Ih OH
is disclosed in US 5,047,431. A method for the production of E-;-[4 -(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene is also described in US 5,047,431 in which the E/Z-stereoisomer mixture of formula (III) as a free base ~ W095/18786 PCT~P94/00001 o~N(C H3)2 OH
is obtained by dehydrating compounds of the general formula (II) o ~N(C H3)2 '. 1~11 R/O
where R is an easily hydrolyzable protecting group in the presence of dilute hydrochloric acid.- The yield of the E/Z-isomer mixture of formula (III) in this process is 90%.
The E/Z-isomer mixture of formula (III) is subsequently isolated, refluxed in concentrated hydrochloric acid, and the hydrochloride of E-1-[4'-(2- dimethylaminoethoxy) -phenyl]
(3 -hydroxyphenyl) -2-phenyl-1-butene is isolated by crystallization with a yield of 48~. The E-isomer hyarochloride is then converted to E-1-[4'-(2-di~ethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene by crystallization (yield 96~). The entire process from cc~pound (II) to compound (I) has a theoretical yield of 41~
and involves a total of two synthetic and three crystallization steps. The afore-mentioned method is unsatisfactory due to the ^ WO95/18786 PCT~P94/00001 low yield of therapeutically active E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phen butene.
In EP 0313799, the process for the production of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phen butene of formula (I) is disclosed in which the carbinol of formula (IV) o--~N(CH3)2 is reacted with either sulfuric acid or hydrochloric acid, and subsequently crystallized to give E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene with yields ranging from 90-96% and purities ranging from 59.4-99.7%. The procedure disclosed in EP 0313799 has the disadvantages that the starting compound, the carbinol of formula (IV) is only obtained with a yield of 90% from the compound of formula (II) previously described in US 5,047,431.
Thus, the overall yield of the conversion of the compound of formula (II) to E-1-[4 -(2- dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phenyl-1-butene is only at-best between 81 and 86%, and the total process involves two synthetic and three crystallization steps. Furthermore, the purity of E-1-[4'-(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene obtained by the afore-mentioned methods is insufficient to allow for direct formulation of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene into pharmaceutical `~ W095/18786 PCT~P94/00001 preparations. Therefore, additional purification steps are necessary to obtain E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3 -hydroxyphenyl) -2-phenyl-l-butene in a form sufficiently pure to use for the production of a medicinal preparation. The object of the present invention is to provide methods involving fewer steps than previously described methods for the production of E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3~-hydroxyphenyl) -2-phenyl-l-butene from compounds of the general formula (II) which result in an excellent overall yield and exceptional purity of E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-phenyl-l-butene suitable for direct use in the formulation of pharmaceutical preparation.
Brief Summary of the Invention Surprisingly, it has been found that the carbinols of the general formula (II) can be directly converted to the E/Z-stereoisomer mixtures of formula (III) with remarkably high yield, and that the isolated E/Z-stereoisomer mixture can be ccnverted to the biologically active E-l-[4'-(2-dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-phenyl-l-butene with high yield and exceptional purity. The purity of the resulting products of the present invention allow for the direct formulation of pharmaceutical preparations, thereby circumventing the previous need to further purify E-l-[4'-(2-dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-phenyl-l-bu;ene for use in manufacturing pharmaceuticals.
Detailed Description of the Invention Tr.e present invention provides methods for the production of E-l-[4'-(2- dimethylaminoethoxy) -phenyl]-l-(3'-hydroxyphenyl) -2-~henyl-l-butene of formula I
- ~voss/18786 PCT~P94/00001 -o--~N(cH3)2 ,b f 11 OH
which comprises the steps of a) heating the compound of formula (II) O - ~N(cH3)2 ,b where R is an easily hydrolyzable protecting group, preferably a tetrahydropyranyl group, at a temperature within the range of 70-80C for a time within the range of 4-6 hours in the presence of an organic solvent, preferably 2-propanol, and HCl gas, and then cooling the reaction to a temperature within a range of -5 to 5C, preferably 0C, for a time within the range of 4-6 hours, preferably 5.5 hours, to obtain E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl~-1-(3 -hydroxyphenyl) -2-phenyl-l-butene x hydrochloride of formula (IIIa) 95/l8786 PCT~P94/00001 o~N(cH3)2 (IIIa) 1~, 1 )I XHCI
OH
and b) heating the compound of formula(IIIa) at a temperature within the range of 50-60C for a time within the range of 10-24 hours in the absence of an organic solvent and in the presence of 40-S0~ by volume sulfuric acid, preferably S0~ by volume sulfuric acid, or 32-37~
hydrochloric acid, preferably 37~ hydrochloric acid. When sulfuric acid is used in step b, the E/Z-stereoisomer mixture of formula (IIIa) obtained by step a is heated at a temperature, preferably within the range of 55-60~C for a time of preferably 14 hours. When hydrochloric acid is used in step b, the E/Z-stereoisomer mixture of formula (IIIa) obtained by step a is heated at a temperature, preferably within the range of 50-55C for a time of preferably 16 hours. When the ratio of the Z- to the E-stereoisomer of formula (IIIa) obtained by step a is greater than 3:7, and preferably greater than 5:1, the E/Z-stereoisomer mixture of formula (IIIa) is heated at a temperature preferably within the range of 55-60~C for a time of preferably 22-24 hours. Thereafter, the reaction mixture is alkalinized, preferably with a 25~ solution of ammonia in an organic solvent, such as dichloromethane.
The following examples are set forth as representative and preferred embodiments of the present invention. These examples are not to be construed as limiting the scope of the invention - -- WO95/18786 PCT~P94/00001 in any manner. It should be understood that variations and modifications can be made while remaining within the spirit and scope of the invention.
Example 1 a) 25 parts of 1-[4~-(2-dimethylaminoethoxy)-phenyl] -2-phenyl-1- [3 -(2-tetrahydropyranyloxy)-phenyl]-n-butan-1-ol in 150 parts 2-propanol are stirred and heated at a temperature of 70-80C and hydrochloric gas is introduced.
After ca. 5.5 hours, the suspension is cooled to 0C and kept at this temperature for 12 hours. The precipitate is filtered by vacuum and washed with 25 parts 2-propanol.
After drying, 21 parts (96~ theoretical yield) E/Z -1-(4 -2-dimethylaminoethoxy)-phenyl]-1-(3 -hydroxyphenyl)-2-phenyl-1-butene x HCl having a content of greater than 70 of the E-stereoisomer (lH-NMR) are obtained; melting point 215-217C.
lH-NMR- spectrum (CDCl3/DMSO-d6) (100 MHz, chemical shifts are given in ppm. TMS (~ = 0.0) s = singlet, t = triplet, q = quartet, m = multiplet):
0.9 (3H, t) CH2C~3 2.4 (2H, q) C~2CH3 2.88 s N(C~3)2/ E-isomer, 2.95 s N(C~3)2/ Z-isomer 3.4 (2H, t) C_2N
4.3 t OC~2/ E-isomer, 4.5 t OC~2/ Z-isomer 6.2 - 7.1 (13 H, m) aromatic protons 6.9 and 12.0 (wide) OH, NH+.
b) 3 parts of E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl]
(3 -hydroxyphenyl) -2-phenyl-1-butene x HCl (isomer mixture) are stirred into 25 parts 37~ hydrochloric acid and the suspension is heated at 50C for 16 hours with vigorous stirring. Subsequently the suspension is cooled - - WO95/l8786 PCT~P94m000l and alkalinized by the addition of 15 parts ice and 50 parts dichloromethane with 25~ ammonia. The organic phase is washed several times with water. After the removal of the organic solvent 2.6 parts (95~ theoretical yield) of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene having a content of 100 of the E-stereoisomer (HPLC) remain. Crystals from acetone have a melting point of 164C.
Exa~ple 2 a) 25 parts of 1-[4 -(2-dimethylaminoethoxy)-phenyl] -2-phenyl-l- [3 -(2-tetrahydropyranyloxy)-phenyl]-n-butan-1-ol in 150 parts 2-propanol are stirred and heated at a temperature of 70-80C and hydrochloric gas is introduced.
After ca. 5.5 hours, the suspension is cooled to 0C and kept at this temperature for 12 hours. The precipitate is filtered by vacuum and washed with 25 parts 2-propanol.
After drying, 21 parts (96~ theoretical yield) E/Z -1-(4 -2-dimethylaminoethoxy)-phenyl]-1-(3 -hydroxyphenyl)-2-phenyl-1-butene x HCl having a content of greater than 70 of the E-stereoisomer (lH-NMR) are obtained; melting point 215-217C.
lH-NMR- spectrum (CDC13/DMSO-d6) (100 MHz, chemical shifts are given in ppm. TMS (~ = 0.0) s = singlet, t = triplet, q = quartet, m = multiplet):
0.9 (3H, t) CH2C_3 2.4 (2H, q) C~2CH3 2.88 s N(C~3)2/ E-isomer, 2.95 s N(C~3)2/ Z-isomer 3.4 (2H, t) C~2N
4.3 t OC~2/ E-isomer, 4.5 t OC~2/ Z-isomer 6.2 - 7.1 (13 H, m) aromatic protons 6.9 and 12.0 (wide) OH, NH+ .
- _ W095/18786 2 1 8 0 3 4 l PCT~P94/0000l b) 6 parts of E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene x HCl (isomer mixture) are stirred into 33 parts 50~ by volume sulfuric acid and heated at 55C for 14 hours with vigorous shaking. After the addition of lO parts water and 80 parts toluene, the reaction mixture is alkalinized with 25~ 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 by vacuum and washed with 6 parts toluene.
After drying, 5.3 parts (97~ theoretical yield) of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene having a content of lOO~ of the E-stereoisomer (HPLC) remain. Crystals from acetic acid ethylester have a melting point of 164C.
Example 3 3 parts of E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene x HCl having a content of more than 90~ of the Z-stereoisomer are stirred into 30 parts 50~ by volume sulfuric acid and heated at a temperature of 55-60C for 24 hours with vigorous shaking.
Subsequently the reaction mixture is cooled and alkalinized by the addition of 8 parts water and 20 parts dichloromethane with 25~ ammonia. The organic phase is washed with water. After the removal of the organic solvent by vacuum distillation, 2.3 parts (-83~ theoretical yield) of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene having a content of 99.8~ of the E-stereoisomer (HPLc) remain. Crystals from ethanol have a melting point of 164C.
_ WOgS/l8786 PcT~Ps4/oooo Example 4 A pharmaceutical preparation containing E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene can be prepared by mixing 111 g, mannitol, 15 g, corn starch and 6 g, alginic acid, 20.0 g, and finely powdered E-l-[4~-(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene, granulating the mixture and drying the granules. After carefully mixing the granules with 0.75 g, methyl cellulose and 1.5 g, magnesium stearate, the mixture is compressed into one thousand tablets, each containing 20 mg, active ingredient.
b) 3 parts of E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl]
(3 -hydroxyphenyl) -2-phenyl-1-butene x HCl (isomer mixture) are stirred into 25 parts 37~ hydrochloric acid and the suspension is heated at 50C for 16 hours with vigorous stirring. Subsequently the suspension is cooled - - WO95/l8786 PCT~P94m000l and alkalinized by the addition of 15 parts ice and 50 parts dichloromethane with 25~ ammonia. The organic phase is washed several times with water. After the removal of the organic solvent 2.6 parts (95~ theoretical yield) of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene having a content of 100 of the E-stereoisomer (HPLC) remain. Crystals from acetone have a melting point of 164C.
Exa~ple 2 a) 25 parts of 1-[4 -(2-dimethylaminoethoxy)-phenyl] -2-phenyl-l- [3 -(2-tetrahydropyranyloxy)-phenyl]-n-butan-1-ol in 150 parts 2-propanol are stirred and heated at a temperature of 70-80C and hydrochloric gas is introduced.
After ca. 5.5 hours, the suspension is cooled to 0C and kept at this temperature for 12 hours. The precipitate is filtered by vacuum and washed with 25 parts 2-propanol.
After drying, 21 parts (96~ theoretical yield) E/Z -1-(4 -2-dimethylaminoethoxy)-phenyl]-1-(3 -hydroxyphenyl)-2-phenyl-1-butene x HCl having a content of greater than 70 of the E-stereoisomer (lH-NMR) are obtained; melting point 215-217C.
lH-NMR- spectrum (CDC13/DMSO-d6) (100 MHz, chemical shifts are given in ppm. TMS (~ = 0.0) s = singlet, t = triplet, q = quartet, m = multiplet):
0.9 (3H, t) CH2C_3 2.4 (2H, q) C~2CH3 2.88 s N(C~3)2/ E-isomer, 2.95 s N(C~3)2/ Z-isomer 3.4 (2H, t) C~2N
4.3 t OC~2/ E-isomer, 4.5 t OC~2/ Z-isomer 6.2 - 7.1 (13 H, m) aromatic protons 6.9 and 12.0 (wide) OH, NH+ .
- _ W095/18786 2 1 8 0 3 4 l PCT~P94/0000l b) 6 parts of E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene x HCl (isomer mixture) are stirred into 33 parts 50~ by volume sulfuric acid and heated at 55C for 14 hours with vigorous shaking. After the addition of lO parts water and 80 parts toluene, the reaction mixture is alkalinized with 25~ 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 by vacuum and washed with 6 parts toluene.
After drying, 5.3 parts (97~ theoretical yield) of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene having a content of lOO~ of the E-stereoisomer (HPLC) remain. Crystals from acetic acid ethylester have a melting point of 164C.
Example 3 3 parts of E/Z-1-[4 -(2- dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene x HCl having a content of more than 90~ of the Z-stereoisomer are stirred into 30 parts 50~ by volume sulfuric acid and heated at a temperature of 55-60C for 24 hours with vigorous shaking.
Subsequently the reaction mixture is cooled and alkalinized by the addition of 8 parts water and 20 parts dichloromethane with 25~ ammonia. The organic phase is washed with water. After the removal of the organic solvent by vacuum distillation, 2.3 parts (-83~ theoretical yield) of E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene having a content of 99.8~ of the E-stereoisomer (HPLc) remain. Crystals from ethanol have a melting point of 164C.
_ WOgS/l8786 PcT~Ps4/oooo Example 4 A pharmaceutical preparation containing E-1-[4 -(2-dimethylaminoethoxy) -phenyl]-1-(3 -hydroxyphenyl) -2-phenyl-1-butene can be prepared by mixing 111 g, mannitol, 15 g, corn starch and 6 g, alginic acid, 20.0 g, and finely powdered E-l-[4~-(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene, granulating the mixture and drying the granules. After carefully mixing the granules with 0.75 g, methyl cellulose and 1.5 g, magnesium stearate, the mixture is compressed into one thousand tablets, each containing 20 mg, active ingredient.
Claims (13)
1. A method for the production of E-1-[4'-(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene of formula (I) (I) which comprises the steps of a) heating the compound of formula (II) (II) where R is an easily hydrolyzable protecting group at a temperature within the range of 70-80°C for a time within the range of 4-6 hours in the presence of an organic solvent and HCl gas and then cooling the reaction to a temperature within a range of -5 to 5°C for a time within the range of 10-14 hours to obtain E/Z-1-[4'-(2-dimethylaminoethoxy) -phenyl]-1-(3'-hydroxyphenyl) -2-phenyl-1-butene x hydrochloride of formula (IIIa), and (IIIa) b) heating the ccmpound of formula(IIIa) at a temperature within the range of 50-60°C for a time within the range of 10-24 hours in the absence of an organic solvent and in the presence of 40-50% by volume sulfuric acid or 32-37%
hydrochloric acid, and alkalinizing the reacticn mixture to obtain the compound according to formula (I).
hydrochloric acid, and alkalinizing the reacticn mixture to obtain the compound according to formula (I).
2. A method according to claim 1 characterized in that the organic solvent of step a is 2-propanol.
3. A method according to claim 1 characterized in that the reaction mixture of step a is cooled at 0°C.
4. A method according to claim 1 characterized in that the reaction mixture of step a is cooled for 12 hours.
5. A method according to claim 1 characterized in that the protecting group of R of formula (II) is a tetrahydropyranyl group.
6. A method according to claim 1 characterized in that the reaction mixture of step b is heated for a time within the range of 14-16 hours.
7. A method according to claim 1 characterized in that sulfuric acid is present in the reaction mixture of step b at 48-50% volume.
8. A method according to claim 7 characterized in that the reaction mixture of step b is heated at a temperature within the range of 55-60°C.
9. A method according to claim 7 characterized in that the reaction mixture of step b is heated for a time within the range of 22-24 hours.
10. A method according to claim 1 characterized in that hydrochloric acid is present in the reaction mixture of step b at 35-37%.
11. A method according to claim 10 characterized in that the reaction mixture of step b is heated at a temperature within the range of 50-60°.
12. A method according to claim 10 characterized in that when the ratio of the Z- to the E-stereoisomer of the compound of formula (IIIa) produced in step a is greater than 3:7, the reaction mixture of step b is heated for a time within the range of 14-24 hours.
13. A method according to claim 10 characterized in that when the ratio of the Z- to the E-stereoisomer of the compound of formula (IIIa) produced in step a is greater than 5:1, the reaction mixture of step b is heated at a time within the range of 22-24 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002180341A CA2180341A1 (en) | 1994-01-03 | 1994-01-03 | Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002180341A CA2180341A1 (en) | 1994-01-03 | 1994-01-03 | Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2180341A1 true CA2180341A1 (en) | 1995-07-13 |
Family
ID=4158523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002180341A Abandoned CA2180341A1 (en) | 1994-01-03 | 1994-01-03 | Method for the production of e-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydroxyphenyl)-2-phenyl-1-butene |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2180341A1 (en) |
-
1994
- 1994-01-03 CA CA002180341A patent/CA2180341A1/en not_active Abandoned
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