CA2127274A1 - Process for preparing 3-acylestratrienes and acylbenzenes - Google Patents
Process for preparing 3-acylestratrienes and acylbenzenesInfo
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- CA2127274A1 CA2127274A1 CA002127274A CA2127274A CA2127274A1 CA 2127274 A1 CA2127274 A1 CA 2127274A1 CA 002127274 A CA002127274 A CA 002127274A CA 2127274 A CA2127274 A CA 2127274A CA 2127274 A1 CA2127274 A1 CA 2127274A1
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- benzo
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- H—ELECTRICITY
- H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
- H10N—ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
- H10N30/00—Piezoelectric or electrostrictive devices
- H10N30/20—Piezoelectric or electrostrictive devices with electrical input and mechanical output, e.g. functioning as actuators or vibrators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
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Abstract
Invented is an improved process for the preparation of benzo esters and benzo acids. Also invented are novel intermediates used in said process.
Description
W093/14107 PCTIUS~3/~078 ,, i ~ ., ; i "PRO~ESS FOR PREPARING 3-ACYLESTRATRIENES AND ACYLBEN~ENES"
1 0 ~
The present invention relates to an improved process for the preparation of substituted s~eroidal benzo esters and substi~uted steroidal benzo acids. Such compounds are described in U.S. Patent Nos. 4,954,446;
4,937,237; 4,970,205 and 4,882,3l9 as being useful for or preparing compounds which are useful for inhibiting steroid S-a-reductase.
Processes for the preparation of substituted steroidal benzo esters and substitut:ed steroidal benzo acids have previously been described. In particul2- the use of ~rifluoxomethane sulfonic anhydride to convert steroidal A--ring phenols to steroidal tri.luoromethyl sulfonate intexmediates (in ~95% yield) followed by metal-catalyzed carbonylation to the benzoic ester (in 73% yield) with subsequent hydrolysis to the corresponding benzoic acid ~in 90% yield1 is reported ir.
U.S. Patent No. 4,954,446 Further, said steroidal trifluoromethyl sulfonate intermediate has been reacted in metal-catalyzed coupling reactions in the presence o~ various couplinq reagents (followed by an optional, if applicable hydrolysis reaction1 to form the corresponding steroidal WO93/14107 PCT/US93/~078 h , 7 2 7 i -- 2 benzo esters and the corresponding steroidal benzo acids in U.S. Patent Nos. 4,937,237 and 4,882,319.
In addition to a low overall yield, the principle shortcoming of these disclosures is that trifluoromethane sulfonic anhydride is an expensive reagent adding significant cost to an industrial process. Thus, there is a need in the art for a safe, economical and reliable method to convert steroidal phenols to steroidal benzo esters and steroidal benzo acids.
SUMMAR~ OF THE INVENTIO~
This invention relates to an improved process ior converting phenols to benzo es~ers and benzo acids.
This invention relates to an improved process for converting steroidal phenols to steroidal benzo esters and steroidal benzo acids.
This invention specifically relates to an improved process for the preparation of 17B-(N-t-butylcarboxamide)-estr-l,3,5(l0)-triene-3-carboxylic acid and hydrates thereof.
In a further aspect of the invention there are provided novel intermediates useful in the presently invented process.
DE~aILED D~CRIPTION OF THE IN~E~TION
The present invention provides a process for the production of a benzo acid or a benzo ester which comprises reacting a phenol with fluorosulfonic anhydride and a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine in an appropriate solvent to form a benzo fluorosulfonate compound and subsequently reacting said benzo WO93/14107 '~ ~ i7 2 7 :~ PCT/US93/00078 fluorosulfonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent followed by an optional, if applicable hydrolysis reaction.
The present invention specifically provides a process for the production of a compound of Formula (I) R ~ tI) Rl is (i) H and NR3R4, where R3 and R4 are each independently selected form hydrogen, Cl_galkyl, C3_6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered lS saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or moieties which are chemically conterible to moieties of (i) and R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate of solvate thereof, which comprises reac:ting a compound of the Formula (II) ~\/
HO (II) in which Rl and the broken lines are as described above with fluorosulfonic anhydride and a base in a solvent to form a compound of Formula III
W~93/14107 P~T/US~3/~07~
21 7 `! ~ 4 _ f~
F ~ O ~III) in which Rl and the broken lines are as described above and subsequently reacting said compound of Formula (III) in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable, hydrolysis reaction to fo:rm a compound of Formula (I), and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
Preferably the reaction to convert Formula II
compounds to formula III is preformed at a temperature from -78C to 20C, particularly preferred temperature range is from -lO to 10C.
Preferably the reaction to convert Formula III
compounds to Formula I compounds is preferred at a temperature of 25C to 100C a particular preferred temperature range is from 50 to gOC.
As used above and ~hroughout the remainder of the speciication and claims the carbons of the steroid nucleus are numbered ar.d the rings are let~ered as follows:
l 7 1 ~ C 1 3 D
/1 ~9\ /14--15 I A ¦ 8 1 3 \ " ^~ /7 2 .~? ~ PCT/US93/~078 Compounds of Formula I comprise Rl or moieties which can be chemically conver~ed to those of Rl by known chemical reactions such as described in J. Fried and J.
Edwardsj ~ , Pub:
Van Nostrand Reinhold Company (1972) provided that Rl does not include any such moieties that render inoperative the presently invented process. Reactions to convert said moieties to ~l are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways. For example, carboxylic acid substituents can be converted to the car~oxamide by conversion to the acid halide followed by reacting the same with an amine. Carboxylate substituents can be converted to the acid and treated as above. Nitriles can be converted to the carboxamide by reaction with an alkylating agent, such as t-butylacetate or t-butanol under acidic catalysis.
As used herein, unless otherwise specified, Cl_nalkyl means a straight or branched hydrocarbon chain having l to n carbons.
In utilizing the presently invented process to prepare the preferred sterQidal benzo acids and preferred steroidal benzoesters, of Formula (I),-novel in~ermediates of the following Formula (IV) are synthesized;
F (IV) in which:
Rl is WO93J14107 PCT/US93/~078 7 ~ 6 ~ .. . , ,~ , ., (i) H and CoNR3R4, where R3 and R4 are each independently selected from hydrogen, C1_galkyl, C3_6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;
or moieties which are chemically convertible to moieties of ~i).
By the term "metal-catalyzed coupling reaction"
as used herein is meant that the prepared fluorosulfonated compound is reacted in a suitable organic solvent, preferably a dimethylsulfoxide-C1_l60H
solution (when an ester is desired) or toluene, dimethylformamide or THF (when an acid is desired) with a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine, a phosphine su~h as bis(diphenylphosphino)alkane, preferably l,3 bis(diphenylphosphino)propane or tri-o-tolylphosphine, or a Cl_6alKOH, and a metal catalyst, preferably a palladium catalyst such as palladium (II) acetate, palladium (II) chloride and bis(triphenylphosphine) palladium II acetate, and a coupling reagent.
By the term l'coupling reagent" as used herein is meant a compound which is capable of reacting wit~ an axyl radical to form an acid or an ester. Preferred coupling reagents, which when added to the metal-catalyzed coupling reaction, as described herein, yield preferred acid and ester sroups, as disclosed herein, are carbon monoxide (to yield -COOH~, ethyltributylstannyl acetate (to yield -CH~COOH), dimethyl phosphite (to yield -P(O)(OH)2) and hypophosphorous acid crys~als (to yield -PH(O)OH).
By the term "phenol" as used herein is meant a hydroxylated six membered aromatic ring, unsubstituted W093/14107 ~ PCT/US93/~078 or substituted with non reactive substituents, said aromatic ring may also be part of a polycyclic molecule such as a naphthyl or steroidal moleucle, said molecule being unsubstituted or substituted with non reactive substituents.
By the term "acid" as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H
and -(CH~ 3-COOH.
iO By the term "ester" as used herein is meant a g:roup consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.
By the term "steroidal benzo" as used herein is meant a steroid with an aromatic A ring.
8y the term "solvent" as used herein is meant an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene,~ethyl acetate, dimethylsulfoxide, methanol or dimethylfoxamide.
Preferably the base utilized to prepare compounds of Formula II is triethylamine. Preferably the solvent utilized to prepare compounds of Formula II is methylene chloride. Preferably the catalyst utilized in said metal catalyzed coupling reaction is palladium (II) acetate. Preferred acids used to describe R2 in Formula (I) include; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H, and -(CH2)l_COOH. Particularly preferred among the above acids is -COOH.
The present invention is usuful for the conversion of phenols to benzo esters and benzo acids.
WO 93/14107 PCI`/US93/00078 r~ ^) j.t ,_/ . ! i .-- 8 A preferred aspect of the invention is the conversion of steroidal phenols to steroidal ~enzo esters and steroidal benzo acids.
Pharmaceutically acceptable salts of Formula (I) compounds are formed, where appropriate, by methods well known to those of skill in the art.
Preferably, therefore the process of the present invention is particularly useful for preparing a compound of Structure IIIA.
~ N-H
~/
FO~O
~ (IIIA) and converting the same in one or two steps into the following compound of structure (IA) o t ~ N-H
HO-C (IA) or a pharmaceutically acceptable salt, hydrate of solvate thereof.
WO93/14107 ~ r~ ! PCI/US93/00078 _ g _ The following examples illustrate preparation of ~enzo esters and benzo acids from phenols utilizing fluorosulfonic anhydride. The examples are not intended to lim1t the scope of the invention as defined above or as claimed below.
I. SYN~HF.TTC EXAMPLES
Dimethylformamide, oxalyl chloride, tert-butylamine, triethylamine, dimethylsulfoxide, 1,3-bis(diphenylphosphino)propane, palladium acetate, tri-n-butylamine, formic acid, bis(triphenylphosphine)-palladium acetate, zinc chloride, tri-o-tolylphosphine, sodium fluoride, phenol, 1,3-dimethylphenol, estrone, trimethylsilylcyanide, zinc iodide, phosphorus oxychloride, 10% palladium on carbon, tert-butylacetate, and 3-hydroxypyridine are available from Aldrich Chemical Co. (Milwaukee, WI).
Carbcn monoxide is available from Matheson Gas Products (E. Rutherford, NJ).
17~-Cyanoestra-1,3,5(10)-triene-3-yl methanesulphonate was prepared as described by Barton, et. al. J J. Chem. Soc. (CJ, 1968, 2283. Fluorosufonic anhydride was prepared as described by S. Kongpricha, et. al., Inorg. Syn. 1968, XI, 151. Ethyltributylstannyl acetate was prepared as described by A. Zapata, et. al., Syn. Comm. 1984, 1~1, 27.
~mple 1 ~5=~ L~c~LhI~ e. ~ tL~
~t 3-Hydroxyestra-1~3,~(10~-trien~ 17-~arboxylic s~i~L_~L~L iL~s~5_ WO93/14107 PCT/US93/~078 `' 71 -lo-A mixture of 17~-cyanoestra-1,3,5(10)-triene-3-yl methanesulphonate_(10.0 grams, 1 molar equivalent), sodium hydroxide (34 grams, 30.5 molar equivalents), and ethylene glycol (200 mL) was heated to 150C for 5 hours. The hot reaction solution was cooled to 110C and diluted with water (200 mL). The pH of the solution was adjusted to 2.0 with concentrated hydrochloric acid, and the resulting slurry was chilled to 0C and stirred for l hour. The product was isolated by filtration, washed thoroughly with water (600 mL), and dried under vacuum at 100C to afford a mixture of 3-hydroxyestra-1,3,5(10~-triene-17-carboxylic acid, 17~p isomers (8.5 grams, 77/23:17~ isomers) in 99% yield. mp 250-270C.
B. 3-Hydroxye$~ra-1,3 ~ -tLiene-l7~-N-t-A vigorously stirred solution of DMF (348 mL, 4.1 molar equivalents) and methylene chloride (4800 mL) was slowly charged with oxalyl chloride (384 mL, 4.0 molar equivalents) while maintaining the reaction temperature between 5-15C. A white flocculant suspension formed while the reaction mixture was stirred for 30 minutes.
The reaction was charged with 3-hydroxyestra-1,3,5(10)-triene-17-carboxylic acid, 17~ isomers (329 g, 1 molar ?5 equivalent, 77/23:17~ isomers) and was stirred for two hours. The reaction solution was slowly quenched into a vigorously stirred mixture of tert-butylamine (1200 mL, 10.4 molar equivalents) and methylene chloride (1600 mL) while maintaining the reaction temperature between 5-15 C. The reaction mixture was stirred for 45 mi~utes~ The reaction was charged with water (3.0 L) and stirred for one hour. The product was suction filtered and the filter cake was washed with water (14.0 L). The product was dried in a vacuum oven (65C, house vacuum~ to constant weight to afford 3-hydroxyestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (233 grams) as a white solid in 60% yield. mp 304-305C.
WO 93/141~)7 ~ ~ "; r~ ;7 r~ PCI`/US93/00078 C. 3-Fluorosulfonylestra~ tlO~-triene-17~-N-t-butylcarboxamlde A well-stirred solution of 3-hydroxyestra-1,3,5(10)-triene-17~-N-t butylcarboxamide (231 grams, 1 molar equivalent), methylene chloride (2300 mL), and triethylamine (132 grams, 2 molar equivalents) was cooled to 0-10C. The resulting slurry was treated with fluorosulfonic anhydride (154 grams, 1.3 molar equivalents) while maintaining the reaction ~emperature below 10C. The reaction was stirred for 30 min and water (1.0 L) was added with vigorous stirring. The organic phase was separated and distilled at atmospheric pressure to a final volume of about 986 ml. Water (1283 mL) was added, and the distillation was continued until the methylene chloride was completely removed, as indicated by a drop in the head temperature below 35C.
Dimethylsulfoxide (4.26 L) was added to the residue and the mixture was warmed to 100C. The stirred mixture was cooled to room temperature over a 4 hour period, during which the product crystallized. The reaction mixture was stirred at 15-20C for 1.0 hour and was isolated by filtration.The solid product was washed with water (1.0 L) and air dry thoroughly. This material was crushed and ' reslurried in 4 L of water for 30 minutes. The product-was isolated by filtration and dried at 80C under vacuum to afford 3-fluorosulfonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (237.3 grams) in 83% yield. mp 138-141C.
~ c~boxamideL~I~=
A vessel was charged with dimethylsulfoxide (1350 mL), methanol (75 mL, 5.4 molar equivalents), 3-fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (lS0 g, 1 molar equivalent), triethylamine (76.3 q, 2.2 molar equivalents), and 1,3-WO93/14107 PCTIUS93/~07X
bis(diphenylphosphino)propane (1.41 g, 0.01 molar equivalent). The mixture was stirred until a solution was obtained. Palladium acetate (0.768 g, 0.01 molar equivalent) was added and the flask was filled and evacuated with carbon monoxide three times. The vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly~ The reaction solution was heated to 75C. The carbon monoxide uptake was finished in about 1.5 hours. The reaction was cooled to 15C and stirred for 2 hours.The solid product was isolated by suction filtration, and the mother liquors were used to rinse out the inside of the reactor. The solid product was thoroughly washed with water (1.5 L) and dried lander vacuum at 95C to afford pure methyl 17~-~N-tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate (116.4 g) in 85% yield. mp 155-157C.
~ l?~-N-t=~yl~2xks~amide-~ra-l~3~5(lQ)-triene 3-carboxyl~c_acid ~anhydrnu~ and hydr~d~.
A mixture of methanol (80 mL), water (80 mL), methyl 17~-(N-tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate (15.9 g, 1 molar equivalent), and sodium hydroxide (~.80 g, 3 molar equivalents) was heated to reflux for 8-12 hours. The hot reaction solution was filtered through celite and the filter pad was washed with 60C water (80 mL). The filtrate was diluted with water (80 mL). The methanol was removed by distillation to a head temperature of 100C. The mixture was cooled to 60C and was quenched with vigorous stirring into 1.5 N hydrochloric acid (160 mL). The resulting white suspension was stirred for 15 minutes.
The slurry was cooled to 0-5C and stirred for 1 hour.
The product was isolated by filtration, washed with deionized water, and dried under vacuum at 100C to afford crude 17~-N-t-butylcarboxamide-estra-1,3,5(10)-triene-3-carboxylic acid (15.1 grams) in 99% yield. mp 235-238C.
WO93/14107 ~ PCT/US93/~07X
Anhydrous 17~-N-t-butylcarboxamide~estra-1,3,5(10)-triene-3-carboxylic acid was prepared by azeotropic removal of water from the crude material by distilling from acetonitrile, concentration, and cooling. The solid was isolated by filtration and dried. Yield 71%.
Alternatively a hydrated form of 17~-N-t-butylcarboxamide-estra-1,3,5(10)-triene-3-carboxylic acid was prepared by recrystallization from aqueous isopropanol. Yield 70-80%.
17~-(N-tert-Butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid is a compound which is currently undergoing clinical investiga~ion for the treatment of benign prostatic hypertrophy. The isolation of anhydrous and hydrated forms of said compound is necessary in order to establish an optimal and reproducible bioavailability profile for said compound.
2~ E~m~1~ 2 A vessel was charged with 5 volumes of dimethylformamider 3-fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (1 molar equivalent, prepared as described in Example lC), tri-n-butylamine (4.5 molar eq~ivalentsj, formic acid (2 molar equivalents) and bis(triphenylphosphine)palladium acetate (0.02 molar equivalents). The flask was evacuated and filled with carbon monoxide three times.
The vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly. The reaction solution was heated to 75C until the uptake of carbon monoxide was complete. The reaction was cooled to xoom temperature. Ethyl acetate and water were added, and the organic layer was separated. The organic phase was WO93/14107 PCT/US93/~078 ,_ .. ` I .~; i -- 14 --washed with water and dried over magnesium sulfate. The organic phase was concentrated under vacuum to yield a crude 17~(N-tert-butylcarboxamide)-estra-1,3,5~10)-triene-3-carboxylic acid. Anhydrous and hydrated 17~(N-tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid were prepared as described in ~xample lE. Yield 70-80%.
Example 3 F~hyl-17-heta-tN-tert-butylcarboxamide~-e~tra-1.3~5(10)-,triene-3-acetic acid Zinc Chloride (1.91 g, 1.4 molar equivalents) was weighed into a 200 mL flask fitted with a stir bar and serum cap. The mixture was heated to 150C under vacuum ~1.0 mm) ~or 1 hour. The flask was cooled to 25C and the vacuum was broken with argon. 3-Fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (4.38 g, 1 molar equivalent, prepared as described in Example lC), ethyltributylstannyl acetate (5.28 g, 1.4 molar equivalents), and dimethylformamide ( 20.0 mL) were added to the flask~
The ~lask was evacuated and flushed with argon three times. Tri-o-tolylphosphine (0.091 ~, 0.03 molar equivalent) and palladium acetate (0.045 g, 0.02 molar equivalent) were added and the reaction vessel was evacuated and flushed with argon three times. The mixture was heated for 1.0 hour at 80C. Toluene (100 mL) and water (100 mL) were added and the mixture was stirred for 5 minutes. The mixture was filtered ~hrough celite and poured 1nto a separatory funnel. The aqueous layer was separated and discarded. The organic phase was washed again with water (lO0 mL). The organic phase was washed with saturated sodium fluoride (2 x 50 mL) and filtered through celite after each wash. The organic phase was washed with water (2 x 50 mL), dried over ~ ? a ~ ~ rI ~. ;, s ! ~l WO93/14107 ;~ ` PCT/US93/~078 sodium sulfate, filtered and concentrated under vacuum.
The product was isolated as a thick oil.
ExampL~ 4 ~ethyl Benzoate ~
A solution of phenol (1 molar equivalent) and triethylamine (2.5 molar equivalents) in methylene chloride was cooled to -5~C and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -5 and 0C. After stirring for one hour the reaction was quenched with water (100 mL). The organic phase was separated, washed with water ~100 mL~, and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford phenylfluorosulphonate as a crude eolorless oil.
B Methy~ benzoate Phenyl fluorosulfonate (1.0 g, 1 molar equivalent) was dissolved in dimethylsulfoxide (10 mL) under a gentle stream of carbon monoxide with stirri~g at 23C.
Methanol (5.0 mL, 2.2 molar equivalents) and triethylamine (1.15 g, 2 molar equivalents) were added 2S all at once. Palladium acetate (0.064 ~, 0.05 molar equ iva l ent ) and 1, 3-bis(diphenylphosphino)propane (0.116 g, 0.05 molar equivalent) were mixed and added all at once to the rapidly stirred mix~ure. The reaetion temperature was raised to 70C over a fifteen minute 3G period. The color of the reaction solution went from light yellow to red/black. After 1.0 hour the reaction was cooled to 23C. The reaction mixture was poured into water (SC mL) and the mixture was extracted with methylene chloride (S0 mL). The methylene chloride layer was extracted with water (5Q mL) three times and was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was WO93/14107 PCT/US93/~078 2 ~ ~ r! 2 5~ /~ 16 purified by bulb to bulb distillation to yield methyl benzoate (0.62 gram) as a colorless oil.
Exa~l~ 5 Benzoi~_a~ld A vessel was chaxged with 5 volumes of dimethylformamide, phenylfluorosulphonate (1 molar equivalent, prepared as described in Example 4~), tri-n-butylamine (4.5 molar equivalents), formic acid ~ molarequivalents) and bis(triphenylphosphine)-palladium acetate (0.02 molar equivalents). The flask was evacuated and filled with carbon monoxide three times.
The vessel was pressurized with 7 psi carbon monoxicle and the reaction was stirred rapidly. The reaction solution was heated to 75C until the uptake of carbon monoxide was complete. The reaction was cooled to room temperature. Ethyl acetate and water were added, and the organic layer was separated. The organic phase was washed with water and dried over magnesium sulfate. The organic phase was concentrated under vacuum to yield a crude benzoic acid which was purified by silica chromatography (hexane/ethyl acetate).
Ea~m~ h ~ethyl ~,5-~imethyl~en7Qate A solution of 1,3~dimethylphenol (1 molar equivalent) and triethylamine (2.5 molar equivalen~s) in methylene chloride was cooled to -SC and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -~ and 3C. After stirring for one hour the reaction was quenched with water (100 mL). The organic phase was separated, washed with water (100 mL), and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford WO93/14107 ~ PCT/US93/~07X
1,3-dime~hylphenyl fluorosulfonate as a crude colorless oil.
B. Methyl~3_9=2i~9~ ~lL~
1,3-Dimethylphenylfluorosulfonate (1.16 g, molar equivalent) was combined with dimethylsulfoxide (10 mL), triethylamine (1.15 g, 2 molar equivalents), and methanol (5.0 mL, 2.2 molar equivalents). The mixture was evàcuated and flushed with carbon monoxide three times. The mixture was kept under a slight positive pressure of carbon monoxide. Palladium acetate (0.()64 g, O.OS molar equivalent) and 1,3-bis~diphenylphosphino)propane (0.116 g, 0.05 molar equivalent) were added all at once. The mixture was evacuated and flushed with carbon monoxide. The mixt:ure was heated to 65C for two hours under a slight positive carbon monoxide pressure. The mixture was poured into water (50 mL) and was extracted with methylene chloride (3 x S0 mL). The methylene chloride layers were combined and extracted with water (2 x 100 mL). The methylene chloride layer was dried over magnesium sulfate and filtered. The solvent was removed under vacuum to afford methyl-3,5-dimethylbenzoate, 0.7S0 g, as a colorless oil.
~am~
car~oxylic acid. (a~hydrQ~ and ~y~ra~d) ~ ~ o~ iene~ll~Qn~
A solution of estrone (10.0 grams~ l molar equivalent) and triethylamine (9.3 grams, 2.S molar equivalents) in methylene chloride (200 mL) was cooled to -5C and treated with fluorosulfonic anhydride (4.9 grams, 1.3 molar equivalents) while maintaining the temperature between -5 and 0C. After stirring for one hour the reaction was quenched with water (100 mL). The WOg3/14107 PCT/US93/00078 ~ 18 -organic phase was separated, washed with water (100 mI.), and dried over magnesium sulfate. The solution was concentrated under vacuum to afford a crude solid which was recrystalli~ed fxom methanol using decolorizing carbon, to afford 3-fluorosulfonylestra-1,3,5(10)-triene-17-one (9.6 grams) in 74% yield. mp 99-102C.
B. 17n-Cy~nn~11~-trimethyLsilylQ~yestra-1,3~10~-trien~-yL fluQrQsulfon~t~
A mixture of 3 fluorosulfonyl-estra-1,3,5(10~-triene-17-one t2.0 grams, 1 molar equivalent), trimethylsilylcyanide (1.4 grams, 2.5 molar equivalents), zinc iodide (0.1 gram, 0.05 molar equivalent), and methylene chloride ~20 mL) was warmed to 45C and stirred for 45 minutes. The reaction was quenched with water (25 mL). The organic phase was separated, washed with water ~25 mL), and dried over magnesium sulfate. The organic phase was concentrated under vacuum to afford a crude solid which was recrystalli~ed from methanol to afford 17a-cyano-17~-trimethylsilyloxyestra-1,3,5(10)-triene-3-yl fluorosulfonate (1.9 grams) in 76% yield. mp~104-108C.
~ ss~ e A mixture of 17~-cvano-17~-trimethylsilyloxyestra-1,3,5(10~-triene-3-yl fluorosulfonate (2.0 qrams, 1 molar equivalent), phosphorus oxychloride (2.2 grams, 2.5 molar equivalents), and pyridine (8 mL) was heated to reflux for 17 hours. The reaction was cooled to room temperature and was quenched into a mixture of concentrated hydrochloric acid (25 mL) and crushed ice (20 mL). The aqueous phase was separated and extracted ethyl acetate ~50 mL). The organic phases were combined, washed with water (2 x 25 mL), and dried over magnesium sulfate. The orqanic phase was concentrated under vacuum to afford a crude oil which was triturGted and WO93/14107 ~ 72 1 ~ PCT/US93/~0~8 recrystallized from ethanol to afford 17-cyano-1,3,5(10),16-tetraene-3-yl fluorosulfonate (1.0 grams) in 50% yield. mp 110-112C.
D. 17~-Cyano-1,3.5(1Q)-~Iiene-3-yl fluor~sulfoD~e A mixture of 17-cyano-1,3,5(10),16-tetraene-3-yl fluorosulfonate (0.5 gram, 1 molar equivalent), 10%
palladium on carbon (35 mg), glacial acetic acid (2 mL), and ethyl acetate (25 mL) was stirred at room temperature over one atmosphere of hydrogen for 6 hours.
The catalyst was removed by filtration, and the filtrate was concentrated under vacuum to afford an oil which was triturated with ethanol and recrystallized from the same solvent to afford 17~-cyano-1,3,5(10)-triene-3-yl fluorosulfonate (0.45 gram) in 90% yield. mp 126-129C.
A well-stirred solution of 17~-cyano-1,3,5(10)-triene-3-yl fluorosulfonate(5 grams, 1 molar equivalent), and tert-butylacetate (40 mL~ was warmed to 60C~ Concentrated sulfuric acid (1.0 mL, 1.3 molar equivalents) was added, and the solution was stirred at 40-55C for 6.5 hours. The solution was cooled to room ~emperature, and was quenched into water (30 mL). More water (40 mL) w~s added, and the mixture was extracted with methylene chloride (?00 mL). The mixture was adjusted to pH 7 with 3N aqueous sodium hydroxide. The organic phase was separated and concentrated under vacuum to give a crude solid. This solid was recryst~llized from DMSO (90 mL)/water (4S mL) and dried to afford 3-fluorosulfonylestr~ 3r5(lo)-triene-l7~-N
t-butylcarboxamide (5.23 grams) in 85% yield. mp 148-150C.
3-Fluorosulfonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide was treated as described in Examples lD
WO93/14107 PCT/US93/~078 7 `) l ~ 20 and lE to prepare 17~-tN-tert-butylcarboxamide)-estra-l,3,5(10)-triene-3-carboxylic acid, anhydrous and hydrated.
~mel~
Methyl nicotinate Pyridine-3-fluorQ~ulf-)nate A solution of 3-hydroxypyridine (1 molar equivalent) and triethylamine (2.5 molar equivalents) in methylene chloride was cooled to -5C and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -5 and 0C. After stirring for one hour the reaction was quenched with water (100 mL). The organic phase was separated, washed with water (100 mL), and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford pyridine-3-fluorosulfonate as a crude colorless oil.
B. Methyl nicotinate Pyridine-3-fluorosulfonate (1 molar equivalent) was dissolved in dimethylsulfoxide ( 10 mL) under a gentle s~ream of carbon monoxide with stirring at 23C.
Methanol (5.0 mL) and triethylamine (2 molar equivalents) were added all at once~ Palladium acetate (0.~5 molar equivalents) and 1,3-bis(diphenylphosphirlo)propane (0.05 molar equivalents) were mixed and ad~ed all at once to the rapidly stirred mixture. The reaction temperature was raised to 70C
over a fifteen minute period. After 1.0 hour the reaction was cooled to 23C. The reaction mixture was poured into water (50 mL) and the mixture was extracted with methylene chloride (50 mL). The methylene chloride layer was extracted with water (50 mL) three times and was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was WO 93/14107 ~ ' rlJ ,;~ PCI'/US93/0007X
;-purified by silica gel chromatography to yield methyl nicotinate as a crystals.
1 0 ~
The present invention relates to an improved process for the preparation of substituted s~eroidal benzo esters and substi~uted steroidal benzo acids. Such compounds are described in U.S. Patent Nos. 4,954,446;
4,937,237; 4,970,205 and 4,882,3l9 as being useful for or preparing compounds which are useful for inhibiting steroid S-a-reductase.
Processes for the preparation of substituted steroidal benzo esters and substitut:ed steroidal benzo acids have previously been described. In particul2- the use of ~rifluoxomethane sulfonic anhydride to convert steroidal A--ring phenols to steroidal tri.luoromethyl sulfonate intexmediates (in ~95% yield) followed by metal-catalyzed carbonylation to the benzoic ester (in 73% yield) with subsequent hydrolysis to the corresponding benzoic acid ~in 90% yield1 is reported ir.
U.S. Patent No. 4,954,446 Further, said steroidal trifluoromethyl sulfonate intermediate has been reacted in metal-catalyzed coupling reactions in the presence o~ various couplinq reagents (followed by an optional, if applicable hydrolysis reaction1 to form the corresponding steroidal WO93/14107 PCT/US93/~078 h , 7 2 7 i -- 2 benzo esters and the corresponding steroidal benzo acids in U.S. Patent Nos. 4,937,237 and 4,882,319.
In addition to a low overall yield, the principle shortcoming of these disclosures is that trifluoromethane sulfonic anhydride is an expensive reagent adding significant cost to an industrial process. Thus, there is a need in the art for a safe, economical and reliable method to convert steroidal phenols to steroidal benzo esters and steroidal benzo acids.
SUMMAR~ OF THE INVENTIO~
This invention relates to an improved process ior converting phenols to benzo es~ers and benzo acids.
This invention relates to an improved process for converting steroidal phenols to steroidal benzo esters and steroidal benzo acids.
This invention specifically relates to an improved process for the preparation of 17B-(N-t-butylcarboxamide)-estr-l,3,5(l0)-triene-3-carboxylic acid and hydrates thereof.
In a further aspect of the invention there are provided novel intermediates useful in the presently invented process.
DE~aILED D~CRIPTION OF THE IN~E~TION
The present invention provides a process for the production of a benzo acid or a benzo ester which comprises reacting a phenol with fluorosulfonic anhydride and a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine in an appropriate solvent to form a benzo fluorosulfonate compound and subsequently reacting said benzo WO93/14107 '~ ~ i7 2 7 :~ PCT/US93/00078 fluorosulfonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent followed by an optional, if applicable hydrolysis reaction.
The present invention specifically provides a process for the production of a compound of Formula (I) R ~ tI) Rl is (i) H and NR3R4, where R3 and R4 are each independently selected form hydrogen, Cl_galkyl, C3_6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered lS saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or moieties which are chemically conterible to moieties of (i) and R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate of solvate thereof, which comprises reac:ting a compound of the Formula (II) ~\/
HO (II) in which Rl and the broken lines are as described above with fluorosulfonic anhydride and a base in a solvent to form a compound of Formula III
W~93/14107 P~T/US~3/~07~
21 7 `! ~ 4 _ f~
F ~ O ~III) in which Rl and the broken lines are as described above and subsequently reacting said compound of Formula (III) in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable, hydrolysis reaction to fo:rm a compound of Formula (I), and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.
Preferably the reaction to convert Formula II
compounds to formula III is preformed at a temperature from -78C to 20C, particularly preferred temperature range is from -lO to 10C.
Preferably the reaction to convert Formula III
compounds to Formula I compounds is preferred at a temperature of 25C to 100C a particular preferred temperature range is from 50 to gOC.
As used above and ~hroughout the remainder of the speciication and claims the carbons of the steroid nucleus are numbered ar.d the rings are let~ered as follows:
l 7 1 ~ C 1 3 D
/1 ~9\ /14--15 I A ¦ 8 1 3 \ " ^~ /7 2 .~? ~ PCT/US93/~078 Compounds of Formula I comprise Rl or moieties which can be chemically conver~ed to those of Rl by known chemical reactions such as described in J. Fried and J.
Edwardsj ~ , Pub:
Van Nostrand Reinhold Company (1972) provided that Rl does not include any such moieties that render inoperative the presently invented process. Reactions to convert said moieties to ~l are performed on products of the synthetic pathways disclosed or claimed herein or, where appropriate or preferable on certain intermediates in these synthetic pathways. For example, carboxylic acid substituents can be converted to the car~oxamide by conversion to the acid halide followed by reacting the same with an amine. Carboxylate substituents can be converted to the acid and treated as above. Nitriles can be converted to the carboxamide by reaction with an alkylating agent, such as t-butylacetate or t-butanol under acidic catalysis.
As used herein, unless otherwise specified, Cl_nalkyl means a straight or branched hydrocarbon chain having l to n carbons.
In utilizing the presently invented process to prepare the preferred sterQidal benzo acids and preferred steroidal benzoesters, of Formula (I),-novel in~ermediates of the following Formula (IV) are synthesized;
F (IV) in which:
Rl is WO93J14107 PCT/US93/~078 7 ~ 6 ~ .. . , ,~ , ., (i) H and CoNR3R4, where R3 and R4 are each independently selected from hydrogen, C1_galkyl, C3_6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;
or moieties which are chemically convertible to moieties of ~i).
By the term "metal-catalyzed coupling reaction"
as used herein is meant that the prepared fluorosulfonated compound is reacted in a suitable organic solvent, preferably a dimethylsulfoxide-C1_l60H
solution (when an ester is desired) or toluene, dimethylformamide or THF (when an acid is desired) with a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine, a phosphine su~h as bis(diphenylphosphino)alkane, preferably l,3 bis(diphenylphosphino)propane or tri-o-tolylphosphine, or a Cl_6alKOH, and a metal catalyst, preferably a palladium catalyst such as palladium (II) acetate, palladium (II) chloride and bis(triphenylphosphine) palladium II acetate, and a coupling reagent.
By the term l'coupling reagent" as used herein is meant a compound which is capable of reacting wit~ an axyl radical to form an acid or an ester. Preferred coupling reagents, which when added to the metal-catalyzed coupling reaction, as described herein, yield preferred acid and ester sroups, as disclosed herein, are carbon monoxide (to yield -COOH~, ethyltributylstannyl acetate (to yield -CH~COOH), dimethyl phosphite (to yield -P(O)(OH)2) and hypophosphorous acid crys~als (to yield -PH(O)OH).
By the term "phenol" as used herein is meant a hydroxylated six membered aromatic ring, unsubstituted W093/14107 ~ PCT/US93/~078 or substituted with non reactive substituents, said aromatic ring may also be part of a polycyclic molecule such as a naphthyl or steroidal moleucle, said molecule being unsubstituted or substituted with non reactive substituents.
By the term "acid" as used herein is meant any group which is capable of acting as a proton donor including but not limited to; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H
and -(CH~ 3-COOH.
iO By the term "ester" as used herein is meant a g:roup consisting of an acid, as defined above, in which the donatable proton or protons are replaced by alkyl substituents.
By the term "steroidal benzo" as used herein is meant a steroid with an aromatic A ring.
8y the term "solvent" as used herein is meant an organic solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene,~ethyl acetate, dimethylsulfoxide, methanol or dimethylfoxamide.
Preferably the base utilized to prepare compounds of Formula II is triethylamine. Preferably the solvent utilized to prepare compounds of Formula II is methylene chloride. Preferably the catalyst utilized in said metal catalyzed coupling reaction is palladium (II) acetate. Preferred acids used to describe R2 in Formula (I) include; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H, and -(CH2)l_COOH. Particularly preferred among the above acids is -COOH.
The present invention is usuful for the conversion of phenols to benzo esters and benzo acids.
WO 93/14107 PCI`/US93/00078 r~ ^) j.t ,_/ . ! i .-- 8 A preferred aspect of the invention is the conversion of steroidal phenols to steroidal ~enzo esters and steroidal benzo acids.
Pharmaceutically acceptable salts of Formula (I) compounds are formed, where appropriate, by methods well known to those of skill in the art.
Preferably, therefore the process of the present invention is particularly useful for preparing a compound of Structure IIIA.
~ N-H
~/
FO~O
~ (IIIA) and converting the same in one or two steps into the following compound of structure (IA) o t ~ N-H
HO-C (IA) or a pharmaceutically acceptable salt, hydrate of solvate thereof.
WO93/14107 ~ r~ ! PCI/US93/00078 _ g _ The following examples illustrate preparation of ~enzo esters and benzo acids from phenols utilizing fluorosulfonic anhydride. The examples are not intended to lim1t the scope of the invention as defined above or as claimed below.
I. SYN~HF.TTC EXAMPLES
Dimethylformamide, oxalyl chloride, tert-butylamine, triethylamine, dimethylsulfoxide, 1,3-bis(diphenylphosphino)propane, palladium acetate, tri-n-butylamine, formic acid, bis(triphenylphosphine)-palladium acetate, zinc chloride, tri-o-tolylphosphine, sodium fluoride, phenol, 1,3-dimethylphenol, estrone, trimethylsilylcyanide, zinc iodide, phosphorus oxychloride, 10% palladium on carbon, tert-butylacetate, and 3-hydroxypyridine are available from Aldrich Chemical Co. (Milwaukee, WI).
Carbcn monoxide is available from Matheson Gas Products (E. Rutherford, NJ).
17~-Cyanoestra-1,3,5(10)-triene-3-yl methanesulphonate was prepared as described by Barton, et. al. J J. Chem. Soc. (CJ, 1968, 2283. Fluorosufonic anhydride was prepared as described by S. Kongpricha, et. al., Inorg. Syn. 1968, XI, 151. Ethyltributylstannyl acetate was prepared as described by A. Zapata, et. al., Syn. Comm. 1984, 1~1, 27.
~mple 1 ~5=~ L~c~LhI~ e. ~ tL~
~t 3-Hydroxyestra-1~3,~(10~-trien~ 17-~arboxylic s~i~L_~L~L iL~s~5_ WO93/14107 PCT/US93/~078 `' 71 -lo-A mixture of 17~-cyanoestra-1,3,5(10)-triene-3-yl methanesulphonate_(10.0 grams, 1 molar equivalent), sodium hydroxide (34 grams, 30.5 molar equivalents), and ethylene glycol (200 mL) was heated to 150C for 5 hours. The hot reaction solution was cooled to 110C and diluted with water (200 mL). The pH of the solution was adjusted to 2.0 with concentrated hydrochloric acid, and the resulting slurry was chilled to 0C and stirred for l hour. The product was isolated by filtration, washed thoroughly with water (600 mL), and dried under vacuum at 100C to afford a mixture of 3-hydroxyestra-1,3,5(10~-triene-17-carboxylic acid, 17~p isomers (8.5 grams, 77/23:17~ isomers) in 99% yield. mp 250-270C.
B. 3-Hydroxye$~ra-1,3 ~ -tLiene-l7~-N-t-A vigorously stirred solution of DMF (348 mL, 4.1 molar equivalents) and methylene chloride (4800 mL) was slowly charged with oxalyl chloride (384 mL, 4.0 molar equivalents) while maintaining the reaction temperature between 5-15C. A white flocculant suspension formed while the reaction mixture was stirred for 30 minutes.
The reaction was charged with 3-hydroxyestra-1,3,5(10)-triene-17-carboxylic acid, 17~ isomers (329 g, 1 molar ?5 equivalent, 77/23:17~ isomers) and was stirred for two hours. The reaction solution was slowly quenched into a vigorously stirred mixture of tert-butylamine (1200 mL, 10.4 molar equivalents) and methylene chloride (1600 mL) while maintaining the reaction temperature between 5-15 C. The reaction mixture was stirred for 45 mi~utes~ The reaction was charged with water (3.0 L) and stirred for one hour. The product was suction filtered and the filter cake was washed with water (14.0 L). The product was dried in a vacuum oven (65C, house vacuum~ to constant weight to afford 3-hydroxyestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (233 grams) as a white solid in 60% yield. mp 304-305C.
WO 93/141~)7 ~ ~ "; r~ ;7 r~ PCI`/US93/00078 C. 3-Fluorosulfonylestra~ tlO~-triene-17~-N-t-butylcarboxamlde A well-stirred solution of 3-hydroxyestra-1,3,5(10)-triene-17~-N-t butylcarboxamide (231 grams, 1 molar equivalent), methylene chloride (2300 mL), and triethylamine (132 grams, 2 molar equivalents) was cooled to 0-10C. The resulting slurry was treated with fluorosulfonic anhydride (154 grams, 1.3 molar equivalents) while maintaining the reaction ~emperature below 10C. The reaction was stirred for 30 min and water (1.0 L) was added with vigorous stirring. The organic phase was separated and distilled at atmospheric pressure to a final volume of about 986 ml. Water (1283 mL) was added, and the distillation was continued until the methylene chloride was completely removed, as indicated by a drop in the head temperature below 35C.
Dimethylsulfoxide (4.26 L) was added to the residue and the mixture was warmed to 100C. The stirred mixture was cooled to room temperature over a 4 hour period, during which the product crystallized. The reaction mixture was stirred at 15-20C for 1.0 hour and was isolated by filtration.The solid product was washed with water (1.0 L) and air dry thoroughly. This material was crushed and ' reslurried in 4 L of water for 30 minutes. The product-was isolated by filtration and dried at 80C under vacuum to afford 3-fluorosulfonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (237.3 grams) in 83% yield. mp 138-141C.
~ c~boxamideL~I~=
A vessel was charged with dimethylsulfoxide (1350 mL), methanol (75 mL, 5.4 molar equivalents), 3-fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (lS0 g, 1 molar equivalent), triethylamine (76.3 q, 2.2 molar equivalents), and 1,3-WO93/14107 PCTIUS93/~07X
bis(diphenylphosphino)propane (1.41 g, 0.01 molar equivalent). The mixture was stirred until a solution was obtained. Palladium acetate (0.768 g, 0.01 molar equivalent) was added and the flask was filled and evacuated with carbon monoxide three times. The vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly~ The reaction solution was heated to 75C. The carbon monoxide uptake was finished in about 1.5 hours. The reaction was cooled to 15C and stirred for 2 hours.The solid product was isolated by suction filtration, and the mother liquors were used to rinse out the inside of the reactor. The solid product was thoroughly washed with water (1.5 L) and dried lander vacuum at 95C to afford pure methyl 17~-~N-tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate (116.4 g) in 85% yield. mp 155-157C.
~ l?~-N-t=~yl~2xks~amide-~ra-l~3~5(lQ)-triene 3-carboxyl~c_acid ~anhydrnu~ and hydr~d~.
A mixture of methanol (80 mL), water (80 mL), methyl 17~-(N-tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate (15.9 g, 1 molar equivalent), and sodium hydroxide (~.80 g, 3 molar equivalents) was heated to reflux for 8-12 hours. The hot reaction solution was filtered through celite and the filter pad was washed with 60C water (80 mL). The filtrate was diluted with water (80 mL). The methanol was removed by distillation to a head temperature of 100C. The mixture was cooled to 60C and was quenched with vigorous stirring into 1.5 N hydrochloric acid (160 mL). The resulting white suspension was stirred for 15 minutes.
The slurry was cooled to 0-5C and stirred for 1 hour.
The product was isolated by filtration, washed with deionized water, and dried under vacuum at 100C to afford crude 17~-N-t-butylcarboxamide-estra-1,3,5(10)-triene-3-carboxylic acid (15.1 grams) in 99% yield. mp 235-238C.
WO93/14107 ~ PCT/US93/~07X
Anhydrous 17~-N-t-butylcarboxamide~estra-1,3,5(10)-triene-3-carboxylic acid was prepared by azeotropic removal of water from the crude material by distilling from acetonitrile, concentration, and cooling. The solid was isolated by filtration and dried. Yield 71%.
Alternatively a hydrated form of 17~-N-t-butylcarboxamide-estra-1,3,5(10)-triene-3-carboxylic acid was prepared by recrystallization from aqueous isopropanol. Yield 70-80%.
17~-(N-tert-Butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid is a compound which is currently undergoing clinical investiga~ion for the treatment of benign prostatic hypertrophy. The isolation of anhydrous and hydrated forms of said compound is necessary in order to establish an optimal and reproducible bioavailability profile for said compound.
2~ E~m~1~ 2 A vessel was charged with 5 volumes of dimethylformamider 3-fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (1 molar equivalent, prepared as described in Example lC), tri-n-butylamine (4.5 molar eq~ivalentsj, formic acid (2 molar equivalents) and bis(triphenylphosphine)palladium acetate (0.02 molar equivalents). The flask was evacuated and filled with carbon monoxide three times.
The vessel was pressurized with 7 psi carbon monoxide and the reaction was stirred rapidly. The reaction solution was heated to 75C until the uptake of carbon monoxide was complete. The reaction was cooled to xoom temperature. Ethyl acetate and water were added, and the organic layer was separated. The organic phase was WO93/14107 PCT/US93/~078 ,_ .. ` I .~; i -- 14 --washed with water and dried over magnesium sulfate. The organic phase was concentrated under vacuum to yield a crude 17~(N-tert-butylcarboxamide)-estra-1,3,5~10)-triene-3-carboxylic acid. Anhydrous and hydrated 17~(N-tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid were prepared as described in ~xample lE. Yield 70-80%.
Example 3 F~hyl-17-heta-tN-tert-butylcarboxamide~-e~tra-1.3~5(10)-,triene-3-acetic acid Zinc Chloride (1.91 g, 1.4 molar equivalents) was weighed into a 200 mL flask fitted with a stir bar and serum cap. The mixture was heated to 150C under vacuum ~1.0 mm) ~or 1 hour. The flask was cooled to 25C and the vacuum was broken with argon. 3-Fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide (4.38 g, 1 molar equivalent, prepared as described in Example lC), ethyltributylstannyl acetate (5.28 g, 1.4 molar equivalents), and dimethylformamide ( 20.0 mL) were added to the flask~
The ~lask was evacuated and flushed with argon three times. Tri-o-tolylphosphine (0.091 ~, 0.03 molar equivalent) and palladium acetate (0.045 g, 0.02 molar equivalent) were added and the reaction vessel was evacuated and flushed with argon three times. The mixture was heated for 1.0 hour at 80C. Toluene (100 mL) and water (100 mL) were added and the mixture was stirred for 5 minutes. The mixture was filtered ~hrough celite and poured 1nto a separatory funnel. The aqueous layer was separated and discarded. The organic phase was washed again with water (lO0 mL). The organic phase was washed with saturated sodium fluoride (2 x 50 mL) and filtered through celite after each wash. The organic phase was washed with water (2 x 50 mL), dried over ~ ? a ~ ~ rI ~. ;, s ! ~l WO93/14107 ;~ ` PCT/US93/~078 sodium sulfate, filtered and concentrated under vacuum.
The product was isolated as a thick oil.
ExampL~ 4 ~ethyl Benzoate ~
A solution of phenol (1 molar equivalent) and triethylamine (2.5 molar equivalents) in methylene chloride was cooled to -5~C and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -5 and 0C. After stirring for one hour the reaction was quenched with water (100 mL). The organic phase was separated, washed with water ~100 mL~, and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford phenylfluorosulphonate as a crude eolorless oil.
B Methy~ benzoate Phenyl fluorosulfonate (1.0 g, 1 molar equivalent) was dissolved in dimethylsulfoxide (10 mL) under a gentle stream of carbon monoxide with stirri~g at 23C.
Methanol (5.0 mL, 2.2 molar equivalents) and triethylamine (1.15 g, 2 molar equivalents) were added 2S all at once. Palladium acetate (0.064 ~, 0.05 molar equ iva l ent ) and 1, 3-bis(diphenylphosphino)propane (0.116 g, 0.05 molar equivalent) were mixed and added all at once to the rapidly stirred mix~ure. The reaetion temperature was raised to 70C over a fifteen minute 3G period. The color of the reaction solution went from light yellow to red/black. After 1.0 hour the reaction was cooled to 23C. The reaction mixture was poured into water (SC mL) and the mixture was extracted with methylene chloride (S0 mL). The methylene chloride layer was extracted with water (5Q mL) three times and was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was WO93/14107 PCT/US93/~078 2 ~ ~ r! 2 5~ /~ 16 purified by bulb to bulb distillation to yield methyl benzoate (0.62 gram) as a colorless oil.
Exa~l~ 5 Benzoi~_a~ld A vessel was chaxged with 5 volumes of dimethylformamide, phenylfluorosulphonate (1 molar equivalent, prepared as described in Example 4~), tri-n-butylamine (4.5 molar equivalents), formic acid ~ molarequivalents) and bis(triphenylphosphine)-palladium acetate (0.02 molar equivalents). The flask was evacuated and filled with carbon monoxide three times.
The vessel was pressurized with 7 psi carbon monoxicle and the reaction was stirred rapidly. The reaction solution was heated to 75C until the uptake of carbon monoxide was complete. The reaction was cooled to room temperature. Ethyl acetate and water were added, and the organic layer was separated. The organic phase was washed with water and dried over magnesium sulfate. The organic phase was concentrated under vacuum to yield a crude benzoic acid which was purified by silica chromatography (hexane/ethyl acetate).
Ea~m~ h ~ethyl ~,5-~imethyl~en7Qate A solution of 1,3~dimethylphenol (1 molar equivalent) and triethylamine (2.5 molar equivalen~s) in methylene chloride was cooled to -SC and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -~ and 3C. After stirring for one hour the reaction was quenched with water (100 mL). The organic phase was separated, washed with water (100 mL), and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford WO93/14107 ~ PCT/US93/~07X
1,3-dime~hylphenyl fluorosulfonate as a crude colorless oil.
B. Methyl~3_9=2i~9~ ~lL~
1,3-Dimethylphenylfluorosulfonate (1.16 g, molar equivalent) was combined with dimethylsulfoxide (10 mL), triethylamine (1.15 g, 2 molar equivalents), and methanol (5.0 mL, 2.2 molar equivalents). The mixture was evàcuated and flushed with carbon monoxide three times. The mixture was kept under a slight positive pressure of carbon monoxide. Palladium acetate (0.()64 g, O.OS molar equivalent) and 1,3-bis~diphenylphosphino)propane (0.116 g, 0.05 molar equivalent) were added all at once. The mixture was evacuated and flushed with carbon monoxide. The mixt:ure was heated to 65C for two hours under a slight positive carbon monoxide pressure. The mixture was poured into water (50 mL) and was extracted with methylene chloride (3 x S0 mL). The methylene chloride layers were combined and extracted with water (2 x 100 mL). The methylene chloride layer was dried over magnesium sulfate and filtered. The solvent was removed under vacuum to afford methyl-3,5-dimethylbenzoate, 0.7S0 g, as a colorless oil.
~am~
car~oxylic acid. (a~hydrQ~ and ~y~ra~d) ~ ~ o~ iene~ll~Qn~
A solution of estrone (10.0 grams~ l molar equivalent) and triethylamine (9.3 grams, 2.S molar equivalents) in methylene chloride (200 mL) was cooled to -5C and treated with fluorosulfonic anhydride (4.9 grams, 1.3 molar equivalents) while maintaining the temperature between -5 and 0C. After stirring for one hour the reaction was quenched with water (100 mL). The WOg3/14107 PCT/US93/00078 ~ 18 -organic phase was separated, washed with water (100 mI.), and dried over magnesium sulfate. The solution was concentrated under vacuum to afford a crude solid which was recrystalli~ed fxom methanol using decolorizing carbon, to afford 3-fluorosulfonylestra-1,3,5(10)-triene-17-one (9.6 grams) in 74% yield. mp 99-102C.
B. 17n-Cy~nn~11~-trimethyLsilylQ~yestra-1,3~10~-trien~-yL fluQrQsulfon~t~
A mixture of 3 fluorosulfonyl-estra-1,3,5(10~-triene-17-one t2.0 grams, 1 molar equivalent), trimethylsilylcyanide (1.4 grams, 2.5 molar equivalents), zinc iodide (0.1 gram, 0.05 molar equivalent), and methylene chloride ~20 mL) was warmed to 45C and stirred for 45 minutes. The reaction was quenched with water (25 mL). The organic phase was separated, washed with water ~25 mL), and dried over magnesium sulfate. The organic phase was concentrated under vacuum to afford a crude solid which was recrystalli~ed from methanol to afford 17a-cyano-17~-trimethylsilyloxyestra-1,3,5(10)-triene-3-yl fluorosulfonate (1.9 grams) in 76% yield. mp~104-108C.
~ ss~ e A mixture of 17~-cvano-17~-trimethylsilyloxyestra-1,3,5(10~-triene-3-yl fluorosulfonate (2.0 qrams, 1 molar equivalent), phosphorus oxychloride (2.2 grams, 2.5 molar equivalents), and pyridine (8 mL) was heated to reflux for 17 hours. The reaction was cooled to room temperature and was quenched into a mixture of concentrated hydrochloric acid (25 mL) and crushed ice (20 mL). The aqueous phase was separated and extracted ethyl acetate ~50 mL). The organic phases were combined, washed with water (2 x 25 mL), and dried over magnesium sulfate. The orqanic phase was concentrated under vacuum to afford a crude oil which was triturGted and WO93/14107 ~ 72 1 ~ PCT/US93/~0~8 recrystallized from ethanol to afford 17-cyano-1,3,5(10),16-tetraene-3-yl fluorosulfonate (1.0 grams) in 50% yield. mp 110-112C.
D. 17~-Cyano-1,3.5(1Q)-~Iiene-3-yl fluor~sulfoD~e A mixture of 17-cyano-1,3,5(10),16-tetraene-3-yl fluorosulfonate (0.5 gram, 1 molar equivalent), 10%
palladium on carbon (35 mg), glacial acetic acid (2 mL), and ethyl acetate (25 mL) was stirred at room temperature over one atmosphere of hydrogen for 6 hours.
The catalyst was removed by filtration, and the filtrate was concentrated under vacuum to afford an oil which was triturated with ethanol and recrystallized from the same solvent to afford 17~-cyano-1,3,5(10)-triene-3-yl fluorosulfonate (0.45 gram) in 90% yield. mp 126-129C.
A well-stirred solution of 17~-cyano-1,3,5(10)-triene-3-yl fluorosulfonate(5 grams, 1 molar equivalent), and tert-butylacetate (40 mL~ was warmed to 60C~ Concentrated sulfuric acid (1.0 mL, 1.3 molar equivalents) was added, and the solution was stirred at 40-55C for 6.5 hours. The solution was cooled to room ~emperature, and was quenched into water (30 mL). More water (40 mL) w~s added, and the mixture was extracted with methylene chloride (?00 mL). The mixture was adjusted to pH 7 with 3N aqueous sodium hydroxide. The organic phase was separated and concentrated under vacuum to give a crude solid. This solid was recryst~llized from DMSO (90 mL)/water (4S mL) and dried to afford 3-fluorosulfonylestr~ 3r5(lo)-triene-l7~-N
t-butylcarboxamide (5.23 grams) in 85% yield. mp 148-150C.
3-Fluorosulfonylestra-1,3,5(10)-triene-17~-N-t-butylcarboxamide was treated as described in Examples lD
WO93/14107 PCT/US93/~078 7 `) l ~ 20 and lE to prepare 17~-tN-tert-butylcarboxamide)-estra-l,3,5(10)-triene-3-carboxylic acid, anhydrous and hydrated.
~mel~
Methyl nicotinate Pyridine-3-fluorQ~ulf-)nate A solution of 3-hydroxypyridine (1 molar equivalent) and triethylamine (2.5 molar equivalents) in methylene chloride was cooled to -5C and treated with fluorosulfonic anhydride (1.3 molar equivalents) while maintaining the temperature between -5 and 0C. After stirring for one hour the reaction was quenched with water (100 mL). The organic phase was separated, washed with water (100 mL), and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford pyridine-3-fluorosulfonate as a crude colorless oil.
B. Methyl nicotinate Pyridine-3-fluorosulfonate (1 molar equivalent) was dissolved in dimethylsulfoxide ( 10 mL) under a gentle s~ream of carbon monoxide with stirring at 23C.
Methanol (5.0 mL) and triethylamine (2 molar equivalents) were added all at once~ Palladium acetate (0.~5 molar equivalents) and 1,3-bis(diphenylphosphirlo)propane (0.05 molar equivalents) were mixed and ad~ed all at once to the rapidly stirred mixture. The reaction temperature was raised to 70C
over a fifteen minute period. After 1.0 hour the reaction was cooled to 23C. The reaction mixture was poured into water (50 mL) and the mixture was extracted with methylene chloride (50 mL). The methylene chloride layer was extracted with water (50 mL) three times and was dried over magnesium sulfate and filtered. The solvent was removed under vacuum. The crude product was WO 93/14107 ~ ' rlJ ,;~ PCI'/US93/0007X
;-purified by silica gel chromatography to yield methyl nicotinate as a crystals.
Claims (14)
1. A process for the preparation of a compound of Formula (I) (I) in which and R1 is (i) H and CONR3R4, where R3 and R4 are each independently selected from hydrogen, C1-8alkyl, C3.
6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5 6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;
or moieties which are chemically convertible to moieties of (i) R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate of solvate thereof, which comprises reacting a compound of Formula (II) (II) in which R1 is as described above with fluorosulfonic anhydride and a base in a solvent to form a compound of Formula III
(III) in which R1 is as described in Formula (II) and subsequently reacting said compound of Formula (III) in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable, hydrolysis reaction to form a compound of Formula I, and thereafter optionally if applicable, forming a pharmaceutically acceptable salt, hydrate or solvate.
6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5 6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;
or moieties which are chemically convertible to moieties of (i) R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate of solvate thereof, which comprises reacting a compound of Formula (II) (II) in which R1 is as described above with fluorosulfonic anhydride and a base in a solvent to form a compound of Formula III
(III) in which R1 is as described in Formula (II) and subsequently reacting said compound of Formula (III) in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable, hydrolysis reaction to form a compound of Formula I, and thereafter optionally if applicable, forming a pharmaceutically acceptable salt, hydrate or solvate.
2. A process according to claim 1 in which said base is triethylamine .
3. A process according to claim 1 in which said metal catalyst is a palladium catalyst.
4. A process according to claim 1 in which the prepared compound of Formula I is isolated by crystallization from an aqueous organic solvent thereby forming a hydrated product.
5. The process of claim 4 in which the compound prepared is in the monohydrate form.
6. The process of claim 5 in which the compound prepared is 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10 -triene-3-carboxylic acid monohydrate.
7. A process according to claim 1, in which R2 is:
-SO3H, -P(O)(OH)2, -PH(O)OH or -(CH2)1-3COOH.
-SO3H, -P(O)(OH)2, -PH(O)OH or -(CH2)1-3COOH.
8. A process according to claim 1 in which R2 is -COOH.
9. A process according to claim 8 in which the compound prepared is or a pharmaceutically acceptable salt, hydrate or solvate thereof.
10. A process for the preparation of steroidal benzo esters or steroidal benzo acids which comprises reacting a steroidal phenol with fluorosulfonic anhydride and a base in a solvent to form the corresponding benzo fluorosulfonate steroid and subsequently reacting said benzo fluorosulfonate steroid in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable, hydrolysis reaction.
11. A process for the preparation of benzo esters or benzo acids which comprises reacting a phenol with fluorosulfonic anhydride and a base in a solvent to form the corresponding benzo fluorosulfonate compound and subsequently subjecting said benzo fluorosulfonate compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, followed by an optional, if applicable hydrolysis reaction.
12. A compound of the structure in which R1 is (i) H and CONR3R4, where R3 and R4 are each independently selected from hydrogen, C1-8alkyl, C3-6cycloalkyl, phenyl; or R3 and R4 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;
or moieties which are chemically convertible to moieties of (i).
or moieties which are chemically convertible to moieties of (i).
13. A compound of claim 12 wherein R1 is -CN,-COOH, CON(H) t-butyl.
14. The process of claim 4 in which the compound of Formula I is 17.beta.-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81718092A | 1992-01-06 | 1992-01-06 | |
| US07/817,180 | 1992-01-06 | ||
| PCT/US1993/000078 WO1993014107A1 (en) | 1992-01-06 | 1993-01-06 | Process for preparing 3-acylestratrienes and acylbenzenes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2127274A1 true CA2127274A1 (en) | 1993-07-22 |
Family
ID=25222515
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002127274A Abandoned CA2127274A1 (en) | 1992-01-06 | 1993-01-06 | Process for preparing 3-acylestratrienes and acylbenzenes |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0621866A4 (en) |
| JP (1) | JPH07503008A (en) |
| KR (1) | KR940704064A (en) |
| CN (1) | CN1077200A (en) |
| AP (1) | AP361A (en) |
| AU (1) | AU3434793A (en) |
| BG (1) | BG98888A (en) |
| BR (1) | BR9305707A (en) |
| CA (1) | CA2127274A1 (en) |
| FI (1) | FI943213A0 (en) |
| HU (1) | HUT67566A (en) |
| IL (1) | IL104303A0 (en) |
| MA (1) | MA22762A1 (en) |
| MX (1) | MX9300026A (en) |
| NO (1) | NO942531D0 (en) |
| OA (1) | OA09959A (en) |
| RU (1) | RU94037761A (en) |
| SI (1) | SI9300005A (en) |
| SK (1) | SK80194A3 (en) |
| WO (1) | WO1993014107A1 (en) |
| ZA (1) | ZA938B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993022333A1 (en) * | 1992-04-30 | 1993-11-11 | Smithkline Beecham Corporation | 17α AND 17β-SUBSTITUTED ESTRA-1,3,5(10)-TRIENE-3-CARBOXYLIC ACID |
| GB9411103D0 (en) * | 1994-06-03 | 1994-07-27 | Smithkline Beecham Corp | Compounds |
| GB9608045D0 (en) * | 1996-04-18 | 1996-06-19 | Pharmacia Spa | Process for preparing steroids having a carboxamide side-chain |
| JP2000309599A (en) | 1999-04-13 | 2000-11-07 | Kyowa Hakko Kogyo Co Ltd | Estra-1,3,5(10),16-tetraene derivative |
| JP5793996B2 (en) * | 2011-06-29 | 2015-10-14 | セントラル硝子株式会社 | Method for producing fluorosulfuric acid aromatic ester |
| EP4295841A3 (en) | 2014-06-06 | 2024-03-13 | The Scripps Research Institute | Sulfur (vi) fluoride compounds and their use in click-reaction |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954446A (en) * | 1988-05-25 | 1990-09-04 | Smithkline Beecham Corporation | Aromatic steroid 5-α-reductase inhibitors |
| US4937237A (en) * | 1988-12-23 | 1990-06-26 | Smithkline Beckman Corporation | Phosphinic acid substituted aromatic steroids as inhibitors of steroid 5-60 -reductase |
| US4970205A (en) * | 1988-12-23 | 1990-11-13 | Smithkline Beecham Corporation | Sulfonic acid substituted aromatic steroids as inhibitors of steroid 5-α-reductase |
-
1993
- 1993-01-04 ZA ZA938A patent/ZA938B/en unknown
- 1993-01-04 IL IL104303A patent/IL104303A0/en unknown
- 1993-01-05 MA MA23051A patent/MA22762A1/en unknown
- 1993-01-05 AP APAP/P/1993/000474A patent/AP361A/en active
- 1993-01-06 HU HU9402029A patent/HUT67566A/en unknown
- 1993-01-06 CA CA002127274A patent/CA2127274A1/en not_active Abandoned
- 1993-01-06 EP EP93902956A patent/EP0621866A4/en not_active Withdrawn
- 1993-01-06 WO PCT/US1993/000078 patent/WO1993014107A1/en not_active Application Discontinuation
- 1993-01-06 SI SI19939300005A patent/SI9300005A/en unknown
- 1993-01-06 BR BR9305707A patent/BR9305707A/en not_active Application Discontinuation
- 1993-01-06 AU AU34347/93A patent/AU3434793A/en not_active Abandoned
- 1993-01-06 SK SK801-94A patent/SK80194A3/en unknown
- 1993-01-06 MX MX9300026A patent/MX9300026A/en unknown
- 1993-01-06 KR KR1019940702342A patent/KR940704064A/en not_active Application Discontinuation
- 1993-01-06 RU RU94037761/04A patent/RU94037761A/en unknown
- 1993-01-06 CN CN93101174A patent/CN1077200A/en active Pending
- 1993-01-06 JP JP5512541A patent/JPH07503008A/en active Pending
-
1994
- 1994-06-30 OA OA60530A patent/OA09959A/en unknown
- 1994-07-05 FI FI943213A patent/FI943213A0/en not_active Application Discontinuation
- 1994-07-05 BG BG98888A patent/BG98888A/en unknown
- 1994-07-05 NO NO942531A patent/NO942531D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA938B (en) | 1994-06-16 |
| AP9300474A0 (en) | 1993-01-31 |
| MA22762A1 (en) | 1993-10-01 |
| BR9305707A (en) | 1996-12-31 |
| SI9300005A (en) | 1993-09-30 |
| NO942531L (en) | 1994-07-05 |
| MX9300026A (en) | 1993-12-01 |
| BG98888A (en) | 1995-05-31 |
| NO942531D0 (en) | 1994-07-05 |
| RU94037761A (en) | 1997-05-27 |
| WO1993014107A1 (en) | 1993-07-22 |
| AU3434793A (en) | 1993-08-03 |
| HU9402029D0 (en) | 1994-09-28 |
| SK80194A3 (en) | 1994-12-07 |
| EP0621866A4 (en) | 1996-03-20 |
| HUT67566A (en) | 1995-04-28 |
| FI943213A (en) | 1994-07-05 |
| JPH07503008A (en) | 1995-03-30 |
| FI943213A0 (en) | 1994-07-05 |
| KR940704064A (en) | 1994-12-12 |
| CN1077200A (en) | 1993-10-13 |
| IL104303A0 (en) | 1993-05-13 |
| AP361A (en) | 1994-09-09 |
| OA09959A (en) | 1995-12-11 |
| EP0621866A1 (en) | 1994-11-02 |
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