CN1064366C - 3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法 - Google Patents
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Abstract
本发明提供了在提高最终产物的同时,还可以高纯度地得到3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法,其中包括在70-140℃下,将N-烷氧基羰基-β-丙氨酸、氯化磷及亚磷酸以1∶1∶1~1∶3∶3的摩尔比在二甲苯反应溶剂中反应步骤、加水反应步骤、用相分离的方法得到3-氨基-1-羟基丙烷-1,1-二膦酸的步骤。
Description
上述3-氨基-1-羟基丙烷-1,1-二膦酸作为骨质疏松症治疗剂的化合物是有效的。
骨质疏松症(Osteoporosis)是病态的骨密度减少的疾病,骨中的无机质减少,根据部位及程度的轻重,会伴随着腰部的疼痛或身长减少的变形及病态的骨折,对于年长者,特别是更年期的女性是常见的疾病。
因此,在努力开发有效地治疗骨质疏松症的新药的同时,对于目前作为有效的治疗剂的公知的3-氨基-1-羟基丙烷-1,1-二膦酸探索高效的制备方法,其代表例可以举出德国专利2130794号所公开的制造方法。
上述的德国专利2130794号中提出了将β-丙氨酸和三氯化磷及亚磷酸的混合物在反应溶剂氯苯中反应,而得到3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法。
可是,按照上述的德国专利,不仅收率及纯度低,而且还生成尚未确认结构的黄红色无晶形磷-氧化合物的副产物,分离这些不仅很困难,而且在分离时需要很高的费用。
另外,已知的方法有将β-丙氨酸在***及亚磷酸的混合物和氯苯中反应后,加水分解而得到3-氨基-1-羟基丙烷-1,1-二膦酸的方法,但是这些方法也有收率及纯度不佳的缺点。
本发明的目的在于为了解决上述的缺点,提出了使用N-烷氧基羰基-β-丙氨酸作为起始原料,用二甲苯作为反应溶剂,在提高最终产物的同时,可以高纯度地得到3-氨基-1-羟基丙烷-1,1-二膦酸的改进方法。
本发明为了达到上述目的,提供了3-氨基-1-羟基丙烷-1,1-二膦酸的制造方法,其特征在于包括在70~140℃下,将N-烷氧基羰基-β-丙氨酸、氯化磷及亚磷酸以1∶1∶1~1∶3∶3的摩尔比在二甲苯反应溶剂中反应的步骤、加水分解的反应步骤以及用相分离的方法得到3-氨基-1-羟基丙烷-1,1-二膦酸的步骤。
以下具体的说明本发明的制备方法。
将β-丙氨酸和氯甲酸酯反应制得的N-烷氧基羰基-β-丙氨酸作为起始原料。在70~140℃下,将起始原料N-烷氧基羰基-β-丙氨酸1~3摩尔、五氯化磷或三氯化磷1~3摩尔和亚磷酸1~3摩尔以1∶1∶1~1∶3∶3,最好以1∶1∶1的摩尔比进行反应。
上述的氯甲酸酯可以举出氯甲酸甲酯、氯甲酸乙酯、氯甲酸异丙酯、氯甲酸丙酯、氯甲酸烯丙酯、氯甲酸叔丁酯、或氯甲酸苄基酯等。
接着,使用水,在25~110℃的温度下,加水分解反应混合物后,分离水层得到3-氨基-1-羟基丙烷-1,1-二膦酸。
另一方面,为了增加3-氨基-1-羟基丙烷-1,1-二膦酸的收率,可以添加甲醇。甲醇的添加量是150~250ml,优选的是200ml,其与二甲苯的比例,即二甲苯∶甲醇=2.0~3.2∶1,优选的是2.5∶1。
以下,通过实施例及比较例详细说明本发明。
(上式中,R是CH3、CH3CH2、(CH3)2CH、CH3CH2CH2、CH2=CHCH2、(CH3)3(C或PhCH2)
将1N的NaOH滴入到17.8g(0.2摩尔)β-丙氨酸和1N的NaOH(200ml)的溶液中,在维持pH为9.0~9.5条件下,在每1小时内慢慢添加2~3摩尔的烷氧甲酰氯(共滴加105摩尔)。而后将反应混合物的温度降低到0℃,用***(3×100ml)萃取后,用磷酸调节pH为1。接着用氯化钠使水层饱和,用100ml的二氯甲烷萃取三次,使有机层蒸发后,制得N-烷氧羰基-β-丙氨酸。其结果收率为85%。
实施例1
将五氯化磷(312.36g,1.5摩尔)悬浮在二甲苯500ml中后,向其中再添加亚磷酸(123.00g,1.5摩尔)。此反应是放热反应,成为透明的溶液。将此溶液冷却到常温后,添加上述制得的N-烷氧羰基-β-丙氨酸(147.13g,1.5摩尔)。而后,搅拌15分钟后,慢慢上升到100℃的温度,并回流5小时。将此混合物冷却到常温后,添加100ml的水。再次将反应混合物的温度慢慢上升到100℃后,回流5小时。接着分离水层后,冷却,制得3-氨基-1-羟基丙烷-1,1-二膦酸。其结果,收率为65%。
使用KBr压片(pellet),用帕金埃尔马(Perkin-Elmer)公司的621型分光光度计测定红外线分光光谱,或者在使用EM-390-90MHz分光计的D2O中测定NMR光谱时,可以确认最终生成物是3-氨基-1-羟基丙烷-1,1-二膦酸,其结果如下。
IR:在2900-3200cm-1有较宽的谱,在1600及540cm-1处有峰。
NMR:在2.2ppm处有多重峰、在3.3ppm处有三重峰。
另外,将从ICN化学和放射同位素区,得到的β-丙氨酸(1-14C)作为放射性表层起始物质,测定放射性纯度。β-丙氨酸(1-14C)的比活性是13.9mCi/mmole。放射性扫描是使用Packard社的7220/21型扫描器完成的,比活性是用LS9000液体闪烁计数器进行测定,薄层色谱(TLC)是使用Polygramcell 300纤维板完成的,对于最终产物得到的单一峰,所以产物为纯粹的单一物质,其结果如下。
放射性纯度:
水∶乙醇∶氢氧化铝=80∶10∶15,r.f.0.8
水∶丙酮=70∶30,r.f.0.8
甲酸∶水= 1∶1,r.f.1.0
实施例2
将N-烷氧羰基-β-丙氨酸(147.13g,1摩尔)添加到二甲苯500ml中后,加入三氯化磷(137.33g,1摩尔)和亚磷酸(82.00g,1摩尔),温度慢慢升到100℃后,回流5小时。将此反应混合物冷却到常温,加入1000ml水后,再次升温到100℃后,回流5小时。接着分离水层后,在减压下浓缩,制得3-氨基-1-羟基丙烷-1,1-二膦酸。IR及NMR测定结果表明,确认最终生成物是3-氨基-1-羟基丙烷-1,1-二膦酸,收率是63%。
实施例3
加水分解后,在分离的水层中添加200ml甲醇,这是为了提高结晶度,除此之外,与实施例1相同地进行操作,制得3-氨基丙烷-1,1-二膦酸。IR及NMR测定结果表明,最终生成物是3-氨基-1-羟基丙烷-1,1-二羧酸,收率是72.0%。
实施例4
加水分解后,在分离的水层中添加200ml甲醇,这是为了提高结晶度,除此之外,与实施例2相同地进行操作,制得3-氨基丙烷-1,1-二膦酸。IR及NMR测定结果表明,最终生成的是3-氨基-1-羟基丙烷-1,1-二羧酸,收率是69.1%。
比较例1~2
使用氯苯500ml代替反应溶剂二甲苯,其它与实施例1~2相同地制得3-氨基-1-羟基丙烷-1,1-二膦酸,其收率分别是35%及32%。
从上述实施例及比较例的结果,可以看出作为反应溶剂使用氯苯时的最终生成物的收率要比使用二甲苯的收率低,其理由可认为是不仅副产物的生成率比较高,而且由于其比重比水大,所以包含生成物的有机层的比重变大,成为类似水的状态,这样就引起了从包含在有机层中的最终生成物进行相分离的效率下降。
另外,从实施例3及4可以看出,添加甲醇时,3-氨基-1-羟基丙烷-1,1-二膦酸的收率稍有增加。
如上所述,按照本发明,不仅可以减少不能确认的副产物生成,而且还可有效地对于溶解在二甲苯层中的副产物和溶解在水层的最终生成物进行相分离,所以可以高收率、高纯度地制造3-氨基-1-羟基丙烷-1,1-二膦酸,同时作为反应溶剂由于二甲苯比氯苯价格低,也可以降低成本。
Claims (5)
1.3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法,其特征是由以下步骤构成的:
(1)在70~140℃下,将N-烷氧基羰基-β-丙氨酸、氯化磷及亚磷酸以1∶1∶1~1∶3∶3的摩尔比在二甲苯反应溶剂中反应;
(2)加水进行分解反应;以及
(3)用相分离的方法得到3-氨基-1-羟基丙烷-1,1-二膦酸。
2.根据权利要求1所述的3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法,其特征是进一步包括以二甲苯:甲醇=2.0~3.2∶1的比例添加150~250ml的甲醇的步骤。
3.根据权利要求1所述的3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法,其特征是N-烷氧基羰基-β-丙氨酸、氯化磷及亚磷酸以1∶1∶1的摩尔比进行反应。
4.根据权利要求1所述的3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法,其特征是所述氯化磷是五氯化磷或三氯化磷。
5.根据权利要求3所述的3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法,其特征是所述氯化磷是五氯化磷或三氯化磷。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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KR1019960037983A KR100192215B1 (ko) | 1996-09-03 | 1996-09-03 | 3-아미노-1-히드록시프로판-1,1-디포스폰산의 제조방법 |
KR37983/1996 | 1996-09-03 | ||
KR37983/96 | 1996-09-03 |
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CN1175582A CN1175582A (zh) | 1998-03-11 |
CN1064366C true CN1064366C (zh) | 2001-04-11 |
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CN97116850A Expired - Fee Related CN1064366C (zh) | 1996-09-03 | 1997-09-01 | 3-氨基-1-羟基丙烷-1,1-二膦酸的制备方法 |
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US (1) | US5792885A (zh) |
JP (1) | JP2841295B2 (zh) |
KR (1) | KR100192215B1 (zh) |
CN (1) | CN1064366C (zh) |
BR (1) | BR9704595A (zh) |
CA (1) | CA2212313A1 (zh) |
DE (1) | DE19737923A1 (zh) |
ES (1) | ES2138539B1 (zh) |
FR (1) | FR2752841B1 (zh) |
GB (1) | GB2316945B (zh) |
IT (1) | IT1294370B1 (zh) |
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US5847172A (en) * | 1995-06-07 | 1998-12-08 | Magainin Pharmaceuticals Inc. | Certain aminosterol compounds and pharmaceutical compositions including these compounds |
US6984400B2 (en) * | 1998-07-14 | 2006-01-10 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Method of treating restenosis using bisphosphonate nanoparticles |
IL125336A0 (en) | 1998-07-14 | 1999-03-12 | Yissum Res Dev Co | Compositions for inhibition and treatment of restinosis |
US7008645B2 (en) * | 1998-07-14 | 2006-03-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Method of inhibiting restenosis using bisphosphonates |
US6562974B2 (en) | 2000-02-01 | 2003-05-13 | The Procter & Gamble Company | Process for making geminal bisphosphonates |
PE20011061A1 (es) | 2000-02-01 | 2001-11-20 | Procter & Gamble | Cristalizacion selectiva del acido 3-piridil-1-hidroxi-etiliden-1,1-bisfosfonico sodio como el hemipentahidrato o el monohidrato |
ITMI20020908A1 (it) * | 2002-04-29 | 2003-10-29 | Chemi Spa | Processo di preparazione di sodio alendronato |
AU2003233569A1 (en) | 2002-05-17 | 2003-12-02 | Teva Pharmaceutical Industries Ltd. | Use of certain diluents for making bisphosphonic acids |
US20060051407A1 (en) * | 2003-06-27 | 2006-03-09 | Yoram Richter | Method of treating ischemia-reperfusion injury |
US10517883B2 (en) | 2003-06-27 | 2019-12-31 | Zuli Holdings Ltd. | Method of treating acute myocardial infarction |
WO2006134603A1 (en) * | 2005-06-13 | 2006-12-21 | Jubilant Organosys Limited | Process for producing bisphosphonic acids and forms thereof |
WO2007096896A1 (en) * | 2006-02-20 | 2007-08-30 | Alembic Limited | An improved process for the preparation of biphosphonic derivatives |
US9993427B2 (en) | 2013-03-14 | 2018-06-12 | Biorest Ltd. | Liposome formulation and manufacture |
CN106179235A (zh) * | 2016-08-29 | 2016-12-07 | 江苏海普功能材料有限公司 | 一种除化学镍吸附剂及其制备方法 |
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DE2130794C3 (de) * | 1971-06-22 | 1974-07-11 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | Verfahren zur Herstellung von l-Hydroxy-S-amino-propan-ljl-diphosphonsäure |
DE2943498C2 (de) * | 1979-10-27 | 1983-01-27 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur Herstellung von 3-Amino-1-hydroxypropan-1,1-diphosphonsäure |
DE3016289A1 (de) * | 1980-04-28 | 1981-10-29 | Henkel KGaA, 4000 Düsseldorf | Verfahren zur herstellung von omega -amino-1-hydroxyalkyliden-1,1-bis-phosphonsaeuren |
US4304734A (en) * | 1980-10-16 | 1981-12-08 | Vysoka Skola Chemicko-Technologicka | 6-Amino-1-hydroxyhexylidene diphosphonic acid, salts and a process for production thereof |
DE3540150A1 (de) * | 1985-11-13 | 1987-05-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
DE3623397A1 (de) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US5019651A (en) * | 1990-06-20 | 1991-05-28 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof |
-
1996
- 1996-09-03 KR KR1019960037983A patent/KR100192215B1/ko not_active IP Right Cessation
-
1997
- 1997-08-05 CA CA002212313A patent/CA2212313A1/en not_active Abandoned
- 1997-08-13 FR FR9710351A patent/FR2752841B1/fr not_active Expired - Fee Related
- 1997-08-13 US US08/910,851 patent/US5792885A/en not_active Expired - Fee Related
- 1997-08-25 ES ES009701836A patent/ES2138539B1/es not_active Expired - Lifetime
- 1997-08-27 DE DE19737923A patent/DE19737923A1/de not_active Withdrawn
- 1997-08-29 IT IT97MI001989A patent/IT1294370B1/it active IP Right Grant
- 1997-09-01 JP JP9235518A patent/JP2841295B2/ja not_active Expired - Lifetime
- 1997-09-01 CN CN97116850A patent/CN1064366C/zh not_active Expired - Fee Related
- 1997-09-03 BR BR9704595A patent/BR9704595A/pt not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
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FR2752841A1 (fr) | 1998-03-06 |
KR100192215B1 (ko) | 1999-06-15 |
GB2316945A8 (en) | 1998-09-02 |
JP2841295B2 (ja) | 1998-12-24 |
CN1175582A (zh) | 1998-03-11 |
US5792885A (en) | 1998-08-11 |
KR19980019751A (ko) | 1998-06-25 |
CA2212313A1 (en) | 1998-03-03 |
GB2316945B (en) | 2000-07-05 |
BR9704595A (pt) | 1998-10-27 |
IT1294370B1 (it) | 1999-03-24 |
MX9706430A (es) | 1998-07-31 |
GB2316945A (en) | 1998-03-11 |
JPH10101685A (ja) | 1998-04-21 |
ITMI971989A1 (it) | 1999-03-01 |
ES2138539B1 (es) | 2000-09-16 |
DE19737923A1 (de) | 1998-03-05 |
ES2138539A1 (es) | 2000-01-01 |
FR2752841B1 (fr) | 1999-12-24 |
GB9718725D0 (en) | 1997-11-12 |
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