CN1149222C - 糠酸莫米松的制备方法 - Google Patents
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- 239000002253 acid Substances 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title description 4
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims abstract description 12
- 229960001664 mometasone Drugs 0.000 claims abstract description 12
- OFTKFKYVSBNYEC-UHFFFAOYSA-N 2-furoyl chloride Chemical compound ClC(=O)C1=CC=CO1 OFTKFKYVSBNYEC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000032050 esterification Effects 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 150000003512 tertiary amines Chemical class 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 3
- -1 enol furoate Chemical class 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 abstract description 7
- 230000004224 protection Effects 0.000 abstract description 3
- 239000012442 inert solvent Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-M 2-furoate Chemical compound [O-]C(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 1
- 150000001243 acetic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960002744 mometasone furoate Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
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- Health & Medical Sciences (AREA)
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Abstract
本发明提供了一种制备可用于治疗炎症的甾类衍生物莫米松17-糠酸酯的新方法。该方法无需事先保护11位游离羟基官能团,而直接实现17位羟基的酯化。
Description
技术领域
本发明涉及一种制备糠酸莫米松的新方法,该方法不需要事先保护11位上的羟基,即可通过酯化莫米松(mometasone)17位羟基来实现莫米松的制备。
背景技术
糠酸莫米松(Mometasone furoate)一种众所周知的(Shapiro和Grove,USP4,472,393和Kwok,Tsi,Tan和Fu;WO98/00437)有效的抗炎症甾类化合物,其结构式为:
USP4,472,393描述了两种生产糠酸莫米松的方法。在实施例12中,方法I以9β,11β-环氧-17α,21-二羟基-16α-甲基-1,4-孕(甾)二烯-3,20-二酮为起始原料,而方法II则使用的是21-氯-17α-羟基-16α-甲基-1,4,9(11)-孕(甾)三烯-3,20-二酮。WO98/00437描述了一种有所改进的方法,使用的是9β,11β-环氧-17α,21-二羟基-16α-甲基-1,4-孕(甾)二烯-3,20-二酮。
大量临床上有用的甾类化合物中,17位羟基被酯化而11位羟基以游离形式存在,它们被作为临床上有用的皮质甾类而为人们所熟知。典型情况下,17位酯基是在分子中不存在其它羟基时引入的,其它自由羟基是在合成后期生成或被去掩蔽的。当存在比如11位羟基等其它羟基时,则使用间接方法。可以通过水解17,21-原酸酯类,或者在保护了分子中的其它羟基之后再进行酯化来引入17位酯基。例如,将11位羟基保护成三卤代乙酸酯,三烷基甲硅烷基醚,或者掩蔽成9,11-环氧等,都已经被用于实现这一目的。
发明内容
我们很惊讶的发现在发明本方法中,17位羟基可以在不借助于保护11位羟基或者掩蔽11位羟基的情况下被酯化。在现有技术中,通常是在分子中存在9,11-环氧基时进行17位糠酸酯基官能团的引入,之后再将环氧基转化成所需的9α-氯,11β-羟基衍生物。莫米松本身可以通过现有技术中的不同方法来制备。
我们已经很惊奇地发现,在叔胺存在下,在惰性溶剂中,莫米松与2-糠酰氯反应可以得到产率很高的莫米松17-(2-糠酸酯)。其中2-糠酰氯应当过量,优选2.5~4摩尔当量,但在此范围之外的用量同样可行。对于叔胺的性质没有限制,它的作用是活化2-糠酰氯并且中和反应中释放出的盐酸,不过优选三乙胺。使用过量的3~6摩尔当量所述叔碱,但也可使用比这更多或更少的量。所述溶剂优选是一种非极性的且与水不互溶的溶剂,以使在反应过程中反应混合物的所有成分,特别是酰化剂的任何一种活化形态都能被保留在溶液中。尽管可以使用符合以上标准的其它溶剂,二氯甲烷被证明是合适的溶剂。所述反应在低温至中等温度、通常在0~25℃下进行,反应持续几小时;不过温度也可以更高或更低,从而相应地缩短或延长反应时间。10℃时,使用三乙胺在二氯甲烷中进行反应,通常在10~15小时之内反应便可完成。
反应会生成副产物,比如3位和20位烯醇糠酸酯。由于这些化合物可以通过稀盐酸水溶液处理而转化为糠酸莫米松,所以它们丝毫不会危害最终产物的产率和纯度。通常在酯化完成后,先将反应液粗略酸洗以除去过量的碱,再用盐酸水溶液处理几小时,使这些副产物转化成所需的糠酸莫米松。可以在10~25℃的两相体系中完成这一处理,然而其它温度同样可行。为了保证两相的大面积接触,优选将两相充分混合并使用大量的盐酸水溶液,进而来缩短反应时间。作为一种替代方法,也可以加入一种既能和水混溶又能和反应溶剂混溶的有机溶剂,以增加有机相中的盐酸的浓度。比如可以加入比例为0.5~2体积的乙醇或乙酸来实现这一目的,这种情况下25℃时的反应时间通常为3~5小时。
可以通过标准方法分离出糠酸莫米松。水洗除去水溶性物质、然后用低分子量的醇,如甲醇或乙醇来置换二氯甲烷,进而从中得到纯净的、高产量的产品结晶。进一步重结晶可以在许多适用于药物产品纯化的溶剂中进行,比如丙酮、甲醇和乙醇。
具体实施方式
以下实施例用于解释本发明,但决不限制本发明。
实施例1
莫米松17-(2-糠酸酯)的制备
将30克莫米松悬浮在300ml二氯甲烷中,将所得的悬浮液冷却到0~5℃,并在此温度下加入57ml三乙胺。然后在温度为5-10℃的条件下,慢慢加入24ml 2-糠酰氯。然后在8~12℃下搅拌所得混合物,直到用HPLC测得混合物中莫米松的含量低于0.2%。然后,将该反应液冷却到-5~5℃,并在搅拌的同时加入120ml水。混合物在10~15℃下搅拌1小时后冷却到0~5℃,加入浓盐酸调节水层pH值为1~2。将物相分离后用60ml二氯甲烷萃取水层。在15~25℃下,向合并的有机相中加入90ml浓盐酸和30ml乙酸。两相反应混合物在20~25℃下搅拌直到通过HPLC监测得到其中副产物的残存量低于0.1%,将所得反应混合物冷却到0~5℃,并加入120ml水。分离出底层有机层,加入120ml水以及约30ml 8N的氢氧化钠水溶液,调节pH值为5~6。搅拌2小时后分离出有机层,并用120ml水洗涤。
将含有莫米松17-(2-糠酸酯)的有机溶液蒸馏浓缩到体积为120ml,进一步加入120ml甲醇,然后将混合物浓缩到120mL。再重复以上步骤两次。将反应混合物慢慢冷却到20~25℃,然后再冷却到0~5℃并搅拌2小时。之后,过滤出莫米松17-(2-糠酸酯)粗产品,并用0~5℃的冷甲醇洗涤(2×24ml)。
莫米松17-(2-糠酸酯)的纯化
将湿滤饼溶解于395ml丙酮中并加入3g活性炭。在15~25℃下至少搅拌24小时,然后过滤掉活性炭并用90ml丙酮洗涤。再向该溶液中加入3g活性炭并在15~25℃下搅拌至少24小时。然后过滤掉活性炭并用75ml丙酮洗涤。
将溶液蒸馏浓缩到体积为120ml,浓缩过程中莫米松17-(2-糠酸酯)开始结晶。然后加入120ml甲醇,再将溶液浓缩至120ml。重复此步骤两次。
将所得悬浮液慢慢冷却到20~25℃,再冷却到0~5℃并在此温度下搅拌2小时。之后,过滤出纯的莫米松17-(2-糠酸酯)并用0~5℃的冷甲醇洗涤两次,每次24ml,所得产品在60~70℃下干燥,产量为29.92克。
Claims (7)
1.一种制备糠酸莫米松的方法,该方法在叔胺存在下,在溶剂中通过莫米松与2-糠酰氯反应来制备糠酸莫米松,没有预先保护游离的1-羟基而直接酯化17-羟基,所述的溶剂是一种非极性、与水不混溶的溶剂,使得在反应中2-糠酰氯的任何活化形态保留在溶液中。
2.根据权利要求1的方法,其中所述的叔胺为三乙胺。
3.根据权利要求1的方法,其中所述的溶剂为二氯甲烷。
4.根据权利要求1的方法,其中每摩尔莫米松使用2.5~4摩尔2-糠酰氯。
5.根据权利要求1的方法,其中每摩尔莫米松使用3~6摩尔三乙胺。
6.根据权利要求1的方法,其中所述反应在0℃~25℃的温度进行。
7.根据权利要求1的方法,进一步包括用盐酸水溶液来处理反应产物以除去在糠酸莫米松的3位和20位形成的烯醇糠酸酯。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PT102.343 | 1999-08-02 | ||
PT102343A PT102343B (pt) | 1999-08-02 | 1999-08-02 | Processo para a preparacao de furoato mometasona |
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Publication Number | Publication Date |
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CN1282744A CN1282744A (zh) | 2001-02-07 |
CN1149222C true CN1149222C (zh) | 2004-05-12 |
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CNB991243803A Expired - Lifetime CN1149222C (zh) | 1999-08-02 | 1999-11-26 | 糠酸莫米松的制备方法 |
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US (1) | US6177560B1 (zh) |
EP (1) | EP1074558B1 (zh) |
JP (1) | JP3746174B2 (zh) |
KR (1) | KR100640066B1 (zh) |
CN (1) | CN1149222C (zh) |
AT (1) | ATE229970T1 (zh) |
AU (1) | AU765592B2 (zh) |
CA (1) | CA2295455C (zh) |
DE (1) | DE69904585T2 (zh) |
DK (1) | DK1074558T3 (zh) |
ES (1) | ES2189354T3 (zh) |
HR (1) | HRP990341B1 (zh) |
HU (1) | HU227494B1 (zh) |
IL (1) | IL133752A (zh) |
NO (1) | NO321154B1 (zh) |
NZ (1) | NZ500555A (zh) |
PL (1) | PL191103B1 (zh) |
PT (1) | PT102343B (zh) |
RU (1) | RU2208616C2 (zh) |
SI (1) | SI1074558T1 (zh) |
UA (1) | UA60333C2 (zh) |
ZA (1) | ZA996758B (zh) |
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CN107266518A (zh) * | 2016-04-08 | 2017-10-20 | 天津金耀集团有限公司 | 一种糠酸莫米松新晶型及其制备方法 |
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US20070099883A1 (en) * | 2005-10-07 | 2007-05-03 | Cheryl Lynn Calis | Anhydrous mometasone furoate formulation |
EP1790754A1 (de) * | 2005-11-24 | 2007-05-30 | Siemens Aktiengesellschaft | Schichtsystem mit Gadolinium-Mischkristall-Pyrochlorphase |
US8021742B2 (en) * | 2006-12-15 | 2011-09-20 | Siemens Energy, Inc. | Impact resistant thermal barrier coating system |
PL3111926T3 (pl) | 2009-05-29 | 2020-06-29 | Pearl Therapeutics, Inc. | Kompozycje, sposoby i układy do dostarczania dwóch lub większej liczby środków czynnych do układu oddechowego |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
PT105139B (pt) * | 2010-06-01 | 2013-01-29 | Hovione Farmaciencia S A | Método para a monofluorometilação de substratos orgânicos para preparação de compostos orgânicos biologicamente activos |
US20140275517A1 (en) | 2013-03-15 | 2014-09-18 | Pearl Therapeutics, Inc. | Methods and systems for conditioning of particulate crystalline materials |
MX2015016058A (es) | 2013-05-22 | 2016-12-20 | Pearl Therapeutics Inc | Composiciones, metodos y sistemas para el suministro por via respiratoria de tres o mas agentes activos. |
CN105481933B (zh) * | 2015-12-25 | 2017-09-19 | 山东京卫制药有限公司 | 一种合成糠酸莫米松的方法 |
CN105566437B (zh) * | 2015-12-30 | 2018-07-20 | 山东京卫制药有限公司 | 一种8dm衍生物及利用其合成糠酸莫米松的方法 |
WO2023283441A1 (en) | 2021-07-09 | 2023-01-12 | Astrazeneca Pharmaceuticals Lp | Compositions, methods and systems for aerosol drug delivery |
WO2023119093A1 (en) | 2021-12-20 | 2023-06-29 | Astrazeneca Ab | Compositions, methods and systems for aerosol drug delivery |
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ATE8790T1 (de) * | 1981-02-02 | 1984-08-15 | Schering Corporation | Aromatische heterocyclische steroidester, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen, die sie enthalten. |
PT923599E (pt) * | 1996-06-28 | 2002-06-28 | Schering Corp | Processo para a preparacao de 17-esteres de 9alfa,21-di-halopregnano-11beta,17alfadiol-20-onas |
US5886200A (en) * | 1996-07-01 | 1999-03-23 | Schering Corporation | Process for the preparation of 17-esters of 9 α, 21-dihalo-pregnane-11 β, 17 α-diol-20-ones |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107266518A (zh) * | 2016-04-08 | 2017-10-20 | 天津金耀集团有限公司 | 一种糠酸莫米松新晶型及其制备方法 |
CN107266518B (zh) * | 2016-04-08 | 2021-03-30 | 天津金耀集团有限公司 | 一种糠酸莫米松晶型及其制备方法 |
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