CN1200930C - 1－甲基－5－对甲苯酰吡咯－2－乙酰氨基乙酸愈创木酯(med 15)的新多晶形物 - Google Patents
1－甲基－5－对甲苯酰吡咯－2－乙酰氨基乙酸愈创木酯(med 15)的新多晶形物 Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/323—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
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Abstract
公开了1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸愈创木酯的一种新晶形，它的制备方法以及具有抗炎、止痛和退热活性的含有该物质的药物组合物。
Description
本发明涉及1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸愈创木酯的一种新晶形，它的制备方法和具有抗炎、止痛和退热活性的含有该物质的药物组合物。
1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸的酯(下文将它称为“MED15-1型”)是一类已知化合物。
实际上，美国专利4,882,349公开了一类具有抗炎、止痛、退热、抗分泌和镇咳性质的1-甲基-5-对甲苯酰吡咯-2-乙酸(被称为“托美丁”)的N-单取代酰胺和N，N-二取代酰胺。
美国专利4,578,481要求保护一种具有有价值的药理活性的具体化合物(包含于上述类型物质中)，确切地说是1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸愈创木酯(它是MED 15-1型)，及其制备方法。
公开于US4,578,481中的方法存在一些缺点，因为它不容易在工业规模应用并且产率低。
按上述方法，在四氢呋喃(THF)中将托美丁与N，N′-碳酰二咪唑反应，再往该反应混合物中添加氨基乙酸乙酯盐酸化物。
接着进行一系列复杂的洗涤以便除去未反应的起始化合物，再从苯/环己烷中结晶，得到1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸乙酯。随后将该化合物转化成相应的酸。
将该酸与N，N′-碳酰二咪唑反应而得相应的咪唑化物，再往该化合物中添加愈创木酚在THF中的溶液。
在数次洗涤、中和和从苯/环己烷中结晶后，从该反应混合物获得MED15-1型。
MED 15-1型的主要物理化学特性如表1的左栏中所示。
有各种已知的施用任何药物的可能途径，例如可方便地通过经口途径，应用合适的药物剂型(例如片剂、糖衣丸和胶囊)，或者通过直肠途径(例如应用栓剂)。
这些施药方法与肠胃外途径(注射途径)相比呈现明显的优点，因为它们不需要医师或能应用注射器的人。
适合口服的上述药物制剂良好的生产操作要求考虑数个参数(取决于药物的性质)。
这些参数的非限制性实例有：该药物在不同的环境条件下用作原料的稳定性；生产过程中的稳定性；以及最终的药物制剂的稳定性。
用于制备上述药物制剂的药物必须是尽可能纯的，并且它在不同环境条件中长期贮存时的稳定性必须受到控制，避免应用降解的药物，或者避免应用效价(titre)比生产方法所要求的意外地更低的药物。在这种情况下，存在于单颗糖衣丸或胶囊中的药物含量会比需要的更低，这是人们所不希望有的。
吸湿会降低药物效价，因为药物由于它吸收水的能力而重量增加。
为此，在长期贮存过程中必须保护倾向于吸湿的药物，例如，应用合适的脱水剂，或者将它们贮存在防湿的环境中。
在生产过程中，当药物在正常条件下暴露于潮湿环境而没有任何保护时，湿度也会降低药物效价。
药物在单颗糖衣丸或胶囊中的准确重量的正确分布是一个关键因素，当应用低药物剂量时尤其如此。
有可能将药物粒子的尺寸减小至合适的值(例如通过研磨)以便达到正确的药物分配。
实际上，在单颗的糖衣丸或胶囊中，小粒子以恒定量分配得更好。
由于研磨可能会引起药物一定程度的降解，所以，研磨时的高稳定性体现制备含预定量药物的胶囊或糖衣丸的重要优势，避免降解产物的存在。
此外，在研磨时，作用于固体产品的机械应力会引起多晶形变化、非晶体化和晶体形状或表面的改变。
这些改变对随后产品经历的工艺处理和对生物药物特性起重要作用。
含于药物组合物中的活性成分的稳定性对于确定药物有效期来说是必需的。在该期间可施用药物而没有由于过量可能有害的降解产物的存在或由于活性成分少于规定的量的低含量而造成的任何危险性。
药物在不同贮存条件下的稳定性对患者和对生产者都是额外的优点；其实，避免了在受控环境中的贮存和经常更换失效的成批药物。
对于口服药物(例如胶囊、片剂或糖衣丸)的固体状态的任何改良，如果与同一药物的较不稳定形态相比该改良能改善其物理和化学稳定性并且导致显著的优势，那么该改良正是需要的目标。
人们熟知，上述改良的一个明显实例包括所述药物的新晶形，它克服了上述缺点。
本发明的一个目的是提供MED 15的一种新晶形(下文中的MED 15-2型)，它不表现上述缺点。
本发明的另一目的是提供一种方法，它克服了已知方法的缺点。该方法可在工业上应用，产率高，并且适合制备高纯度的MED 15-2型。
现已发现了，下式的1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸愈创木酯
表现出多晶现象，并且，除了上述MED 15-1型之外，它还存在第二种晶形(被称为MED 15-2型)，其特征在于下列物理化学特性：
熔点：133-136℃；
DSC
峰 136.2℃ 136.7℃
开始 132.5℃ 133.7℃
δH 97.3J/g 98.3J/g
IR光谱
[在下列波数(以cm-1为单位)呈现特征信号]
3302.98 1550.27 1113.95 699.06
3092.37 1501.85 1037.43 620.38
2948.24 1480.85 1022.34 576.81cm-1
2842.00 1458.18 976.95
1785.85 1377.94 885.21
1762.26 1310.86 833.34
1646.73 1262.66 788.30
1626.80 1202.46 769.16
1607.82 1179.67 749.21
1564.93 1162.83 729.28
为比较起见，将一些基本的物理化学特性值(熔点、差示扫描量热法(DSC)和I.R.光谱)示于表1中。这些值示出两种形态之间的差异。
表1：MED 15的1型和2型之间物理化学特性(熔点、DSC、IR光谱)的比较
| MED 15-1型 | MED 15-2型 | |||||||
| 熔点* | 117-120℃ | 132-136℃ | ||||||
| DCS**峰开始δH | 129.5-130.9℃125.4-125.9℃97.7-101.1J/g | 136.2-136.7℃132.5-133.7℃97.3-98.3J/g | ||||||
| IR光谱***(以cm-1为单位的波数) | 3315.473296.853066.962931.052841.601775.591690.251608.541549.691501.99 | 1486.291455.291408.701375.951312.381261.401195.711149.651110.651032.86 | 968.53936.82918.44882.01838.68786.11771.47748.46740.19687.71 | 636.42621.99556.44 | 3302.983092.372948.242842.001785.851762.261646.731626.801607.821564.93 | 1550.271501.851480.851458.181377.941310.861262.661202.461179.671162.83 | 1113.951037.431022.34976.95885.21833.34788.30769.16749.21729.28 | 699.06620.38576.81 |
*通过Capillar Buchi装置测定的。
**仪器：DSC Mettler 30；温度：从50到200℃；扫描速度：10℃/分；称量的样品量：3～8mg。
***FTIR分光光度测定仪：Nicolet 20SXC型；样品形式：片；样品浓度：2％，在KBr上；温度：室温。
本发明的方法如下列反应图解所示：
上述方法包括如下步骤：
(a)用碱金属氢氧化物在碱性环境中水解托美丁
1甲酯，获得托美丁
2碱金属盐；
(b)将
2与氯甲酸异丁酯
3缩合而得混合酐
4；
(c)将
4与甘氨酸
5反应而得1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸
6；
(d)将
6与氯甲酸异丁酯
3缩合而得混合酐
7；以及
(e)将混合酐
7与愈创木酚
8反应而得
9，MED 15-2型。
下述非限制性实施例阐述了按本发明的方法制备MED 15-2型。
1-甲基-对甲苯酰吡咯-2-乙酰氨基乙酸的制备。
在搅拌下，将500mL甲苯、100g托美丁乙酯和10g Terre deco于1L烧瓶中的混合物加热到70℃并保持在该温度达20～30min。然后在预热过的布氏漏斗(buckner)上过滤该混合物，用50mL热甲苯洗涤固相。将脱色的甲苯溶液转入2L烧瓶，往其中添加溶于100mL水的15g氢氧化钠(97％)。
在回流温度下加热该溶液并回流加热1小时。往在回流温度下加热的该溶液中添加22mL异丁醇；用Marcusson装置完全除去水(约120mL)(内部温度达104～105℃)。
往在氮气氛中冷却到-5℃±2℃的托美丁钠悬浮液中添加0.2mL N-甲基吗啉。将温度保持在0℃±3℃，在5～10min内滴加53mL氯甲酸异丁酯。约1小时后，该悬浮液变成流体。在0℃±3℃下反应3小时，在预先制备的甘氨酸溶液中滴加该混合酐溶液。所述甘氨酸溶液是在含230mL软化水，47g氢氧化钾(90％)的烧瓶中制备的，冷却该溶液至20℃±2，添加60g甘氨酸，再冷却到10℃±2℃。
在搅拌下5～10min内，往所述甘氨酸溶液中滴加混合酐，保持温度在20℃±2℃。
添加完毕，让温度升高到室温，1小时后完成反应。往该混合物中添加325mL软化水，用稀(16％)盐酸(约100mL)调节该混合物至pH6.0±2。
将该溶液的温度升到73℃±2℃，并将pH调节到pH5.0±0.2。
在热温下分成两相：将甲苯相放在一边而回收酸-托美丁(如果有的话)，将水相保持在73℃±2℃并用稀盐酸调节到pH4.0±0.2。
在开始沉淀时，用稀(16％)盐酸(100mL)将溶液缓慢调节到pH3.0±0.2。
冷却该混合物至15℃±3℃，30min后过滤。用2×100mL软化水洗涤固体滤饼，在60℃下真空干燥该产品直到恒重。获得100g 1-甲基-对甲苯酰吡咯-2-乙酰氨基乙酸。
MED 15-2型的制备
在含730mL甲苯的2L烧瓶中，溶解上述步骤的100g干燥化合物。往该溶液中添加溶于65mL水的18.8g氢氧化钾(tit.90％)。
干燥该溶液(保持内部温度在95～100℃)，再冷却到55～60℃。然后添加碳酸氢钾溶液，干燥形成的混合物(保持内部温度在105℃±2℃)。
在氮气氛中将该混合物冷却到5℃±2℃，往其中添加24mL异丁醇和0.3mL N-甲基吗啉。
将温度保持在10℃±3℃，在5～10分钟内滴加47mL氯甲酸异丁酯。让该混合物在10℃±3℃下反应两小时而得酐溶液，将它添加到预先制备的愈创木酚溶液中。
该愈创木酚溶液是通过在2L烧瓶中加入295mL水、25g氢氧化钾(90％)和0.3g焦亚硫酸钠而制备的。
加料完毕，将温度调到35～40℃。
在5～10min内滴加所述酐，让温度升到室温。
将该悬浮液搅拌下保持1小时，用稀盐酸调节至pH6.0±0.5。加热该悬浮液至70℃±5℃，用稀盐酸保持在pH3～4。
趁热进行相分离。弃去水相，往有机相中添加250mL水。
将温度保持在70±5℃，用稀氢氧化钠调节溶液至pH8.0±0.5，趁热进行相分离，弃去水相。
用250mL水洗涤有机相。在70±5℃下进行相分离。然后用代卡利特(dicalite)清洁甲苯相，过滤，让它结晶。
缓慢地冷却该混合物至30℃～35℃，再将温度调到10±3℃，1小时后过滤，用甲苯(2×100mL)洗涤。
在60℃真空下使产品干燥，给出100g化合物MED 15-2型。理论产量：133.7g；产率％：74.8％。
Claims (2)
1.下式的1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸愈创木酯的2型：
其特征在于下列物理化学特性：
熔点：133-136℃；
DSC
峰 136.2℃ 136.7℃
开始 132.5℃ 133.7℃
δH 97.3J/g 98.3J/g
IR光谱，在下列以cm-1为单位的波数时呈现特征信号
3302.98 1550.27 1113.95 699.06
3092.37 1501.85 1037.43 620.38
2948.24 1480.85 1022.34 576.81cm-1
2842.00 1458.18 976.95
1785.85 1377.94 885.21
1762.26 1310.86 833.34
1646.73 1262.66 788.30
1626.80 1202.46 769.16
1607.82 1179.67 749.21
1564.93 1162.83 729.28
2.一种按下列反应图解制备权利要求1的化合物的方法：
该方法包括如下步骤：
(a)用碱金属氢氧化物在碱性环境中水解托美丁甲酯
1，获得托美丁碱金属盐
2；
(b)将
2与氯甲酸异丁酯
3缩合而得混合酐
4；
(c)将
4与甘氨酸
5反应而得1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸
6；
(d)将
6与氯甲酸异丁酯
3缩合而得混合酐
7；
(e)将混合酐
7与愈创木酚
8反应而得
9；以及
(f)将
9在甲苯中结晶得到权利要求1所述的1-甲基-5-对甲苯酰吡咯-2-乙酰氨基乙酸愈创木酯的2型。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT97RM000811A IT1297140B1 (it) | 1997-12-24 | 1997-12-24 | Forma cristallina del guaiacil estere dell'acido l-metil-5-p-toluoil- pirrol-2-acetammidoacetico, procedimento per la sua preparazione e |
| ITRM97A000811 | 1997-12-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1283185A CN1283185A (zh) | 2001-02-07 |
| CN1200930C true CN1200930C (zh) | 2005-05-11 |
Family
ID=11405418
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988126567A Expired - Lifetime CN1200930C (zh) | 1997-12-24 | 1998-12-16 | 1－甲基－5－对甲苯酰吡咯－2－乙酰氨基乙酸愈创木酯(med 15)的新多晶形物 |
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| Country | Link |
|---|---|
| US (1) | US6288241B1 (zh) |
| EP (1) | EP1082304B1 (zh) |
| JP (1) | JP4693236B2 (zh) |
| KR (1) | KR100554704B1 (zh) |
| CN (1) | CN1200930C (zh) |
| AT (1) | ATE255562T1 (zh) |
| AU (1) | AU781283B2 (zh) |
| BR (1) | BR9814476A (zh) |
| CA (1) | CA2315835C (zh) |
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| DE (1) | DE69820301T2 (zh) |
| DK (1) | DK1082304T3 (zh) |
| ES (1) | ES2210853T3 (zh) |
| HK (1) | HK1035717A1 (zh) |
| HU (1) | HU228112B1 (zh) |
| IL (1) | IL136828A (zh) |
| IT (1) | IT1297140B1 (zh) |
| PL (1) | PL197768B1 (zh) |
| PT (1) | PT1082304E (zh) |
| SK (1) | SK284777B6 (zh) |
| TR (1) | TR200001867T2 (zh) |
| WO (1) | WO1999033797A1 (zh) |
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| AU2020229118A1 (en) * | 2019-02-28 | 2021-09-23 | Tokyo Institute Of Technology | Method for producing amide |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1210673B (it) * | 1982-02-26 | 1989-09-20 | Medosan Ind Biochimi | Antinfiammatoria amidi pirrolacetiche ad attivita' |
| IT1148117B (it) * | 1982-03-05 | 1986-11-26 | Medosan Ind Biochimi | Attivita'antiflogistica,analgesica,antipiretica,mucolitica e seda tiva della tosse dell'1 metil-5-p-tolilpirrol-2-acetato di 2'metossi-fenile |
| IT1197688B (it) * | 1983-07-29 | 1988-12-06 | Medosan Ind Biochimi | Attivita' antiflogistica,analgesica,antipiretica ed antiaggregante piastrinica di 1-metil-5-metilbenzoilpirrol-2-acetamido acetanilidi |
| IT1278144B1 (it) * | 1995-07-14 | 1997-11-17 | Medosan Ricerca Srl | Impiego dell'amtolmetineguacil (med 15) come farmaco antisecretivo sulla secrezione gastrica e quindi gastroprotettivo. |
| WO1999007363A1 (en) | 1997-08-08 | 1999-02-18 | Medosan, Ricerca S.R.L. | Use of the compound 2-methoxyphenyl-1-methyl-5p-methylbenzoyl-pyrrol-2-acetamido acetate for the production of an anti-inflammatory drug with prevention of gastric hypersecretion and renal impairment |
-
1997
- 1997-12-24 IT IT97RM000811A patent/IT1297140B1/it active IP Right Grant
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1998
- 1998-12-16 AT AT98962664T patent/ATE255562T1/de active
- 1998-12-16 JP JP2000526481A patent/JP4693236B2/ja not_active Expired - Lifetime
- 1998-12-16 AU AU17828/99A patent/AU781283B2/en not_active Expired
- 1998-12-16 PL PL341424A patent/PL197768B1/pl unknown
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- 1998-12-16 DK DK98962664T patent/DK1082304T3/da active
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