HK1073111B - Purified lasofoxifene and a method for purification of racemic lasofoxifene by recrystallization - Google Patents
Purified lasofoxifene and a method for purification of racemic lasofoxifene by recrystallization Download PDFInfo
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- HK1073111B HK1073111B HK05105808.6A HK05105808A HK1073111B HK 1073111 B HK1073111 B HK 1073111B HK 05105808 A HK05105808 A HK 05105808A HK 1073111 B HK1073111 B HK 1073111B
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Description
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Background
The present invention relates to a process for removing impurities from the cis isomer of the compound of formula I, a racemic mixture of cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol (hereinafter referred to as "racemic lasofoxifene" or "racemate").
The invention also relates to purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol, (hereinafter referred to as "purified racemic lasofoxifene" or "purified racemate"), and purified lasofoxifene D-tartrate, (-) cis-6 (S) -phenyl-5 (R) - [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol D-tartrate, which is useful as an estrogen agonist/antagonist and is also known as a selective estrogen receptor modulator ("SERM"). Racemic lasofoxifene is an intermediate in the synthesis of lasofoxifene D-tartrate and has the following structure:
lasofoxifene, lasofoxifene D-tartrate, racemates thereof and methods of preparing the same are disclosed in commonly assigned U.S. patent No.5,552,412, issued 3.9.1996, and U.S. patent No.5,948,809, issued 7.9.1999. The contents of these patent documents, as well as all other references cited in the description thereof, are hereby incorporated by reference in their entirety.
Typically, the drug substance preferably contains less than 0.2% impurities, most preferably less than 0.1% impurities. However, in an expanded scale process for the commercial production of lasofoxifene D-tartrate, the lasofoxifene D-tartrate compound obtained was found to contain more than 0.2% undesirable impurities. It is also believed that purification of lasofoxifene D-tartrate to 0.1% impurity at the proposed scale is not commercially feasible. Therefore, there is a need to obtain an intermediate of lasofoxifene D-tartrate having a purity of less than 0.1% impurities. The method described in the present invention relates to this subject.
Summary of The Invention
The present invention relates to a process for the purification of racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol comprising:
a) suspending racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol in a mixture of ethanol and tetrahydrofuran to form a suspension;
b) stirring and heating the suspension;
c) cooling the suspension of step (b); and
d) collecting the solid purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol.
In a preferred embodiment, the mixture of ethanol and tetrahydrofuran has a volume ratio of about 4: 1.
In a preferred embodiment, the mixture of ethanol and tetrahydrofuran has a volume ratio of about 3: 1.
In a more preferred embodiment, the mixture of ethanol and tetrahydrofuran has a volume ratio of about 2: 1.
In a more preferred embodiment, the mixture of ethanol and tetrahydrofuran has a volume ratio of about 1: 1.
In a preferred embodiment, the suspension formed in step (a) is stirred and heated from ambient temperature to about 70 ℃ in step (b).
In a preferred embodiment, the suspension formed in step (a) is stirred and heated from ambient temperature to about 65 ℃ for about 30 minutes to about 12 hours.
In a preferred embodiment, the suspension thus formed in step (b) is cooled and stirred in step (c) for about 30 minutes to about 18 hours.
In a preferred embodiment, said suspension thus formed in step (c) is collected by filtration to yield purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol containing less than 0.1% impurities.
In another aspect, the invention relates to purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol.
The term "ambient temperature" as used herein means about 15-25 ℃.
The term "non-purified racemic lasofoxifene" or "racemate" as used herein means a racemic mixture of the cis-isomers of cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol (i.e., greater than 0.1% impurity) prior to carrying out the purification process.
The term "purified racemate lasofoxifene" or "purified racemate" as used herein means racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol with less than 0.1% impurities.
The term "purified lasofoxifene D-tartrate" as used herein means (-) cis-6 (S) -phenyl-5 (R) - [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol D-tartrate having less than 0.2% impurities.
Detailed description of the invention
Scheme I
Lasofoxifene is a valuable estrogen/antagonist and is particularly useful for oral contraception; relief of menopausal symptoms; preventing threatened abortion or habitual abortion; relieving dysmenorrhea and functional uterine bleeding; relieving endometriosis; auxiliary ovary development; treating acne; reducing overgrowth of body hair in women (hirsutism); preventing and treating cardiovascular diseases; preventing and treating atherosclerosis; preventing and treating osteoporosis; treating benign prostatic hyperplasia and prostate cancer obesity; and inhibiting postpartum lactation. Lasofoxifene also has a beneficial effect on plasma lipid levels and is therefore useful in the treatment and prevention of hypercholesterolemia. Since lasofoxifene is an estrogen agonist in bone, it is an antiestrogen in breast tissue and, therefore, useful in the treatment and prevention of breast cancer.
Racemic lasofoxifene is the cis-racemate of lasofoxifene containing two asymmetric carbon atoms, corresponding to two optically active compounds. Resolution of the racemate is accomplished by crystallization from a salt of R- (-) -1, 1 'binaphthyl-2, 2' -biphosphate ("R-trap") as described in commonly owned U.S. Pat. No.5,552,412. Resolution of the racemate may also be achieved by adding D-tartaric acid to racemic or partially optically enriched cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol to form a 1: 1 salt in aqueous ethanol, as described in U.S. Pat. No.5,948,809. With cooling, the solid (-) isomer is isolated and collected to give the desired pharmaceutically acceptable salt of the (-) cis-D-tartrate isomer in high yield.
Several purification methods were developed to reduce the amount of impurities in lasofoxifene d-tartrate to less than 0.2%, including recrystallization and chromatography. These processes are unsatisfactory either because of the reduced yield or because of the insufficient purity of the lasofoxifene d-tartrate salt. It was determined that the desired level of purification (less than 0.1% impurities) and optimal yield was achieved by the purification techniques described herein.
Racemic lasofoxifene, which was not purified in step 1(a), was mixed with a mixture of ethanol and tetrahydrofuran as set forth in scheme I and the examples. One of ordinary skill in the art will recognize that the ratio of ethanol to tetrahydrofuran can be varied. Preferably, however, the volume ratio is 1: 1 to 4: 1.
In step 1(b), the resulting suspension is heated from about ambient temperature to about 70 ℃ and stirred for a period of time of about 30 minutes and up to about 12 hours. Preferably, however, the suspension is stirred for about 8 to about 12 hours. The person skilled in the art knows that the stirring time of the above suspension can exceed 12 hours. In step 1(c), the heated suspension is then cooled to room temperature with stirring for about 30 minutes to about 18 hours. Finally, in step 1(d), the solid may be collected by methods well known to those skilled in the art (e.g., filtration) and washed with a suitable solvent (e.g., ethanol) and dried (e.g., in vacuo) to give purified racemic lasofoxifene.
The purified racemic lasofoxifene may be resolved to give purified lasofoxifene D-tartrate as shown in step II and described in us patent 5,948,809.
One of ordinary skill in the art will recognize that the ratio of ethanol to tetrahydrofuran, temperature, and heating and stirring times can be varied. Such variations are within the scope of the invention.
Examples
The following examples are intended to describe in detail specific embodiments of the invention, but are not intended to limit the specification, including the claims, in any way.
Example 1
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 2: 1 ethanol tetrahydrofuran
Purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
60 g of unpurified racemic lasofoxifene are mixed with 150 ml of ethanol and 76.8 ml of tetrahydrofuran. The resulting suspension was heated and stirred at about 65-70 ℃ for about 3 hours, cooled to ambient temperature and stirred for about 18 additional hours. The solid was collected by filtration, washed twice with 25 ml of ethanol and dried under vacuum at about 45 ℃ to give 49.36 g of purified racemic lasofoxifene (82.3% yield).
The impurity profile of unpurified and purified racemic lasofoxifene was analyzed by reverse phase high pressure liquid chromatography (hereinafter "HPLC") using an HPLC system with an ultraviolet detector ("UV") set at 230nm and a symmetrical C18 column (50mm length × 3.9mm diameter, 40 ℃).
The mobile phase consisted of 1400: 600: 5: 4 ratio v/v/v/v water acetonitrile trifluoroacetic acid ammonium hydroxide, pH 3.0, flow rate 2.0 ml/min. The retention time of racemic lasofoxifene was 5.7 minutes. The results obtained are tabulated below and expressed in area percent (%).
Table 1: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.91 | 1.9 | 2.19 | 2.3 | 2.34 |
| Racemic lasofoxifene without purification | 0.19 | 0.38 | 0.2 | 0.38 | 0.42 |
| Purified racemic lasofoxifene | ＜0.02 | 0.09 | ＜0.02 | ＜0.02 | ＜0.02 |
Example 2
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 2: 1 ethanol tetrahydrofuran
Large-Scale purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
24.9 kg of unpurified racemic lasofoxifene were mixed with 62 l of ethanol and 31 l of tetrahydrofuran. The resulting suspension was heated at about 60-65 ℃ and stirred for about 12 hours, cooled to ambient temperature and stirred for about another 2 hours. The solid was collected by filtration, washed with 22 l of ethanol and dried under vacuum at about 45 ℃ to give 20.5 kg of purified racemic lasofoxifene (82.3% yield).
The impurity profile of the unpurified and purified lasofoxifene was analyzed by HPLC as described above. Results are tabulated below and expressed in area percent (%).
Table 2: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.91 | 1.9 | 2.19 | 2.3 | 2.34 |
| Racemic lasofoxifene without purification | 0.19 | 0.38 | 0.2 | 0.38 | 0.42 |
| Purified racemic lasofoxifene | ＜0.02 | 0.05 | ＜0.02 | ＜0.02 | ＜0.02 |
Example 3
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 2: 1 ethanol tetrahydrofuran
Purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
8.14 g of unpurified racemic lasofoxifene were mixed with 20 ml of ethanol and 10 ml of tetrahydrofuran. The resulting suspension was heated at about 60-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about 2 additional hours. The solid was collected by filtration, washed with 2 ml of ethanol, and dried under vacuum at about 40 ℃ to give 6.81 g of purified racemic lasofoxifene (83.7% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 3: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.54 | 0.49 | 0.2 | 0.07 | 0.12 | 0.25 |
| Purified racemic lasofoxifene | ＜0.02 | 0.03 | 0.05 | 0.01 | ＜0.02 | ＜0.02 |
Example 4
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 2: 1 ethanol tetrahydrofuran
Purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
8.2 g of unpurified racemic lasofoxifene were mixed with 41.1 ml of ethanol and 20.6 ml of tetrahydrofuran. The resulting suspension was heated at about 60-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about 2 additional hours. The solid was collected by filtration, washed with 2 ml of ethanol, and dried under vacuum at about 40 ℃ to give 6.76 g of purified racemic lasofoxifene (82.5% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 4: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.18 | 0.29 | 0.38 | ＜0.02 | 0.03 | 0.19 |
| Purified racemic lasofoxifene | ＜0.02 | 0.05 | 0.1 | ＜0.02 | ＜0.02 | ＜0.02 |
Example 5
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 2: 1 ethanol tetrahydrofuran
Purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
8.2 g of unpurified racemic lasofoxifene were mixed with 13.7 ml of ethanol and 6.8 ml of tetrahydrofuran. The resulting suspension was heated at about 60-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about another 2 hours. The solid was collected by filtration, washed with 2 ml of ethanol, and dried under vacuum at about 40 ℃ to give 7.65 g of purified racemic lasofoxifene (93.3% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 5: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.18 | 0.29 | 0.38 | ＜0.02 | 0.03 | 0.19 |
| Purified racemic lasofoxifene | ＜0.03 | 0.07 | 0.16 | ＜0.02 | ＜0.02 | 0.02 |
Example 6
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 1: 1 ethanol tetrahydrofuran
Purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
4.0 g of unpurified racemic lasofoxifene were mixed with 7.5 ml of ethanol and 7.5 ml of tetrahydrofuran. The resulting suspension was heated at about 60-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about another 2 hours. The solid was collected by filtration, washed with 0.5 ml ethanol, and dried under vacuum at about 40 ℃ to give 3.31 g of purified racemic lasofoxifene (82.8% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 6: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.11 | 0.24 | 0.22 | ＜0.02 | 0.05 | 0.12 |
| Purified racemic lasofoxifene | ＞0.02 | 0.04 | 0.07 | ＜0.02 | ＜0.02 | ＜0.02 |
Example 7
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy) with 5: 1 ethanol tetrahydrofuran
Purification of phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol
4.0 g of unpurified racemic lasofoxifene were mixed with 12.5 ml of ethanol and 2.5 ml of tetrahydrofuran. The resulting suspension was heated at about 60-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about another 2 hours. The solid was collected by filtration, washed with 0.5 ml of ethanol, and dried under vacuum at about 40 ℃ to give 3.69 g of purified racemic lasofoxifene (92.3% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 7: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.11 | 0.24 | 0.22 | ＜0.02 | 0.05 | 0.12 |
| Purified racemic lasofoxifene | ＞0.02 | 0.08 | 0.13 | ＜0.02 | ＜0.02 | ＜0.02 |
Example 8
Para cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) benzene with ethanol
Attempted purification of 5, 6, 7, 8-tetrahydronaphthalen-2-ols
4.0 g of unpurified racemic lasofoxifene were mixed with 15 ml of ethanol. The resulting suspension was heated at about 60-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about another 2 hours. The solid was collected by filtration, washed with 0.5 ml ethanol, and dried under vacuum at about 40 ℃ to give 3.31 g of purified racemic lasofoxifene (82.8% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 8: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.11 | 0.24 | 0.22 | ＜0.02 | 0.05 | 0.12 |
| Purified racemic lasofoxifene | 0.05 | 0.13 | 0.18 | ＜0.02 | ＜0.02 | 0.03 |
Example 9
Para-cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) benzene with tetrahydrofuran
Recrystallization of 5, 6, 7, 8-tetrahydronaphthalen-2-ol
4.0 g of unpurified racemic lasofoxifene are mixed with 15 ml of tetrahydrofuran. The resulting solution was heated at about 60-65 c and stirred for about 8 hours, cooled to ambient temperature and no crystallization occurred. Crystallization occurs after seeding. The suspension was stirred at ambient temperature for about 2 hours. The solid was collected by filtration, washed with 0.5 ml ethanol, and dried under vacuum at about 40 ℃ to give 2.65 g of product (66.3% yield).
As described above, the impurity profile of unpurified and purified racemic lasofoxifene was analyzed by HPLC. Results are tabulated below and expressed in area percent (%).
Table 9: impurities percentage of unpurified and purified racemic lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 0.11 | 0.24 | 0.22 | ＜0.02 | 0.05 | 0.12 |
| Purified racemic lasofoxifene | ＜0.02 | ＜0.02 | 0.05 | ＜0.02 | ＜0.02 | ＜0.02 |
Example 10
By recrystallization of para-LasofoxifeneD-tartrate, (-) cis-6 (S) -phenyl-5- (R) - [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydro-l-e from ethanol/water
Attempted purification of chemonaphthalen-2-ol D-tartrate
8.28 g of unpurified lasofoxifene D-tartrate was dissolved in 166 ml of a 1: 1 mixture of ethanol and water by heating at about 50 ℃. After filtration, the solution was allowed to cool slowly to about 0 ℃ at which point crystallization began. The mixture was heated at ambient temperature for approximately 48 hours. The solid was collected by filtration, washed with 10 ml of ethanol, and dried under vacuum at about 45 ℃ to give 6.37 g of purified lasofoxifene D-tartrate (76.9% yield).
The impurity profile of the unpurified and purified lasofoxifene d-tartrate salt was analyzed by HPLC as described above. Results are tabulated below and expressed in area percent (%).
Table 10: unpurified and purified lasofoxifene D-tartrate as a percentage of impurities
| Relative retention time | 0.92 | 2.06 | 2.14 | 2.26 | 2.38 |
| Racemic lasofoxifene without purification | 0.21 | 0.16 | 0.07 | 0.28 | 0.11 |
| Purified racemic lasofoxifene | ＜0.02 | 0.14 | 0.04 | 0.32 | 0.09 |
Example 11
By reacting unpurified racemic Lasofoxifene, cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol with ethanol/tetrahydrofuran
Large scale purification
20.4 kg of unpurified racemic lasofoxifene were mixed with 50 l of ethanol and 25 l of tetrahydrofuran. The resulting suspension was heated at about 55-65 ℃ and stirred for about 8 hours, cooled to ambient temperature and stirred for about another 2 hours. The solid was collected by filtration, washed twice with 40 l of ethanol and dried under vacuum at about 40 ℃ to give 16.8 kg of purified racemic lasofoxifene (82.3% yield).
The impurity profile of the unpurified and purified lasofoxifene was analyzed by HPLC as described above. Results are tabulated below and expressed in area percent (%).
Table 11: impurities percentage of non-purified and purified lasofoxifene
| Relative retention time | 0.92 | 1.93 | 2.08 | 2.25 | 2.36 | 2.43 |
| Racemic lasofoxifene without purification | 1.60 | 0.22 | ＜0.02 | ＜0.02 | 0.06 | 0.11 |
| Purified racemic lasofoxifene | 0.07 | ＜0.02 | ＜0.02 | ＜0.02 | ＜0.02 | ＜0.02 |
Claims (11)
1. A process for the purification of racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol comprising:
a) suspending racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol in a mixture of ethanol and tetrahydrofuran to form a suspension;
b) stirring and heating the suspension;
c) cooling the suspension of step (b); and
d) collecting the solid purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol,
wherein the mixture of ethanol and tetrahydrofuran has a volume ratio of 1: 1 to 4: 1.
2. The process according to claim 1, wherein the mixture of ethanol and tetrahydrofuran has a volume ratio of 4: 1.
3. The process according to claim 1, wherein the mixture of ethanol and tetrahydrofuran has a volume ratio of 3: 1.
4. The process according to claim 1, wherein the mixture of ethanol and tetrahydrofuran has a volume ratio of 2: 1.
5. The process according to claim 1, wherein the mixture of ethanol and tetrahydrofuran has a volume ratio of 1: 1.
6. The method according to claim 1, 2, 3, 4 or 5, wherein the suspension formed in step (a) is stirred and heated from ambient temperature to 70 ℃ in step (b).
7. A process according to claim 6, wherein the suspension formed in step (a) is stirred in step (b) and heated from ambient temperature to 65 ℃ for up to 12 hours.
8. A process according to claim 7, wherein the suspension so formed in step (b) is cooled and stirred in step (c) for up to 18 hours.
9. The process according to claim 8 wherein the solid, purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol containing less than 0.2% impurities in said suspension so formed in step (c) is collected by filtration.
10. The process according to claim 8 wherein said solid formed in step (c) is collected by filtration in purified racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol containing less than 0.1% impurities.
11. The method of claim 1, comprising:
a) suspending racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol in a 2: 1 volume ratio mixture of ethanol and tetrahydrofuran to form a suspension;
b) stirring and heating the suspension from ambient temperature to 65 ℃ for up to 12 hours;
c) cooling the suspension thus formed with stirring for up to 18 hours; and
d) the solid racemic cis-6-phenyl-5- [4- (2-pyrrolidin-1-ylethoxy) phenyl ] -5, 6, 7, 8-tetrahydronaphthalen-2-ol was collected by filtration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36887202P | 2002-03-28 | 2002-03-28 | |
| US60/368,872 | 2002-03-28 | ||
| PCT/IB2003/001033 WO2003082814A1 (en) | 2002-03-28 | 2003-03-17 | Purified lasofoxifene and a method for purification of racemic lasofoxifene by recrystallization |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1073111A1 HK1073111A1 (en) | 2005-09-23 |
| HK1073111B true HK1073111B (en) | 2007-04-13 |
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