Preparation method of exemestane intermediate

Abstract

The invention provides an improved method for preparing an exemestane intermediate 6-hydroxymethyl-androstane-1, 4-diene-3, 17-diketone, and particularly relates to a method for preparing the 6-hydroxymethyl-androstane-1, 4-diene-3, 17-diketone through a reaction of 1, 3-ditetrahydropyrrolyl-androstane-3, 5-diene-17-ketone under the action of phenol and a formaldehyde aqueous solution, and particularly relates to a method for preparing the 6-hydroxymethyl-androstane-1, 4-diene-3, 17-diketone through the reaction of 1, 3-ditetrahydropyrrolyl-androstane-3, 5-diene-17-ketone. Compared with the prior art, the method has the advantages that the generation of a large amount of bis-hydroxymethylation impurities is avoided, the purity and the yield are improved, the cost is reduced, the stability of the process is improved, and industrialization is facilitated.

Description

Technical Field

[0001] The present invention relates to an improved method for preparing 6-hydroxymethyl-androst-1,4-diene-3,17-dione, an intermediate of exemestane, from 1,3-bis(tetrahydro-1H-pyrrol-1-yl)-androst-3,5-diene-17-one. Background Art

[0002] Exemestane (structural formula is as follows), CAS No.: 107868-30-4; English name Exemestane, chemical name 6-methyleneandrost-1,4-diene-3,17-dione. It is an irreversible steroidal aromatase inhibitor developed and marketed by the original research company Pfizer. Its structure is similar to the natural androstenedione substrate, and it is used for the adjuvant treatment of early invasive breast cancer in postmenopausal women with estrogen receptor-positive after 2-3 years of adjuvant treatment with tamoxifen until a total of 5 years of adjuvant endocrine therapy is completed, and also for the advanced breast cancer in natural or surgically menopausal women whose condition still progresses after tamoxifen treatment.

[0003] 。

[0004] The most valuable process route for preparing exemestane starts from androstadienedione, which has been reported in Patent WO2005070951 and the journal literature "Pharmazie, 2006, vol. 61, # 7, p. 575 - 581". Among them, 6-hydroxymethyl-androst-1,4-diene-3,17-dione is a key intermediate, and the technology reported in Patent WO2005070951 has more advantages.

[0005] The route reported in WO2005070951: 。

[0006] In Patent WO2005070951, for the reaction of preparing the key intermediate 6-hydroxymethyl-androst-1,4-diene-3,17-dione from 1,3-bis(tetrahydro-1H-pyrrol-1-yl)-androst-3,5-diene-17-one, a two-phase reaction system was adopted, with the yield range of 75 - 80% and the purity above 96%. The lowest yield described in the screening of process conditions was 54%, and the highest yield was 85%. From these reports, it can be seen that the yield of this step of the reaction fluctuates greatly, the process stability is poor, and the yield is on the low side. Summary of the Invention

[0007] In view of the above-mentioned defects existing in the prior art, the present invention provides an improved preparation method for 6-hydroxymethyl-androst-1,4-diene-3,17-dione, an intermediate of exemestane, which has high yield, high purity, good process stability and low cost.

[0008] The preparation of exemestane intermediate 6-hydroxymethyl-androst-1,4-diene-3,17-dione according to the present invention involves the following steps: 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one can be prepared with reference to WO200507951.

[0009] 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one, phenol and aqueous formaldehyde solution are successively added to dichloromethane, and reacted to obtain exemestane intermediate 6-hydroxymethyl-androst-1,4-diene-3,17-dione.

[0010] In this preparation method, the molar ratio of 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one to phenol in the feed is 1:1.5 - 3; the molar ratio of 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one to formaldehyde in the feed is 1:1; the reaction temperature is 10 - 30 °C, and the reaction time is 1 - 3 h.

[0011] After the reaction is completed, saturated NH 4 Cl aqueous solution is added to the reaction system, stirred for half an hour, allowed to stand for layer separation, the organic layer is separated, the solvent is evaporated to dryness to obtain an oil, and the oil is crystallized with toluene to obtain exemestane intermediate 6-hydroxymethyl-androst-1,4-diene-3,17-dione.

[0012] In the structure of androstadienedione, there are two reaction sites showing the nucleophilic property at the α-position of the carbonyl group, namely the 6-position and the 16-position. In order to increase the reaction selectivity, patent WO200507951 and the journal article "Pharmazie, 2006, vol. 61, #7, p. 575 - 581" adopted this method: forming an enamine to selectively activate the 6-position, increasing the nucleophilic ability of the 6-position, thereby further widening the reaction activity gap between the 6-position and the 16-position. Androstadienedione forms an enamine to activate the 6-position to obtain 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one. After adopting this method, the formation of bis-hydroxymethylation impurities with simultaneous hydroxymethylation at the 6-position and the 16-position in the structure of 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one can be better inhibited, but it is not very ideal, and there is still about 10% of the formation of bis-hydroxymethylation impurities, and the highest yield is 85%. If the feeding ratio of formaldehyde is reduced to 1 eq of the substrate (i.e., the molar ratio of 1,3-bis(tetrahydropyrrolyl)-androst-3,5-diene-17-one to formaldehyde in the feed is 1:1), the reaction is incomplete and the yield is lower. The situation of low yield with reduced amount of formaldehyde is also recorded in patent WO200507951.

[0013] Structural formula of bis-hydroxymethylation impurity: .

[0014] The inventors of this patent believe through scientific analysis that when the activity of the 6-position is strong enough and the activity gap with the 16-position is large enough, the reason for the incomplete reaction when adding 1 eq of formaldehyde is as follows: When a nucleophilic addition reaction occurs between the 6-position in the structure of one molecule of 1,3-ditetrahydropyrrolyl-androst-3,5-diene-17-one and formaldehyde to form the intermediate 6-hydroxymethyl-androst-1,4-diene-3,17-dione, two molecules of tetrahydropyrrole will be generated simultaneously; tetrahydropyrrole may consume formaldehyde to form unstable 1-tetrahydropyrrolyl-methanol. This may be the reason why Patent WO200507951 adopted an experimental scheme of about 2.6 eq of formaldehyde to prepare 6-hydroxymethyl-androst-1,4-diene-3,17-dione. When the amount of formaldehyde used exceeds 1 eq, the probability of hydroxymethylation reaction at the 16-position is greatly increased. Balancing the amount of formaldehyde used and enamine activation may be the solution to the problems of large impurities, low yield, and poor process stability in the preparation of 6-hydroxymethyl-androst-1,4-diene-3,17-dione. In order to balance these two aspects, the inventors of the present invention added an appropriate amount of phenol to the reaction system, which can well reduce the amount of formaldehyde used and inhibit the formation of 1-tetrahydropyrrolyl-methanol; in addition, phenol does not react with the raw materials and products. Therefore, the technical solution provided by the present invention can greatly reduce the formation of impurities while ensuring the conversion rate, and improve the purity and yield.

[0015] Structural formula of 1-tetrahydropyrrolyl-methanol: 。

[0016] In summary, the improved method for preparing exemestane intermediate of the present invention greatly reduces the formation of dihydroxymethyl impurities, improves the purity and yield, reduces the cost, and is easy to industrialize.

[0017] The present invention will be further described below through reference examples and examples. All substitutions or combinations made according to the common general knowledge and conventional means in the art shall be included within the scope of the present invention. Specific Examples

[0018] Example 1 Preparation of 6-hydroxymethyl-androst-1,4-diene-3,17-dione 40.0 g (97.96 mmol) of 1,3 - bis(tetrahydro - 1H - pyrrolyl) - androst - 3,5 - dien - 17 - one, 13.8 g (146.9 mmol) of phenol, and 7.95 g (97.96 mmol) of 37% aqueous formaldehyde solution were successively added to 400 mL of dichloromethane, and the reaction was carried out at 25 °C for 2.5 h. 400 mL of saturated ammonium chloride aqueous solution was added and stirred for half an hour. After standing and separating the layers, the organic layer was taken, and the solvent was evaporated to dryness under reduced pressure at 40 °C to obtain an oily substance. The oily substance was crystallized from 300 mL of toluene at room temperature for 1 h, filtered by suction, and the filter cake was dried at 50 °C under normal pressure to obtain 29.2 g of exemestane intermediate 6 - hydroxymethyl - androst - 1,4 - diene - 3,17 - dione, with an HPLC purity of 99.7% and a molar yield of 94.8%.

[0019] Example 2 Preparation of 6 - hydroxymethyl - androst - 1,4 - diene - 3,17 - dione 40.0 g (97.96 mmol) of 1,3 - bis(tetrahydro - 1H - pyrrolyl) - androst - 3,5 - dien - 17 - one, 27.7 g (293.9 mmol) of phenol, and 7.95 g (97.96 mmol) of 37% aqueous formaldehyde solution were successively added to 400 mL of dichloromethane, and the reaction was carried out at 30 °C for 1 h. 400 mL of saturated ammonium chloride aqueous solution was added and stirred for half an hour. After standing and separating the layers, the organic layer was taken, and the solvent was evaporated to dryness under reduced pressure at 40 °C to obtain an oily substance. The oily substance was crystallized from 300 mL of toluene at room temperature for 1 h, filtered by suction, and the filter cake was dried at 50 °C under normal pressure to obtain 29.3 g of exemestane intermediate 6 - hydroxymethyl - androst - 1,4 - diene - 3,17 - dione, with an HPLC purity of 99.4% and a molar yield of 95.2%.

[0020] Example 3 Preparation of 6 - hydroxymethyl - androst - 1,4 - diene - 3,17 - dione 40 g.0 (97.96 mmol) of 1,3 - bis(tetrahydro - 1H - pyrrolyl) - androst - 3,5 - dien - 17 - one, 20.3 g (215.5 mmol) of phenol, and 7.95 g (97.96 mmol) of 37% aqueous formaldehyde solution were successively added to 400 mL of dichloromethane, and the reaction was carried out at 10 °C for 3 h. 400 mL of saturated ammonium chloride aqueous solution was added and stirred for half an hour. After standing and separating the layers, the organic layer was taken, and the solvent was evaporated to dryness under reduced pressure at 40 °C to obtain an oily substance. The oily substance was crystallized from 300 mL of toluene at room temperature for 1 h, filtered by suction, and the filter cake was dried at 50 °C under normal pressure to obtain 29.6 g of exemestane intermediate 6 - hydroxymethyl - androst - 1,4 - diene - 3,17 - dione, with an HPLC purity of 99.5% and a molar yield of 96.2%.

Claims

1. A method for preparing exemestane intermediate 6-hydroxymethyl-androsta-1,4-diene-3,17-dione, characterized in that 1,3-ditetrahydropyrrolyl-androsta-3,5-diene-17-one, phenol and formaldehyde aqueous solution are added into dichloromethane for reaction to prepare 6-hydroxymethyl-androsta-1,4-diene-3,17-dione.

2. The method according to claim 1, characterized in that: The feeding molar ratio of 1,3-ditetrahydropyrrolyl-androsta-3,5-diene-17-one and phenol is 1:1.5-3.

3. The method according to claim 1, characterized in that: The feeding molar ratio of 1,3-ditetrahydropyrrolyl-androsta-3,5-diene-17-one and formaldehyde is 1:

1.

4. The method according to claim 1, characterized in that: The reaction temperature is 10-30°C.

5. The method according to claim 1, characterized in that: The reaction time is 1-3h.