Clomiphene synthesis using a single solvent

Abstract

The present invention provides a one-pot method for synthesizing clomiphene (a mixture of the isomers cis-clomiphene and trans-clomiphene) utilizing a single solvent. In a preferred embodiment, the single solvent is dichloromethane (DCM, also known as methylene chloride). The present invention provides an improved method for synthesizing clomiphene and purifying clomiphene isomers.

Claims

1. A method for preparing clomiphene comprising dissolving a desired quantity of 1-{4-[2-(diethlamino)ethoxy]phenyl}-1,2-diphenylethanol in a suitable amount of a first solvent and therafter (a) adding to the solution sulfuric acid in an amount effective to dehydrate the 1-{4-[2-(diethylamino)ethoxy]phenyl}-1,2-diphenylethanol thereby producing a 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium salt; and therafter (b) adding to the solution a chlorinating agent in an amount effective to chlorinate the diphenylvinyl]phenoxy}-N,N-diethylethanaminium salt thereby producing 2-{4-{2-chloro-1,2-1,2-diphenylvinyl]phenoxy}-N,N-diethlethanamine, wherein the diphenylvinyl]phenoxy}-N,N-diethylethanaminium salt is not isolated prior to performing step (b).

2. The method of claim 1, wherein the first solvent is dichloromethane.

3. The method of claim 1, wherein the chlorinating agent in step (b) is N-chlorosuccinimide.

4. The method of claim 1, wherein the solution is maintained at a temperature of about 0 C. during addition of the sulfuric acid in step (a).

5. The method of claim 1, further comprising adding a suitable base to the clomiphene solution obtained in step (b) thereby converting clomiphene to the free base form.

6. The method of claim 5, wherein the suitable base is saturated aqueous sodium bicarbonate solution).

7. The method of claim 5, further comprising loading the solution comprising clomiphene free base onto a chromatographic column and eluting the column under conditions suitable for obtaining trans-clomiphene.

8. The method of claim 7, further comprising recrystallizing the trans-clomiphene.

9. The method of claim 1, further comprising (c) dissolving the 2-{4-[2-chloro-1,2-diphenylvinyl]phenoxy}-N,N-diethyl ethanamine produced in step (b) in a suitable second solvent and an amount of racemic binaphthyl-phosphoric acid (BPA) effective to react with the 2-{4-[2-chloro-1,2-diphenylvinyl]phenoxy}-N,N-diethyl ethanamine thereby producing a trans-clomiphene-BPA salt.

10. The method of claim 9, wherein the second solvent in step (c) is methanol.

11. The method of claim 9, further comprising the steps of (d) extracting the trans-clomiphene-BPA salt obtained in step (c) in a suitable third solvent and a basic aqueous solution to produce the trans-clomiphene free base; and (e) adding to the solution obtained in step (d) an amount of citric acid effective to produce trans-clomiphene citrate.

12. The method of claim 11, wherein the basic aqueous solution in step (d) is an NH.sub.3 solution.

13. The method of claim 9, wherein the second solvent in step (c) is ethyl ether or ethyl acetate.

14. The method of claim 11, wherein the second suitable organic solvent is ethyl ether or ethyl acetate.

15. The method of claim 9, wherein the first solvent is dichloromethane.

16. The method of claim 9, wherein the chlorinating agent in step (b) is N-chlorosuccinimide.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows a synthesis route to trans-clomiphene.

(2) FIG. 2 shows an alternate method for the dehydration step in FIG. 1.

(3) FIG. 3 shows the chlorination step including the ratio of isomers obtained.

DETAILED DESCRIPTION

(4) While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

(5) It is to be understood that any ranges, ratios and ranges of ratios that can be formed by any of the numbers or data present herein represent further embodiments of the present invention. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. Accordingly, the skilled person will appreciate that many such ratios, ranges and ranges of ratios can be unambiguously derived from the data and numbers presented herein and all represent embodiments of the invention.

(6) Before the present compounds, compositions and methods are disclosed and described, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It must be noted that, as used in the present specification and the appended claims, the singular forms a, an and the include plural referents unless the context clearly dictates otherwise.

(7) The term dichloromethane (or methylene chloride) is an organic compound with the formula CH.sub.2Cl.sub.2.

(8) Trans-clomiphene refers to the trans-isomer of clomiphene with the chemical name trans-2-(p-(2-chloro-1,2-diphenylvinyl)phenoxy)triethylamine (or trans-2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine). Trans-clomiphene is a selective estrogen receptor modulator (SERM) which is believed to interfere at a hypothalamic level with steroid feedback inhibition of gonadotropin secretion thereby increasing the release of FSH and LH.

(9) The following Examples are meant to be illustrative of the invention and are not intended to limit the scope of the invention as set out is the appended claims.

Example 1

Preparation of trans-clomiphene citrate from 1-{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethanol

(10) Dehydration

(11) 1-{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethanol (6) dissolved in ethanol containing an excess of hydrogen chloride was refluxed 3 hours at 50 C. The solvent and excess hydrogen chloride were removed under vacuum and the residue was dissolved in dichloromethane. 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen chloride (7) was obtained.

(12) Chlorination

(13) The hydrochloride salt (7) solution obtained above was treated with 1.05 equivalents of N-chlorosuccinimide and stirred at room temperature for about 20 hours. Completion of the reaction was confirmed by HPLC. The hydrochloride salt was converted to the free base by addition of saturated aqueous bicarbonate solution. The mixture was stirred at room temperature for 30 minutes after which the phases were separated and the organic phase was evaporated in vacuo. 2-{4-[2-chloro-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanamine (clomiphene 1.8:1 E:Z mixture) (8) was obtained.

(14) Separation of Clomiphene Isomers

(15) Clomiphene (8) obtained above is dissolved in methanol and racemic binaphthyl-phosphoric acid (BPA) is added under stirring. When the precipitate begins separating from the solution, stirring is stopped and the mixture is allowed to settle at room temperature for 2 hours. The precipitate is filtered, washed with methanol and ether and dried. Trans-clomiphene-BPA salt (3) is obtained.

(16) The enclomiphene-BPA salt (3) obtained above is extracted with ethyl acetate and NH.sub.3 solution. To the organic solution washed with water and dried, citric acid dissolved in ethanol is added. The solution is allowed to settle for about one hour at room temperature; the precipitate is then filtered and dried under vacuum. The obtained precipitate, trans-clomiphene citrate (1) is dissolved in 2-butanone for storage.

Example 2

Synthesis of Clomiphene Using a Single Solvent

Step 1Dehydration of 1-{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethanol to form 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7)

(17) The synthesis route described in Example 1 utilized HCl for the dehydration step and utilized ethanol at 50 C. as the solvent. Sulfuric acid was investigated as an alternative to HCl for the dehydration step (as described in Example 1) in part due to the more favorable corrosion profile of sulfuric acid. Dichloromethane (methylene chloride) was investigated as an alternative solvent for the dehydration step as this would render removal of the ethanol solvent prior to the chlorination step unnecessary.

(18) A 100 mL 3-neck round bottom flask, fitted with a temperature probe and a stir bar, was charged with 1-{4-[2-(Diethylamino)ethoxy]phenyl}-1,2-diphenylethanol (6) (6.60 g, 16.9 mmol) and 66 mL (110.sup.3 mmol) of methylene chloride to give a yellow solution which was cooled in an ice bath to 0 C. Concentrated sulfuric acid (H.sub.2SO.sub.4, 0.96 mL, 18.1 mmol) was added at a rate such that the internal temperature did not exceed 5 C. Upon completion of the addition, the mixture was allowed to stir one hour at ambient temperature. Completion of the reaction was confirmed by high performance liquid chromatography (HPLC). The reaction resulted in 7.96 grams of 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7), a yield of 100%. Thus, sulfuric acid was demonstrated to be a suitable acid for the dehydration step.

(19) HPLC Conditions (Dehydration Step):

(20) Sample preparation: Dissolve 1 mg/ml in methanol

(21) Agilent 1100 HPLC

(22) Zorbax Eclipse XDB-C18 504.6 mm 1.8 m column

(23) Solvent AWater (0.1% TFA)

(24) Solvent BAcetonitrile (0.07% TFA)

(25) Flow rate1.50 mL/min

(26) Injection volume5 L

(27) Gradient5 min 95% A to 95% B; 1 min hold; 1 min recycle; 30 sec hold

(28) UV detection @ 210 and 254 nm with no reference

(29) Using these HPLC conditions, starting material has a retention time of 3.30 min and product has a retention time of 4.05 min.

(30) It was determined that removal of water produced by the dehydration reaction was important before performing the chlorination step. When ethanol is used as the solvent for this reaction, as in Example 1, the water is removed azeotropically upon removal of the ethanol. Several methods of drying the dichloromethane solution were attempted. Drying with MgSO.sub.4 had a deleterious effect on the subsequent chlorination step, rendering the chlorination process very messy with a number of new impurities observed following HPLC analysis which were determined to be the corresponding chlorohydrins. On the other hand, a wash with brine was sufficient to remove enough water and had no deleterious effect on the chlorination step. Accordingly, the solution was stirred vigorously with brine (66 ml) for 30 minutes and then the phases were separated prior to chlorination step.

Step 2Synthesis of 2-{4-[2-chloro-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanamine (8)

(31) The solution of 2-{4-[(Z)-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7.94 grams) in methylene chloride obtained in step 1 is stirred at room temperature and treated with N-chlorosuccinimide (2.37 g, 17.7 mmol, 1.05 equivalents) in a single portion and left to stir at room temperature for 12 hours. The yellow solution became orange and then went back to yellow. After 12 hours, a sample was removed, concentrated and assayed by HPLC to confirm the extent of reaction. HPLC analysis revealed that the reaction had proceeded but not to completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred at room temperature for an additional 4 hours. The reaction was again assayed by HPLC which revealed that the reaction was near completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred for an additional 12 hours at room temperature. The reaction was again assayed by HPLC and an additional 0.058 equivalents of N-chlorosuccinimide (131 mg, 0.98 mmol) was added and the solution stirred for an additional 4 hours. HPLC indicated that the reaction was complete at that point. The reaction was carefully quenched by slow addition of 66 mL (600 mmol) of saturated aqueous sodium bicarbonate solution and the quenched mixture was stirred for 30 minutes at room temperaturethe reaction mixture pH should be about 8-9 after addition of saturated aqueous sodium bicarbonate solution. The reaction yielded 6.86 grams of 2-{4-[2-chloro-1,2-diphenylvinyl]phenoxy}-N,N-diethylethanamine (8). The phases were separated and the organic phase was evaporated in vacuo. The resulting light brown oil was transferred to a tared amber bottle using a small volume of dichloromethane.

(32) HPLC Conditions (Chlorination Step):

(33) Sample preparation: Dissolve 1 mg/ml in mobile phase

(34) Agilent 1100 HPLC

(35) Phenomenex Jupiter-C4 2504.6 mm 5 m column

(36) Solvent54.85% Methanol, 44.85% Water, 0.3% triethylamine, pH adjusted to 2.5 by addition of 85% phosphoric acid

(37) Flow rate1.00 mL/min

(38) Injection volume10 L

(39) Gradient30 min isocratic

(40) UV detection @ 234 and 292 nm with no reference

(41) Using these HPLC conditions, the retention time of product is 15 minutes.

(42) Chromatographic Separation of Clomiphene Isomers

(43) Clomiphene (mixture of isomers) in free base form obtained by steps 1 and 2 is loaded onto a chromatographic column (e.g. batch high pressure chromatography or moving bed chromatography) using the same solvent as used in steps 1 and 2 (here DCM) in order to separate the cis- and trans-clomiphene isomers. Trans-clomiphene is preferably eluted using a solvent suitable for recrystallization.