CN106588893A - 维拉佐酮双氧化物的制备 - Google Patents
维拉佐酮双氧化物的制备 Download PDFInfo
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- CN106588893A CN106588893A CN201611089748.9A CN201611089748A CN106588893A CN 106588893 A CN106588893 A CN 106588893A CN 201611089748 A CN201611089748 A CN 201611089748A CN 106588893 A CN106588893 A CN 106588893A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229960003740 vilazodone Drugs 0.000 title claims description 4
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 title claims description 4
- 239000012535 impurity Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- YHYLDEVWYOFIJK-UHFFFAOYSA-N 1h-indole-5-carbonitrile Chemical compound N#CC1=CC=C2NC=CC2=C1 YHYLDEVWYOFIJK-UHFFFAOYSA-N 0.000 claims description 7
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- VSVJHORNUCWLJB-UHFFFAOYSA-N 1,4-dihydroxypiperazine Chemical compound ON1CCN(O)CC1 VSVJHORNUCWLJB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000009977 dual effect Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 229960003381 vilazodone hydrochloride Drugs 0.000 abstract description 6
- RPZBRGFNBNQSOP-UHFFFAOYSA-N vilazodone hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 RPZBRGFNBNQSOP-UHFFFAOYSA-N 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000004451 qualitative analysis Methods 0.000 abstract description 3
- 238000004445 quantitative analysis Methods 0.000 abstract description 3
- GDXSODKRHSNQJT-UHFFFAOYSA-N 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1,4-dioxidopiperazine-1,4-diium-1-yl]-1-benzofuran-2-carboxamide Chemical compound C1=C(C#N)C=C2C(CCCC[N+]3(CC[N+](CC3)([O-])C=3C=C4C=C(OC4=CC=3)C(=O)N)[O-])=CNC2=C1 GDXSODKRHSNQJT-UHFFFAOYSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- IGSSNLHDFIYOIL-UHFFFAOYSA-N furan-2-carboxamide;hydrochloride Chemical class Cl.NC(=O)C1=CC=CO1 IGSSNLHDFIYOIL-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了1‑(2‑氨基甲酰基苯并呋喃‑5‑基)‑4‑(4‑(5‑氰基‑1H‑吲哚‑3‑基)丁基)哌嗪‑1,4‑二氧化物的一种制备方法，它为定性、定量分析药品中杂质提供依据，对于合成高质量的盐酸维拉佐酮具有重要意义，为病人的安全用药提供了有力的保证。
Description
技术领域
本发明属于药物合成技术领域。
背景技术
盐酸维拉佐酮(Vilazodone)，化学名：5-[4-[4-(5-氰基-1H-吲哚-3-基)丁基]-1-哌嗪基]- 2-苯并呋喃甲酰胺，由森林实验室制药公司和德国默克公司共同研发，于2011年在FDA获批上市，用于治疗成人重度抑郁症，该药具有5-HT1A受体部分激动剂和选择性5-羟色胺再摄取抑制剂双重活性，盐酸维拉佐酮所具有得起效快、不增体重、也不影响性功能、耐受性好、不良反应小的特点使其具有很大的前景。其结构式如下:
。
药物的杂质是影响药物质量的主要因素之一，特别是降解杂质对原料药及药物制剂的制备、稳定性及生物利用度等方面有着不可忽视的影响，因此，杂质1-(2-氨基甲酰基苯并呋喃-5-基)-4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1,4-二氧化物的研究具有重要意义。
发明内容
本发明的目的在于提供盐酸维拉佐酮杂质：1-(2-氨基甲酰基苯并呋喃-5-基)-4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1,4-二氧化物的一种制备方法，为定性、定量分析药品中杂质水平提供依据。
1-(2-氨基甲酰基苯并呋喃-5-基)-4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1,4-二氧化物化学结构式如下所示：
。
本发明以5-(4-(4-(5-氰基-1H-吲哚-3-基)甲基)哌嗪-1-基)苯并呋喃-2-甲酰胺盐酸盐为原料，在酸性条件下，以乙醇为溶剂，在回流状态下氧化反应18~26h，反应液浓缩得粗品，柱层析提纯。本方法操作方法简便、反应稳定，产品收率高、纯度高。
反应方程式如下所示：
。
本发明氧化反应所用酸化试剂是无机酸盐酸、硫酸、磷酸，优选盐酸；反应体系pH值为1~3。
本发明反应溶剂为乙醇；反应温度控制在60℃以上，优选回流温度。
本发明的有益效果在于公开了一种盐酸维拉佐酮杂质的制备方法，它为有效制备、考察定性、定量分析药品盐酸维拉佐酮中的杂质水平提供了合格的对照品，对提高药品质量有着重大的意义。
具体实施实例
以下结合实例对本发明进行更详细的描述，但不作为对本发明的限制。
实施例1
向500 mL三口瓶中依次加入10g5-（4-（4-（5-氰基-1H-吲哚-3-基）甲基）哌嗪-1-基）苯并呋喃-2-甲酰胺盐酸盐、300ml乙醇、20mlH2O2、搅拌，升温至回流，TLC监控反应完全。停止加热，减压浓缩，粗品40℃鼓风干燥箱干燥至恒重，柱层析，得双氧化杂质4.0g，纯度96%，收率为40.4%。
实施例2
向500 mL三口瓶中依次加入10g5-（4-（4-（5-氰基-1H-吲哚-3-基）甲基）哌嗪-1-基）苯并呋喃-2-甲酰胺盐酸盐、300ml乙醇、20mlH2O2、搅拌，升温至60℃，TLC监控反应完全。停止加热，减压浓缩，粗品40℃鼓风干燥箱干燥至恒重，柱层析，得双氧化杂质3.8g，纯度95.5%，收率为38.4%。
Claims (6)
1.维拉佐酮双氧化杂质1-(2-氨基甲酰基苯并呋喃-5-基)-4-(4-(5-氰基-1H-吲哚-3-基)丁基)哌嗪-1,4-二氧化物的制备方法：5-(4-(4-(5-氰基-1H-吲哚-3-基)甲基)哌嗪-1-基)苯并呋喃-2-甲酰胺盐酸盐为原料在酸性条件下氧化得到粗品，柱层析分离提纯得到高纯度产品；其反应式如下所示：
。
2.根据权利要求1所述制备方法，其特征在于氧化所用酸化试剂是无机酸盐酸、硫酸、磷酸。
3.根据权利要求1和2所述方法，所用酸化试剂为盐酸，反应体系pH值为1~3。
4.根据权利要求1所述制备方法，其特征在于反应溶剂为乙醇。
5.根据权利要求1所述制备方法，其特征在于反应温度为60℃以上。
6.根据权利要求1及5所述制备方法，其特征在于反应温度为回流温度。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611089748.9A CN106588893A (zh) | 2016-12-01 | 2016-12-01 | 维拉佐酮双氧化物的制备 |
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|---|---|---|---|
| CN201611089748.9A CN106588893A (zh) | 2016-12-01 | 2016-12-01 | 维拉佐酮双氧化物的制备 |
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| CN106588893A true CN106588893A (zh) | 2017-04-26 |
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| CN201611089748.9A Pending CN106588893A (zh) | 2016-12-01 | 2016-12-01 | 维拉佐酮双氧化物的制备 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1909908A (zh) * | 2004-01-22 | 2007-02-07 | 诺瓦提斯公司 | 用于治疗蛋白激酶依赖性疾病的吡唑并[1,5－a]嘧啶－7－基－胺衍生物 |
-
2016
- 2016-12-01 CN CN201611089748.9A patent/CN106588893A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1909908A (zh) * | 2004-01-22 | 2007-02-07 | 诺瓦提斯公司 | 用于治疗蛋白激酶依赖性疾病的吡唑并[1,5－a]嘧啶－7－基－胺衍生物 |
Non-Patent Citations (3)
| Title |
|---|
| CHUN-KIU KWOK ET AL.: "Synthesis and structural characterization of N,N-diarylpiperazine N,N-dioxide tetrahydrates (aryl = o-tolyl, p-tolyl, p-chlorophenyl)", 《CANADIAN JOURNAL OF CHEMISTRY》 * |
| P.D.KALARIYA ET AL.: "Experimental Design Approach for Selective Separation of Vilazodone HCl and Its Degradants by LC-PDA and Characterization of Major Degradants by LC/QTOF-MS/MS", 《CHROMATOGRAPHIA》 * |
| PRADIPBHAI D. KALARIYA ET AL.: "Identification of hydrolytic and isomeric N-oxide degradants of vilazodone by on line LC-ESI-MS/MS and APCI-MS", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
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Application publication date: 20170426 |