CN106632177A - 雷美替胺中间体的制备方法 - Google Patents
雷美替胺中间体的制备方法 Download PDFInfo
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- ramelteon
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- YLXDSYKOBKBWJQ-LBPRGKRZSA-N N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide Chemical compound C1=C2OCCC2=C2[C@H](CCNC(=O)CC)CCC2=C1 YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 title claims abstract description 11
- 229960001150 ramelteon Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract 3
- -1 1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene- Chemical class 0.000 abstract 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 8
- 206010022437 insomnia Diseases 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229940049706 benzodiazepine Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 102000001419 Melatonin receptor Human genes 0.000 description 1
- 108050009605 Melatonin receptor Proteins 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- ZDPALFHDPFYJDY-UHFFFAOYSA-N [Na].OC=O Chemical compound [Na].OC=O ZDPALFHDPFYJDY-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- WNKHIRFTIGKJPT-UHFFFAOYSA-N diethoxy hydrogen phosphate Chemical compound CCOOP(O)(=O)OOCC WNKHIRFTIGKJPT-UHFFFAOYSA-N 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 1
- 229960003528 flurazepam Drugs 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- HUNXMJYCHXQEGX-UHFFFAOYSA-N zaleplon Chemical compound CCN(C(C)=O)C1=CC=CC(C=2N3N=CC(=C3N=CC=2)C#N)=C1 HUNXMJYCHXQEGX-UHFFFAOYSA-N 0.000 description 1
- 229960004010 zaleplon Drugs 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明内容涉及一种制备雷美替胺中间体的方法，该方法以(1,6,7,8‑四氢‑2H‑茚并[5,4‑b]呋喃‑8‑亚基‑)乙腈为原料，经过一系列条件简单的反应过程得到外消旋的雷美替胺中间体。本方法制备的雷美替胺中间体反应条件温和，更适合工业化大规模生产。
Description
技术领域
本发明属于药物合成化学技术领域。
背景技术
雷美替胺,化学名为(S)-N-[2-(1,6,7,8-四氢-2H-茚并[5,4-b]呋喃-8-基-)乙基]丙酰胺，其结构式为：
。
雷美替胺（Ramelteon, RozeremTM）是由日本武田公司研发，并于2005年7月22日通过美国FDA批准上市的口服催眠药物，是第1个应用于临床治疗失眠的褪黑激素受体激动剂，主要用于治疗难以入睡型失眠症，对慢性失眠和短期失眠也有确切疗效。雷美替胺是近35年中首个新治疗作用机制的失眠，不具有成瘾性。目前，市场上的抗失眠药物主要有两种：苯二氮卓类药物和非苯二氮卓类药物。其中，苯二氮卓类药物主要有地西泮、氟西泮、三唑仑等，非苯二氮卓类药物主要有唑吡坦、扎来普隆等。虽然这些药物的临床效果明显，但是研究表明，这些药物的长期服用会导致药物依赖性和成瘾性的发生。所以，非成瘾性的抗失眠药物的研究成为失眠治疗领域的一个研究热点。
发明内容
本发明是在大量实验的基础上开发出的一种常压制备雷美替胺中间体(1,6,7,8-四氢-2H-茚并[5,4-b]呋喃-8-亚基-)乙胺盐酸盐的方法。本发明以6,7-二氢-1H-茚并[5,4-b]呋喃-8(2H)-酮为原料经witting反应和常压氢化后，得到外消旋的(1,6,7,8-四氢-2H-茚并[5,4-b]呋喃-8-亚基-)乙胺盐酸盐，有效的避免高压氢化的危险性和对设备要求高的不足，适合工业化大规模生产。
本发明的具体技术方案如下：
。
所述步骤（a）中包括以下步骤：
将制得的（2）与溶剂混合，加入10%Pd/C和酸，在常温常压下反应5h得到外消旋的雷美替胺中间体；其中反应溶剂为甲醇、乙酸乙酯、四氢呋喃和N,N-二甲基甲酰胺的一种或多种，优选甲醇。所用酸为浓盐酸、冰醋酸或三氟乙酸中的一种；优选浓盐酸，其与化合物（2）的比例为1:1～5:1。
本发明步骤简单，条件温和，收率较好，副产物少，产品纯度高，且不需要高温高压等难于控制的反应条件，适合工业化大规模生产。
说明书附图1：1,6,7,8-四氢-2H-茚并[5,4-b]呋喃-8-亚基-）乙胺盐酸盐的1HNMR图谱。
具体实施方式：
实施例1
室温下，将50.0g 6,7-二氢-1H-茚并[5,4-b]呋喃-8(2H)-酮和1425ml的甲醇加入2000ml单口瓶中，再加入65.0g的无水甲酸钠，搅拌15min后，滴加2-(二乙氧基磷酸基)乙腈。TLC检测至化合物（1）反应完全，加入700ml去离子水，搅拌、抽滤，滤饼为化合物（2）。
实施例2
将4.0g化合物（2）和40ml甲醇加入100ml三口瓶中，在氮气份下，加入0.2g Raney Ni和4ml的冰醋酸。开启搅拌，改换通氢气；常温常压下反应约10h后，体系内气体经氮气置换后，过滤，滤液浓缩得4.3g中间体（3），收率：88.5%。[M+H]=204.2。
实施例3
将20.0g化合物（2）和400ml甲醇加入1L三口瓶中，在氮气份下，加入4.0g 10%Pd/C和20ml的浓盐酸。开启搅拌，改换通氢气；常温常压下反应约5h后，体系内气体经氮气置换后，过滤，滤液浓缩得22.8g中间体（3），收率：93.8%。[M+H]=204.2。
Claims (6)
1.一种雷美替胺中间体（3）的制备方法，其特征在于，包括以下步骤：
，
将化合物（2）与溶剂混合，加入10%Pd/C和酸，在常温常压下反应5h得到外消旋的雷美替胺中间体（3）。
2.根据权利要求1所述方法，反应溶剂为甲醇、乙酸乙酯、四氢呋喃和N,N-二甲基甲酰胺的一种或多种。
3.根据权利要求1及2所述方法，反应溶剂优选甲醇。
4.根据权利要求1所述方法，所用酸为浓盐酸、冰醋酸或三氟乙酸中的一种。
5.根据权利要求1及4所述方法，所用酸优选浓盐酸。
6.根据权利要求1所述方法，酸与化合物（2）的比例为1:1～5:1。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116531A (zh) * | 2020-01-16 | 2020-05-08 | 山东省食品药品检验研究院 | 一种雷美替胺中间体的制备方法 |
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| WO2015138895A1 (en) * | 2014-03-13 | 2015-09-17 | Indiana University Research And Technology Corporation | Hepatitis b core protein allosteric modulators |
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2016
- 2016-12-05 CN CN201611102160.2A patent/CN106632177A/zh active Pending
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111116531A (zh) * | 2020-01-16 | 2020-05-08 | 山东省食品药品检验研究院 | 一种雷美替胺中间体的制备方法 |
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