CN1415624A - Technique for synthesizing the exemestane - Google Patents
Technique for synthesizing the exemestane Download PDFInfo
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- CN1415624A CN1415624A CN 02138489 CN02138489A CN1415624A CN 1415624 A CN1415624 A CN 1415624A CN 02138489 CN02138489 CN 02138489 CN 02138489 A CN02138489 A CN 02138489A CN 1415624 A CN1415624 A CN 1415624A
- Authority
- CN
- China
- Prior art keywords
- exemestane
- hour
- crude product
- androstane
- alkene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 8
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 title claims description 20
- 229960000255 exemestane Drugs 0.000 title claims description 20
- 230000002194 synthesizing effect Effects 0.000 title abstract description 6
- 238000007670 refining Methods 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 claims description 3
- 229960005471 androstenedione Drugs 0.000 claims description 3
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- KQRGETZTRARSMA-DAELLWKTSA-N (8r,9s,10r,13s,14s)-10,13-dimethyl-6-methylidene-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 KQRGETZTRARSMA-DAELLWKTSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000006356 dehydrogenation reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005822 methylenation reaction Methods 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- -1 1,6-methylene Chemical group 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 238000003457 Shi epoxidation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
Abstract
A process for synthesizing Yiximeitan includes such steps as synthesizing 6-methylene-androsta-4-ene 3,17-dione, synthesizing crude Yiximeitan, and refining. Its advantage is high output rate.
Description
Technical field
The present invention relates to a kind of synthesis technique of Exemestane.
Background technology
At present, the synthesis technique of Exemestane mainly contains following three kinds:
1. with androstane-4-alkene-3, the 17-diketone is a raw material, at methylal, heating reflux reaction was 6 hours under phosphorus oxychloride existed, and got androstane-6-methylene radical-4-alkene-3, the 17-diketone, yield 36%, get product two step total recovery 10-20% (al.Tetra hour edron 20:597 of K.Afmen et, 1964) again through the DDQ dehydrogenation.
The starting raw material androstane-4-alkene-3 of this technology, the 17-diketone can be made through the Wo Shi oxidation by dehydroepiandros-sterone, but this operational path total recovery is on the low side, and prediction industrialization cost is higher, and is unfavorable in producing.
2. with androstane-4-alkene-3, the 17-diketone is a raw material, behind 6 methylenations again through bromo, secondary debrominate and get (US4873223.1989).
The starting raw material of this technology is identical with technology 1, and 6-methylenation yield is higher, and is about 70%, and we once explored this route, finds bromo, and the debromination condition should not be controlled, and bromine water liquid is bigger to equipment corrosion, is unfavorable for suitability for industrialized production.
3, with 1,2-dehydrogenation Testosterone is a raw material, through 6 methylenations, and Jones reagent oxidation and get total recovery about 25% (K.Annen, Synt hour esis, 34,1982).
The advantage of this technology is that reaction is simple, and total recovery is than technology 1 height, but starting raw material 1,2-dehydrogenation Testosterone is domestic not to be sold, if by the traditional method preparation, certainly will increase reactions steps and production cost.
Summary of the invention
The technical problem to be solved in the present invention is exactly the not high and industrialization cost problem of higher of prior art yield.
The present invention includes 6-methylene radical-androstane-4-alkene 3, refining three steps of synthesizing, synthesizing crude product Exemestane and crude product Exemestane of 17-diketone with above-mentioned intermediate:
(1) 6-methylene radical-androstane-4-alkene 3, the synthetic of 17-diketone comprises the steps:
A. Androstenedione, tetrahydrofuran (THF), dehydrated alcohol, triethyl orthoformate, tosic acid are added in the reactor successively, 40-45 ℃ of stirring reaction added tosic acid after 1 hour, reacted 1 hour;
B. add methylphenylamine, 37% formaldehyde, and kept this thermotonus 2 hours, be chilled to below 20 ℃, drip concentrated hydrochloric acid, finish, continue reaction 1 hour, be chilled to 0-5 ℃;
C. add water, restir reaction 1 hour, suction filtration is washed, and gets the 6-methylene radical-androstane-4-alkene 3 of yellow solid shape after the drying, the 17-diketone;
(2) the synthetic of Exemestane comprises the steps:
A. with 6-methylene radical-androstane-4-alkene 3,17-diketone, toluene, nitrobenzoic acid are heated to backflow;
B. add DDQ in batches, continue to reflux 5 hours, be chilled to room temperature, suction filtration;
C. filtrate is successively used 5%NaO hour solution, 10% hour
2SO
4Solution, saturated Na hour CO
3Liquid and saturated NaCl solution washing reclaim solvent, promptly get the crude product Exemestane;
(3) the refining of crude product Exemestane comprises the steps:
A. in the Exemestane crude product, add acetone, add water 100ml again, use activated carbon decolorizing, filter;
B. behind reclaim under reduced pressure part acetone-water, separate out faint yellow solid, collect solid;
C. use the alcohol-water recrystallization, ethyl acetate-sherwood oil recrystallization is used in the gained crystallization once more, gets white or off-white color crystalloid finished product Exemestane.
Operational path of the present invention is simple, and raw material is easy to get, and the yield height is fit to domestic industry production.
Be process flow sheet of the present invention below:
Embodiment
1,6-methylene radical-androstane-4-alkene 3,17-diketone synthetic
Androstenedione 40g (0.14mol), tetrahydrofuran (THF) 260ml, dehydrated alcohol 40ml, triethyl orthoformate 40ml (0.24mol), tosic acid 1.04g (6.04mmol), add in the reactor successively, 40-45 ℃ of stirring reaction adds tosic acid 1.04g after 1 hour, reacted 1 hour, adds methylphenylamine 15.6ml (0.14mol) subsequently, 37% formaldehyde 18ml (0.22mol), and kept this thermotonus 2 hours, and be chilled to below 20 ℃, drip concentrated hydrochloric acid 100ml, finish, continue reaction 1 hour, be chilled to 0-5 ℃, add water 700ml, restir reaction 1 hour, suction filtration, washing gets yellow solid 28.6g after the drying, yield 68.6%, m.p.159-162 ℃ (literature value 160-163 ℃)
2, Exemestane is synthetic
6-methylene radical-androstane-4-alkene 3,17-diketone 40g (0.13mol), toluene 1600ml, nitrobenzoic acid 20g, be heated to backflow, add DDQ 60g (0.26mol) in batches, continue to reflux 5 hours, be chilled to room temperature, suction filtration, filtrate are successively used 5%NaO hour solution, 10% hour
2SO
4Solution, saturated Na hour CO
3Liquid and saturated NaCl solution washing reclaim solvent, get crude product 21.3g, yield 53.6%.
3, product is refining:
Crude product 21.3g adds acetone 240ml and makes moltenly, adds water 100ml, activated carbon decolorizing, filter, behind reclaim under reduced pressure part acetone-water, separate out faint yellow solid, collect solid, with alcohol-water (1: 1) recrystallization, ethyl acetate-sherwood oil (1: 1) recrystallization is used in the gained crystallization once more, gets white or off-white color crystallization 16.2g, recrystallization yield 76.1%, m.p.193 ℃.
Simultaneously, we have carried out a hour PLC analysis to the sample purity before and after the recrystallization: content in crude product is about 97.4%, recrystallization content and is about 98.5%, and finished product content is about 99.6%.
Claims (1)
1, a kind of synthesis technique of Exemestane comprises 6-methylene radical-androstane-4-alkene 3, the 17-diketone synthetic, synthesize three steps made from extra care of crude product Exemestane and crude product Exemestane with above-mentioned intermediate, it is characterized in that:
(1) 6-methylene radical-androstane-4-alkene 3, the synthetic of 17-diketone comprises the steps:
A. Androstenedione, tetrahydrofuran (THF), dehydrated alcohol, triethyl orthoformate, tosic acid are added in the reactor successively, 40-45 ℃ of stirring reaction added tosic acid after 1 hour, reacted 1 hour;
B. add methylphenylamine, 37% formaldehyde, and kept this thermotonus 2 hours, be chilled to below 20 ℃, drip concentrated hydrochloric acid, finish, continue reaction 1 hour, be chilled to 0-5 ℃;
C. add water, restir reaction 1 hour, suction filtration is washed, and gets the 6-methylene radical-androstane-4-alkene 3 of yellow solid shape after the drying, the 17-diketone;
(2) the synthetic of Exemestane comprises the steps:
A. with 6-methylene radical-androstane-4-alkene 3,17-diketone, toluene, nitrobenzoic acid are heated to backflow;
B. add DDQ in batches, continue to reflux 5 hours, be chilled to room temperature, suction filtration;
C. filtrate is successively used 5%NaO hour solution, 10% hour
28O
4Solution, saturated Na hour CO
3Liquid and saturated NaCl solution washing reclaim solvent, promptly get the crude product Exemestane;
(3) the refining of crude product Exemestane comprises the steps:
A. in the Exemestane crude product, add acetone, add water again, use activated carbon decolorizing, filter;
B. behind reclaim under reduced pressure part acetone-water, separate out faint yellow solid, collect solid;
C. use the alcohol-water recrystallization, ethyl acetate-sherwood oil recrystallization is used in the gained crystallization once more, gets white or off-white color crystalloid finished product Exemestane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021384894A CN1317293C (en) | 2002-10-24 | 2002-10-24 | Technique for synthesizing the exemestane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021384894A CN1317293C (en) | 2002-10-24 | 2002-10-24 | Technique for synthesizing the exemestane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1415624A true CN1415624A (en) | 2003-05-07 |
| CN1317293C CN1317293C (en) | 2007-05-23 |
Family
ID=4749515
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021384894A Expired - Lifetime CN1317293C (en) | 2002-10-24 | 2002-10-24 | Technique for synthesizing the exemestane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1317293C (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009002510A2 (en) * | 2007-06-25 | 2008-12-31 | Scinopharm Taiwan Ltd. | Crystalline polymorph of exemestane |
| EP2142561A4 (en) * | 2007-05-04 | 2010-04-21 | Scinopharm Taiwan Ltd | Process for preparing aromatase inhibitors |
| WO2010076811A3 (en) * | 2008-12-30 | 2012-06-14 | Ind-Swift Laboratories Limited | Process for the preparation of exemestane |
| CN103360449A (en) * | 2013-07-24 | 2013-10-23 | 江苏久吾高科技股份有限公司 | Method for extracting androstenedione by use of membrane method |
| CN105407499A (en) * | 2015-10-26 | 2016-03-16 | 珠海格力电器股份有限公司 | Information processing method, device and electronic device |
| CN106243179A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of exemestane industrialized preparing process |
| CN112409432A (en) * | 2020-11-16 | 2021-02-26 | 陕西理工大学 | Synthesis method of exemestane |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8517360D0 (en) * | 1985-07-09 | 1985-08-14 | Erba Farmitalia | Substituted androsta-1,4-diene-3,17-diones |
| GB8801697D0 (en) * | 1988-01-26 | 1988-02-24 | Erba Farmitalia | Improvements in synthesis of 6-methylene derivatives of androsta-1 4-diene-3 17-dione |
-
2002
- 2002-10-24 CN CNB021384894A patent/CN1317293C/en not_active Expired - Lifetime
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2142561A4 (en) * | 2007-05-04 | 2010-04-21 | Scinopharm Taiwan Ltd | Process for preparing aromatase inhibitors |
| JP2010526141A (en) * | 2007-05-04 | 2010-07-29 | シノファーム タイワン，リミテッド | Method for producing aromatase inhibitor |
| WO2009002510A2 (en) * | 2007-06-25 | 2008-12-31 | Scinopharm Taiwan Ltd. | Crystalline polymorph of exemestane |
| WO2009002510A3 (en) * | 2007-06-25 | 2009-03-19 | Scinopharm Taiwan Ltd | Crystalline polymorph of exemestane |
| WO2010076811A3 (en) * | 2008-12-30 | 2012-06-14 | Ind-Swift Laboratories Limited | Process for the preparation of exemestane |
| CN103360449A (en) * | 2013-07-24 | 2013-10-23 | 江苏久吾高科技股份有限公司 | Method for extracting androstenedione by use of membrane method |
| CN103360449B (en) * | 2013-07-24 | 2015-03-25 | 江苏久吾高科技股份有限公司 | Method for extracting androstenedione by use of membrane method |
| CN105407499A (en) * | 2015-10-26 | 2016-03-16 | 珠海格力电器股份有限公司 | Information processing method, device and electronic device |
| CN106243179A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of exemestane industrialized preparing process |
| CN112409432A (en) * | 2020-11-16 | 2021-02-26 | 陕西理工大学 | Synthesis method of exemestane |
| CN112409432B (en) * | 2020-11-16 | 2023-07-07 | 陕西理工大学 | Synthesis method of exemestane |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1317293C (en) | 2007-05-23 |
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Address after: Kexinlu Liuhe District of Nanjing City, Jiangsu Province, No. 63 211500 Patentee after: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. Address before: 211500 No. eight hundred, No. 2, Liuhe District, Jiangsu, Nanjing Patentee before: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. |
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Address after: No. 63 Kexin Road, Jiangbei New District, Nanjing City, Jiangsu Province, 210000 Patentee after: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. Address before: Kexinlu Liuhe District of Nanjing City, Jiangsu Province, No. 63 211500 Patentee before: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. |
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Granted publication date: 20070523 |