CN101045704A - 制备纯二水合昂丹司琼盐酸盐的改进方法 - Google Patents
制备纯二水合昂丹司琼盐酸盐的改进方法 Download PDFInfo
- Publication number
- CN101045704A CN101045704A CNA2006101667179A CN200610166717A CN101045704A CN 101045704 A CN101045704 A CN 101045704A CN A2006101667179 A CNA2006101667179 A CN A2006101667179A CN 200610166717 A CN200610166717 A CN 200610166717A CN 101045704 A CN101045704 A CN 101045704A
- Authority
- CN
- China
- Prior art keywords
- ondansetron
- methyl
- hydrochloride dihydrate
- preparation
- ondansetron hydrochloride
- 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.)
- Pending
Links
- 229960005343 ondansetron Drugs 0.000 title claims abstract description 84
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000002360 preparation method Methods 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 33
- -1 dimethylamino-methyl-carbazole ketone Chemical class 0.000 claims description 30
- 238000001556 precipitation Methods 0.000 claims description 28
- 239000003513 alkali Substances 0.000 claims description 25
- 238000002425 crystallisation Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 13
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical class CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 239000012670 alkaline solution Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 238000001953 recrystallisation Methods 0.000 abstract description 5
- VHXLDRBDRZYEQE-UHFFFAOYSA-N 3-(dimethylamino)-2-methylcarbazol-1-one Chemical compound C1=CC=C2C3=CC(N(C)C)=C(C)C(=O)C3=NC2=C1 VHXLDRBDRZYEQE-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 229930040373 Paraformaldehyde Natural products 0.000 description 7
- 229920002866 paraformaldehyde Polymers 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VOOZDTJWSBLXAN-UHFFFAOYSA-N N,N,1-trimethyl-9H-carbazol-2-amine Chemical compound CN(C)C1=C(C=2NC3=CC=CC=C3C2C=C1)C VOOZDTJWSBLXAN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000021962 pH elevation Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- 102100024954 5-hydroxytryptamine receptor 3A Human genes 0.000 description 1
- 101710138027 5-hydroxytryptamine receptor 3A Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Otolaryngology (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
公开了一种制备二甲氨基－甲基－咔唑酮和昂丹司琼碱的改进方法，以及一种制备具有至少99.0％的纯度的纯二水合昂丹司琼盐酸盐的重结晶方法。
Description
本申请是申请号为02806201.9、申请日为2002年1月11日、同题的分案申请。
相关申请的交叉参考
本申请要求2001年1月11日提交的临时申请系列号60/261,051的权益，通过引用该申请所公开内容的全文结合到本文中来。
发明领域
本发明涉及制备二甲氨基甲基咔唑酮的改进方法。本发明涉及制备昂丹司琼碱的改进方法。本发明还涉及重结晶二水合昂丹司琼盐酸盐以得到纯二水合昂丹司琼盐酸盐的改进方法。
发明背景
昂丹司琼也称为1，2，3，9-四氢-9-甲基-3-[(2-甲基-1H-咪唑-1-基)甲基]-4H-咔唑-4-酮，它是一种有效并具有高选择性的5-羟色胺(5-HT3，5-羟色胺受体3)拮抗剂，具有下式的结构：
昂丹司琼目前被用作止吐药，尤其用作癌症化疗中的止吐药，以及用于一些其它的用途，如抗抑郁药、抗偏头痛药和抗精神病药。它普遍用于缓和认知性疾病(如阿尔茨海默病)，用于治疗鼻炎、精神病，用于加重的警醒症和用于控制对麻醉品的依赖性。
转让与Glaxo Group Limited的美国专利4,695,578号中描述了制备昂丹司琼的方法及其用途。但是，按照该方法制备的昂丹司琼含有杂质和副产物，如1，2，3，9-四氢-9-甲基-3-亚甲基-4H-咔唑-4-酮。
因此存在改进制备具有满足临床使用标准的高纯度昂丹司琼的方法的持续需要。
发明目的及概述
制备昂丹司琼的已知方法无法达到药学上所描述的高纯度和颜色。本发明的一个目的是满足本领域对高纯度(即至少大约99.0％)和改进颜色的需要。
本发明的另一个目的是制备基本上不含任何杂质和副产物如1，2，3，9-四氢-9-甲基-3-亚甲基-4H-咔唑-4-酮(如外-亚甲基副产物)的纯二水合昂丹司琼盐酸盐。
本发明的另一个目的是制备具有至少大约99.0％纯度的二水合昂丹司琼盐酸盐。优选所述二水合昂丹司琼盐酸盐的纯度为至少大约99.5％。最优选所述二水合昂丹司琼盐酸盐的纯度为至少大约99.9％。
本发明的另一个目的是提供一种制备二甲氨基-甲基-咔唑酮的方法，所述方法包括以下步骤：
a)制备甲基-咔唑酮溶液；
b)在二甲胺盐酸盐和低聚甲醛存在下加热所述溶液；
c)将所述溶液碱化以形成沉淀；
d)从所述溶液中分离出所形成的沉淀，得到二甲氨基-甲基-咔唑酮；和
e)干燥所得二甲氨基-甲基-咔唑酮。
本发明的另一个目的是制备昂丹司琼碱的方法，所述方法包括以下步骤：
a)制备甲基-咪唑和二甲氨基-甲基-咔唑酮溶液；
b)加热所述溶液；
c)分离出含昂丹司琼碱的沉淀；
d)洗涤所述沉淀；和
e)干燥所述沉淀，得到纯昂丹司琼碱。
优选在步骤e)后，在活性炭和甲醇存在下重结晶所述昂丹司琼碱。
本发明的另一个目的是制备二水合昂丹司琼盐酸盐的方法，所述方法包括以下步骤：
a)制备昂丹司琼碱溶液；
b)用盐酸酸化所述溶液以形成沉淀；
c)洗涤所述沉淀；和
d)将二水合昂丹司琼盐酸盐结晶。
本发明的详细描述
本文所用的术语“外-亚甲基副产物”是指1，2，3，9-四氢-9-甲基-3-亚甲基-4H-咔唑-4-酮。这种物质是在制备昂丹司琼中产生的主要杂质。在制备昂丹司琼中产生的另一个杂质为二聚的外-亚甲基副产物。
除非另有声明，否则“％”是指重量百分数。
本文所用的术语“纯昂丹司琼”是指基本不含外-亚甲基副产物并具有至少约99.0％的高纯度的昂丹司琼。
本文所用的术语“氯化氢”既是指氯化氢气体，又是指氯化氢气体的水溶液。
本文所用的术语“当量”是指摩尔当量。
本文所用的术语“真空蒸馏”是指通过将混合物输送通过真空过滤器而将固体物与液体分离。
本文所用的术语“回流”是指在化学过程中，如蒸馏或液-液萃取中可将部分产物流返回到加工过程中以助于提高转化率或回收率。
本文所用的术语“滤饼”是指从液体中分离出并在加压过滤后保留在过滤器上的浓缩固体或半固体材料。
本发明是一种制备具有至少99.0％纯度的纯二水合昂丹司琼盐酸盐的改进方法。更优选所述二水合昂丹司琼盐酸盐的纯度为至少99.5％。最优选所述二水合昂丹司琼盐酸盐的纯度为至少99.9％。
本发明提供了一种制备二甲氨基-甲基-咔唑酮的改进方法。本发明还提供了一种制备昂丹司琼碱的改进方法。本发明还提供了一种制备纯二水合昂丹司琼盐酸盐的改进方法。
二甲氨基-甲基-咔唑酮的制备
本发明提供了一种制备二甲氨基-甲基-咔唑酮的方法，所述方法包括以下步骤：
a)制备具有下式的甲基-咔唑酮溶液：
(其中R＝C1-4，烷基)
b)在二甲胺盐酸盐和低聚甲醛存在下加热所述溶液；
c)将所述溶液碱化以形成沉淀；
d)从所述溶液中分离出所形成的沉淀，得到二甲氨基-甲基-咔唑酮；和
e)干燥所得二甲氨基-甲基-咔唑酮。
在所述加热步骤中，在二甲胺盐酸盐和低聚甲醛存在下，在有机溶剂中加热所述溶液。优选所述有机溶剂为乙酸。
优选将1当量的甲基-咔唑酮与约1.1至约1.5当量的二甲胺盐酸盐和低聚甲醛一起回流。更优选将1当量的甲基-咔唑酮与约1.2当量的二甲胺盐酸盐和低聚甲醛一起回流。在所述加热步骤的回流反应中可用甲醛代替低聚甲醛。
优选将1当量的甲基咔唑酮与约4至约16体积的乙酸一起回流。最优选将1当量的甲基-咔唑酮与约4体积的乙酸一起回流。
优选在约70℃至约100℃的温度下进行所述加热步骤。最优选在约80℃至约90℃的温度下进行所述加热步骤。
优选所述加热步骤进行约6至约24小时。最优选所述加热步骤进行约6至约12小时。
优选采用过滤来进行所述分离步骤。
优选在没有使用真空蒸馏或萃取下来进行所述加热步骤。在没有真空蒸馏或萃取下进行的加热步骤可稳定地获得更纯的二甲氨基-甲基-咔唑酮。
本发明还提供了一种包括将所得滤饼溶解在丙酮中，并用活性炭和盐酸处理的步骤的制备纯二甲氨基-甲基咔唑酮的方法。
优选在碱化步骤中加入水，然后采用约45％的氢氧化钠(NaOH)将所述溶液碱化至pH值为约13至约14。优选碱化步骤在Celite(10％)存在下进行，随后过滤并干燥。
优选将经干燥的滤饼溶解在丙酮中。优选用活性炭和盐酸处理已溶解的滤饼以沉淀出二甲氨基-甲基-咔唑酮。
昂丹司琼碱的制备
本发明提供了一种合成昂丹司琼碱的方法，所述方法包括以下步骤：
a)制备甲基-咪唑和具有下式的二甲氨基-甲基-咔唑酮溶液
(其中R＝C1-4，烷基)
b)加热所述溶液；
c)从所述溶液中分离出含昂丹司琼碱的沉淀；
d)洗涤所述沉淀；
e)干燥所述沉淀，得到纯昂丹司琼碱。
本发明还提供了一种合成基本纯的昂丹司琼碱的方法，所述方法还包括以下步骤：
在活性炭和甲醇存在下进行重结晶。
在制备甲基-咪唑和二甲氨基-甲基-咔唑酮溶液的步骤中，优选将约4至约6当量的甲基咪唑加入到1当量的二甲氨基-甲基-咔唑酮中。最优选将约5当量的甲基咪唑加入到1当量的二甲氨基-甲基-咔唑酮中。
优选所述制备步骤在10％的celite存在下进行。
优选本发明提供的制备昂丹司琼碱的方法中还包括在活性炭和甲醇存在下重结晶昂丹司琼碱的步骤(在步骤e后进行)。
结晶以制备纯二水合昂丹司琼盐酸盐
本发明提供了一种制备纯二水合昂丹司琼盐酸盐的改进方法。具体地讲，所述制备方法包括在无有机溶剂存在下，用水和活性炭由昂丹司琼碱结晶得到二水合昂丹司琼盐酸盐。
本发明的结晶方法极大地提高了二水合昂丹司琼盐酸盐的纯度，并极大地降低了外-亚甲基副产物杂质的含量。优选进行所述结晶步骤1-3次。最优选进行所述结晶步骤2次。
本发明提供了一种结晶二水合昂丹司琼盐酸盐的方法，所述方法包括以下步骤：
a)制备昂丹司琼碱溶液；
b)用盐酸酸化所述溶液以形成沉淀；
c)洗涤所述沉淀；和
d)将纯二水合昂丹司琼盐酸盐结晶。
优选所述溶液沉淀步骤通过往昂丹司琼碱中加入约3至约7体积的水来实现。最优选通过往昂丹司琼碱中加入约5体积水来实现。
优选所述酸化步骤通过加入盐酸来实现。优选加入约1.0-1.4当量的约32％体积的盐酸来诱导形成沉淀。最优选加入约1.1当量的约32％体积的盐酸来诱导形成沉淀。更优选所述酸化步骤得到的pH值为约1至约4。最优选所述酸化步骤得到的pH值为约3。
优选所述洗涤步骤通过使用异丙醇来实现。优选使用约5至约15ml异丙醇来洗涤沉淀。最优选使用约10ml的异丙醇来洗涤沉淀。
优选所述结晶步骤通过加入约3至约5体积水诱导结晶来进行。最优选使用约4体积水来诱导结晶。
优选所述结晶步骤在活性炭存在下进行。优选活性炭选自SX-2、CA-1、CXV和SX-1。
优选所述结晶步骤在约5至约15％SX-1活性炭存在下进行。最优选所述结晶步骤在约10％SX-1活性炭存在下进行。
通过以下实施例进一步对本发明作出解释。本发明无意受这些具体实施例的限制。本领域普通技术人员会明白如何改变这些示例性的制备方法以得到所需的结果。
实施例
实施例1：纯二甲氨基-甲基-咔唑酮盐的制备
往180ml冰醋酸中加入45g(0.226mol，1.0当量)甲基咔唑酮、22.4g(0.275mol，1.22当量)二甲胺盐酸盐和9g(0.3mol，1.33当量)低聚甲醛。
将所述反应物保持在约80±2℃下12小时，随后往反应器中引入540ml水和4.5g的highflow，将所述批料冷却至约10℃，用约45％NaOH碱化至pH为约13至约14，同时保持批料的温度不超过约25℃。
接着在约5℃至约10℃下再搅拌所述批料1小时，收集随所述highflow一起形成的沉淀，在约60℃的真空烘箱中干燥直至恒重，得到含highflow的粗产物。
用3.3g SX-1型活性炭(购自NORIT)在990ml丙酮中的溶液处理所述粗产物，过滤，冷却至约25℃，用氢氯酸通过所述丙酮溶液鼓泡直到pH值为约3，将所述批料冷却至约0至约5℃，保持在该温度下半小时，过滤，用约20ml丙酮洗涤并在约50℃的烘箱中干燥直至恒重，得到49.6g二甲氨基-甲基-咔唑酮-HCl。
实施例2：纯昂丹司琼碱的制备
往330ml水中加入33g(0.112mol，1当量)二甲氨基-甲基-咔唑酮-HCl、3.3g highflow和46.3g(0.563mol，5当量)甲基-咪唑。
将所述反应物加热回流12小时，冷却至约5℃至约10℃，过滤沉淀，用水洗涤(3×300ml)，在约60℃真空烘箱中干燥直至恒重，得到含highflow的粗产物。
用1.5g SX-1型活性炭(购自NORIT)在930ml丙酮中的溶液处理所述粗产物，过滤(热过滤)除去所述highflow和活性炭，在0至约5℃下结晶1小时。热过滤在约60℃下，用接近沸点(即65℃)的甲醇来进行。过滤收集沉淀，用冷甲醇洗涤(2×20ml)，在约60℃的真空烘箱中干燥直至恒重，得到21.3g昂丹司琼碱。
实施例3：纯二水合昂丹司琼盐酸盐的制备
往100ml水中引入20g昂丹司琼碱。往所述搅拌着的悬浮液中加入7.5ml(1.1当量)的约32％的盐酸(HCl)。发生了稍微的放热反应，悬浮液变得几乎透明，开始形成沉淀。
将反应物冷却，再保持在约3-5℃下1小时，过滤，用约10ml冷异丙醇洗涤，在约50℃真空下干燥。
实施例4：二水合昂丹司琼盐酸盐的制备
在约95℃下，在半小时内从1∶4重量/体积的水和约10％重量/重量的SX-1型活性炭(购自NORIT)中将昂丹司琼-HCl-2H2O结晶两次，过滤(热过滤)，用1体积热水洗涤，冷却至约5℃并保持在该温度下约1小时。收集晶体，用约10ml冷异丙醇洗涤，干燥得到纯昂丹司琼-HCl-2H2O。经HPLC检测所得的纯二水合昂丹司琼盐酸盐，其纯度至少超过99.0％。所得的纯二水合昂丹司琼盐酸盐含有少于0.01％的外-亚甲基副产物，或检测不到该副产物。
Claims (9)
1.一种二水合昂丹司琼盐酸盐，其具有依据HPLC检测的至少约99.5％的纯度。
2.一种二水合昂丹司琼盐酸盐，其具有依据HPLC检测的至少约99.9％的纯度。
3.一种由以下方法制备的二水合昂丹司琼盐酸盐，所述方法包括以下步骤：
a)制备昂丹司琼碱溶液；
b)用盐酸酸化所述溶液以形成沉淀；
c)洗涤所述沉淀；和
d)将纯二水合昂丹司琼盐酸盐从水和在活性炭的存在下结晶；
其中所述二水合昂丹司琼盐酸盐具有依据HPLC检测的至少约99.5％的纯度。
4.一种由以下方法制备的二水合昂丹司琼盐酸盐，所述方法包括以下步骤：
a)制备昂丹司琼碱溶液；
b)用盐酸酸化所述溶液以形成沉淀；
c)洗涤所述沉淀；和
d)将纯二水合昂丹司琼盐酸盐从水和在活性炭的存在下结晶；
其中所述二水合昂丹司琼盐酸盐具有依据HPLC检测的至少约99.9％的纯度。
5.一种由以下方法制备的含有二水合昂丹司琼盐酸盐的药物制剂，所述方法包括以下步骤：
a)制备昂丹司琼碱溶液；
b)用盐酸酸化所述溶液以形成沉淀；
c)洗涤所述沉淀；和
d)将纯二水合昂丹司琼盐酸盐从水和在活性炭的存在下结晶；
其中所述二水合昂丹司琼盐酸盐具有依据HPLC检测的至少约99.5％的纯度。
6.一种由以下方法制备的含有二水合昂丹司琼盐酸盐的药物制剂，所述方法包括以下步骤：
a)制备昂丹司琼碱溶液；
b)用盐酸酸化所述溶液以形成沉淀；
c)洗涤所述沉淀；和
d)将纯二水合昂丹司琼盐酸盐从水和在活性炭的存在下结晶；
其中所述二水合昂丹司琼盐酸盐具有依据HPLC检测的至少约99.9％的纯度。
7.如权利要求3或4的二水合昂丹司琼盐酸盐，其中昂丹司琼碱由以下方法制备：
a)制备甲基-咪唑和具有下式的二甲氨基-甲基-咔唑酮溶液
b)加热所述溶液；
c)从所述溶液中分离出含昂丹司琼碱的沉淀；
d)洗涤所述沉淀；和
e)干燥所述沉淀，得到昂丹司琼碱；
其中甲基-咪唑和二甲氨基-甲基-咔唑酮的溶液是通过往1当量二甲氨基-甲基-咔唑酮中加入约4至约6当量甲基-咪唑来制备的。
8.如权利要求3、4或7的二水合昂丹司琼盐酸盐，其中所述结晶步骤只进行一次。
9.含有如权利要求5或6中所述的二水合昂丹司琼盐酸盐的药物制剂，其中昂丹司琼碱由以下方法制备：
a)制备甲基-咪唑和具有下式的二甲氨基-甲基-咔唑酮溶液
其中R＝C1-4烷基；
b)加热所述溶液；
c)从所述溶液中分离出含昂丹司琼碱的沉淀；
d)洗涤所述沉淀；
e)干燥所述沉淀，得到昂丹司琼碱；
其中甲基-咪唑和二甲氨基-甲基-咔唑酮的溶液是通过往1当量二甲氨基-甲基-咔唑酮中加入约4至约6当量甲基-咪唑来制备的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26105201P | 2001-01-11 | 2001-01-11 | |
| US60/261052 | 2001-01-11 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028062019A Division CN1496350A (zh) | 2001-01-11 | 2002-01-11 | 制备纯二水合昂丹司琼盐酸盐的改进方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101045704A true CN101045704A (zh) | 2007-10-03 |
Family
ID=22991757
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101667179A Pending CN101045704A (zh) | 2001-01-11 | 2002-01-11 | 制备纯二水合昂丹司琼盐酸盐的改进方法 |
| CNA028062019A Pending CN1496350A (zh) | 2001-01-11 | 2002-01-11 | 制备纯二水合昂丹司琼盐酸盐的改进方法 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028062019A Pending CN1496350A (zh) | 2001-01-11 | 2002-01-11 | 制备纯二水合昂丹司琼盐酸盐的改进方法 |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP1355881A4 (zh) |
| JP (1) | JP2004526692A (zh) |
| KR (3) | KR20030068583A (zh) |
| CN (2) | CN101045704A (zh) |
| AU (1) | AU2002236753B2 (zh) |
| CA (1) | CA2433720A1 (zh) |
| CZ (1) | CZ20032090A3 (zh) |
| DE (1) | DE02703115T1 (zh) |
| ES (1) | ES2219201T1 (zh) |
| HR (1) | HRP20030631A2 (zh) |
| HU (1) | HUP0400767A2 (zh) |
| IL (1) | IL156835A0 (zh) |
| IS (1) | IS6869A (zh) |
| MX (1) | MXPA03006215A (zh) |
| NO (1) | NO20033147L (zh) |
| PL (1) | PL368837A1 (zh) |
| SK (1) | SK9892003A3 (zh) |
| TR (1) | TR200401460T3 (zh) |
| WO (1) | WO2002055492A2 (zh) |
| YU (1) | YU56103A (zh) |
| ZA (1) | ZA200305338B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1499623T3 (da) | 2002-04-29 | 2007-10-08 | Teva Gyogyszerg Ar Zartkoeruee | Fremgangsmåde til fremstilling af 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-on |
| HU225885B1 (en) * | 2002-10-17 | 2007-11-28 | Richter Gedeon Nyrt | Process for producing ondansetron hydrochlorid dihydrate of high purity |
| FI6164U1 (fi) * | 2003-01-09 | 2004-03-15 | Synthon Bv | Ondansetronmuotoja |
| GB2398071B (en) * | 2003-01-24 | 2006-06-07 | Synthon Bv | Process for making ondansetron and intermediate thereof |
| US7696356B2 (en) | 2004-08-17 | 2010-04-13 | Taro Pharmaceutical Industries Limited | Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one and ondansetron therefrom |
| EP1828141A4 (en) * | 2004-10-26 | 2009-04-01 | Ipca Lab Ltd | STAINING METHOD FOR PREPARING THE ANTIEMETIC 1,2,3,9-TETRAHYDRO-9-METHYL-3 - [(2-METHYL) -1H-IMIDAZOLE-1-YL) METHYL] -4H-CARBAZOLE-4-ON |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695578A (en) * | 1984-01-25 | 1987-09-22 | Glaxo Group Limited | 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances |
| GB8630071D0 (en) * | 1986-12-17 | 1987-01-28 | Glaxo Group Ltd | Medicaments |
| PL366150A1 (en) * | 2000-10-30 | 2005-01-24 | Teva Pharmaceutical Industries Ltd. | Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation |
-
2002
- 2002-01-11 DE DE02703115T patent/DE02703115T1/de active Pending
- 2002-01-11 EP EP02703115A patent/EP1355881A4/en not_active Withdrawn
- 2002-01-11 CA CA002433720A patent/CA2433720A1/en not_active Abandoned
- 2002-01-11 YU YU56103A patent/YU56103A/sh unknown
- 2002-01-11 PL PL02368837A patent/PL368837A1/xx not_active Application Discontinuation
- 2002-01-11 ES ES02703115T patent/ES2219201T1/es active Pending
- 2002-01-11 KR KR10-2003-7009221A patent/KR20030068583A/ko active IP Right Grant
- 2002-01-11 WO PCT/US2002/000853 patent/WO2002055492A2/en active Application Filing
- 2002-01-11 SK SK989-2003A patent/SK9892003A3/sk not_active Application Discontinuation
- 2002-01-11 CN CNA2006101667179A patent/CN101045704A/zh active Pending
- 2002-01-11 AU AU2002236753A patent/AU2002236753B2/en not_active Expired - Fee Related
- 2002-01-11 MX MXPA03006215A patent/MXPA03006215A/es unknown
- 2002-01-11 KR KR1020077010146A patent/KR20070054749A/ko not_active Application Discontinuation
- 2002-01-11 KR KR1020067020069A patent/KR20060113792A/ko not_active Application Discontinuation
- 2002-01-11 CZ CZ20032090A patent/CZ20032090A3/cs unknown
- 2002-01-11 TR TR2004/01460T patent/TR200401460T3/xx unknown
- 2002-01-11 IL IL15683502A patent/IL156835A0/xx unknown
- 2002-01-11 CN CNA028062019A patent/CN1496350A/zh active Pending
- 2002-01-11 HU HU0400767A patent/HUP0400767A2/hu unknown
- 2002-01-11 JP JP2002556165A patent/JP2004526692A/ja active Pending
- 2002-01-11 ZA ZA200305338A patent/ZA200305338B/xx unknown
-
2003
- 2003-07-08 IS IS6869A patent/IS6869A/is unknown
- 2003-07-09 NO NO20033147A patent/NO20033147L/no not_active Application Discontinuation
- 2003-08-06 HR HR20030631A patent/HRP20030631A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070054749A (ko) | 2007-05-29 |
| NO20033147L (no) | 2003-09-02 |
| ZA200305338B (en) | 2004-07-12 |
| WO2002055492A3 (en) | 2003-02-13 |
| CZ20032090A3 (cs) | 2004-08-18 |
| KR20030068583A (ko) | 2003-08-21 |
| HRP20030631A2 (en) | 2005-06-30 |
| KR20060113792A (ko) | 2006-11-02 |
| PL368837A1 (en) | 2005-04-04 |
| CN1496350A (zh) | 2004-05-12 |
| TR200401460T3 (zh) | 2004-08-23 |
| IL156835A0 (en) | 2004-02-08 |
| EP1355881A4 (en) | 2004-03-31 |
| DE02703115T1 (de) | 2004-10-21 |
| EP1355881A2 (en) | 2003-10-29 |
| AU2002236753B2 (en) | 2007-06-28 |
| JP2004526692A (ja) | 2004-09-02 |
| SK9892003A3 (en) | 2004-05-04 |
| ES2219201T1 (es) | 2004-12-01 |
| MXPA03006215A (es) | 2005-02-17 |
| HUP0400767A2 (hu) | 2004-07-28 |
| YU56103A (sh) | 2006-05-25 |
| NO20033147D0 (no) | 2003-07-09 |
| WO2002055492A2 (en) | 2002-07-18 |
| IS6869A (is) | 2003-07-08 |
| CA2433720A1 (en) | 2002-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8501935B2 (en) | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto | |
| CN101048409A (zh) | 手性8－(3－氨基－哌啶－1－基)－黄嘌呤的制备方法 | |
| CN1466570A (zh) | 晶体和纯莫达非尼及其制备方法 | |
| CN100343227C (zh) | 坦洛新的拆分方法 | |
| US20060089502A1 (en) | Ziprasidone process | |
| CN1034077C (zh) | 新的吡啶并[2，3-f][1，4]硫代吖庚因的制备方法 | |
| CN101062897A (zh) | 一种制备2，3－二氢－1h－茚－1－胺及其衍生物的改进方法 | |
| CN101045704A (zh) | 制备纯二水合昂丹司琼盐酸盐的改进方法 | |
| CN1052979C (zh) | 恩丹西酮的制备方法 | |
| CN103980249B (zh) | 一种苯甲酸阿格列汀的精制方法 | |
| JP2007506702A (ja) | ３−フェニルスルホニル−８−ピペラジン−１−イル−キノリンの多形相 | |
| CN1720228A (zh) | 制备利培酮及其中间体的方法 | |
| CN1250051A (zh) | 新的茚满－1－醇化合物,其制备方法及含有它们的药物组合物 | |
| CN1293031C (zh) | 制备茚满－1,3－二甲酸的方法 | |
| CN1375490A (zh) | 新的茚并吲哚酮化合物,其制备方法和含有这种化合物的药物组合物 | |
| CN1875013A (zh) | 制备西酞普兰的方法 | |
| CN1231481C (zh) | 制备噻唑烷－2,4－二酮衍生物的改进方法 | |
| CN1148594A (zh) | 哌啶基甲基噁唑烷酮 | |
| AU2002236753A1 (en) | An improved process for preparing pure ondansetron hydrochloride dihydrate | |
| CN1030077A (zh) | 法莫丁啶多晶型物及其制备方法 | |
| CN1039245A (zh) | 一种新颖噻吩衍生物和其制备方法 | |
| CN1235880C (zh) | 喹啉酮类衍生物及其可接受的盐，其制备方法、作为制备阿立哌唑的应用及阿立哌唑的制备方法 | |
| CN1249054C (zh) | 一种阿立哌唑的制备方法 | |
| CN1095064A (zh) | 1，4-苯并噁嗪衍生物 | |
| US20020115707A1 (en) | Process for preparing pure ondansetron hydrochloride dihydrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20071003 |