CN110790703A - 月桂酰阿立哌唑的制备方法 - Google Patents
月桂酰阿立哌唑的制备方法 Download PDFInfo
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- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 17
- -1 lauroyl aripiprazole Chemical compound 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229910052987 metal hydride Inorganic materials 0.000 claims description 4
- 150000004681 metal hydrides Chemical class 0.000 claims description 4
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 4
- 150000004692 metal hydroxides Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- OEDMOCYNWLHUDP-UHFFFAOYSA-N bromomethanol Chemical compound OCBr OEDMOCYNWLHUDP-UHFFFAOYSA-N 0.000 claims description 2
- BCUPGIHTCQJCSI-UHFFFAOYSA-N chloromethanol Chemical compound OCCl BCUPGIHTCQJCSI-UHFFFAOYSA-N 0.000 claims description 2
- NWADXBLMWHFGGU-UHFFFAOYSA-N dodecanoic anhydride Chemical compound CCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCC NWADXBLMWHFGGU-UHFFFAOYSA-N 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 9
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 238000007039 two-step reaction Methods 0.000 abstract 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DDINXHAORAAYAD-UHFFFAOYSA-N aripiprazole lauroxil Chemical compound C1=C2N(COC(=O)CCCCCCCCCCC)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl DDINXHAORAAYAD-UHFFFAOYSA-N 0.000 description 2
- 229960003798 aripiprazole lauroxil Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 208000036855 Left sided atrial isomerism Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- UQDUPQYQJKYHQI-UHFFFAOYSA-N dodecanoic acid methyl ester Natural products CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种化学药物——月桂酰阿立哌唑(式I)的合成方法。用阿立哌唑经两步反应制得月桂酰阿立哌唑。
Description
技术领域
本发明属于药物化学领域，涉及一种化学药物月桂酰阿立哌唑的制备方法。
背景技术
月桂酰阿立哌唑，化学名为7-{4-[4-（2,3-二氯苯基-1-哌啶基）丁氧基] - 2-氧-3,4-二氢-2(1H)-喹啉酮-1-基}甲基十二烷酸酯，英文名Aripiprazole Lauroxil，结构式如下：
2015年10月，美国FDA批准Alkerme公司的月桂酰阿立哌唑（aripiprazole lauroxil,Aristada）缓释注射剂用于治疗精神分裂症成年患者。
发明内容
月桂酰阿立哌唑是2015年10月FDA批准上市的一种新型阿立哌唑 LAIs。目前各国均无制备专利报道。本发明将填补这一空白。
一种月桂酰阿立哌唑（式I）的合成方法，其特征包括如下步骤：
1）以式（III）为起始物料，经过一定条件下可转化为式（II）；
2）式（II）经过一定条件下可转化为式（I）。
由式（III）制备式（II）所述的一定条件是与试剂甲醛、溴甲醇、氯甲醇反应，温度在50~150℃之间，由金属氢化物、金属碳酸盐、金属氢氧化物、三乙胺提供碱性环境，碱用量为式（III）的1~5当量，反应时间在2~18小时内。
由式（II）制备式（I）所述的一定条件是与试剂十二烷酸酸酐、十二烷酰氯反应，温度在0~100℃之间，由金属氢化物、金属碳酸盐、金属氢氧化物、三乙胺提供碱性环境，溶剂选用四氢呋喃、1,4-二氧六环、乙醚、甲基叔丁基醚。
本发明所用的试剂和原料均市售可得。
本发明的积极进步效果在于提供了一种月桂酰阿立哌唑的制备方法，目前没有报道。
具体实施方式
下面用实施例来进一步说明本发明，但本发明并不受其限制。
实施例1：化合物II的制备
将40g阿立哌唑溶于溶剂中，加入30g的碳酸钠，搅拌，滴加30g甲醛溶液。滴加完毕后，加热至90℃左右，反应8小时。抽滤，乙酸乙酯萃取，干燥，浓缩得到39.1g化合物II，收率91.7%。
实施例2：化合物II的制备
将40g阿立哌唑溶于溶剂中，加入8.6g氢化钠，搅拌，滴加30g甲醛溶液。滴加完毕后，加热至85℃左右，反应5小时。抽滤，乙酸乙酯萃取，干燥，浓缩得到36.5g化合物II，收率85.6%。
实施例3：化合物I的制备
将30g化合物II溶于300mL四氢呋喃中，加入6.8g氢化钠，低温滴加滴加13.7g十二烷酰氯，搅拌，加热回流5小时。冷却后旋干，二氯甲烷萃取，浓缩，得到32.3g月桂酰阿立哌唑，收率77.9%。
实施例4：化合物I的制备
将30g化合物II溶于300mL 1,4-二氧六环中，加入9.8g氢氧化钠，低温滴加滴加13.7g十二烷酰氯，搅拌，加热回流5小时。冷却后旋干，二氯甲烷萃取，浓缩，得到28.5g月桂酰阿立哌唑，收率68.9%。。
Claims (10)
1.在一种月桂酰阿立哌唑（式I）的合成方法，其特征包括如下步骤：
1）以式（III）为起始物料，经过一定条件下可转化为式（II）；
2）式（II）经过一定条件下可转化为式（I）
2.根据权利要求1所述的制备方法，其中由式（III）制备式（II）所述的一定条件是与试剂甲醛、溴甲醇、氯甲醇反应。
3.根据权利要求1所述的制备方法，其中由式（III）制备式（II）所述的一定条件是温度在50~150℃之间。
4.根据权利要求1所述的制备方法，其中由式（III）制备式（II）所述的一定条件是由金属氢化物、金属碳酸盐、金属氢氧化物、三乙胺提供碱性环境。
5.根据权利要求1所述的制备方法，其中由式（III）制备式（II）所述的一定条件是碱用量为式（III）的1~5当量。
6.根据权利要求1所述的制备方法，其中由式（III）制备式（II）所述的一定条件是反应时间在2~18小时内。
7.根据权利要求1所述的制备方法，其中由式（II）制备式（I）所述的一定条件是与试剂十二烷酸酸酐、十二烷酰氯反应。
8.根据权利要求1所述的制备方法，其中由式（II）制备式（I）所述的一定条件是温度在0~100℃之间。
9.根据权利要求1所述的制备方法，其中由式（II）制备式（I）所述的一定条件是由金属氢化物、金属碳酸盐、金属氢氧化物、三乙胺提供碱性环境。
10.根据权利要求1所述的制备方法，其中由式（II）制备式（I）所述的一定条件是溶剂选用四氢呋喃、1,4-二氧六环、乙醚、甲基叔丁基醚。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010151711A1 (en) * | 2009-06-25 | 2010-12-29 | Alkermes, Inc. | Prodrugs of nh-acidic compounds |
| WO2014080285A2 (en) * | 2012-09-19 | 2014-05-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
| WO2018104953A1 (en) * | 2016-12-07 | 2018-06-14 | Msn Laboratories Private Limited, R&D Center | Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate |
| WO2018109775A1 (en) * | 2016-12-14 | 2018-06-21 | Neuland Pharma Research Private Limited | Improved process for the preparation of aripiprazole lauroxil |
| CN111315722A (zh) * | 2017-07-28 | 2020-06-19 | 因特奎姆私人控股公司 | 制备月桂酰阿立哌唑的方法 |
-
2018
- 2018-08-01 CN CN201810862890.5A patent/CN110790703A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010151711A1 (en) * | 2009-06-25 | 2010-12-29 | Alkermes, Inc. | Prodrugs of nh-acidic compounds |
| WO2014080285A2 (en) * | 2012-09-19 | 2014-05-30 | Alkermes Pharma Ireland Limited | Pharmaceutical compositions having improved storage stability |
| WO2018104953A1 (en) * | 2016-12-07 | 2018-06-14 | Msn Laboratories Private Limited, R&D Center | Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate |
| WO2018109775A1 (en) * | 2016-12-14 | 2018-06-21 | Neuland Pharma Research Private Limited | Improved process for the preparation of aripiprazole lauroxil |
| CN111315722A (zh) * | 2017-07-28 | 2020-06-19 | 因特奎姆私人控股公司 | 制备月桂酰阿立哌唑的方法 |
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