CN1367773A - 萘普生硝基氧基烷基酯的制备方法 - Google Patents
萘普生硝基氧基烷基酯的制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/02—Preparation of esters of nitric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C203/00—Esters of nitric or nitrous acid
- C07C203/02—Esters of nitric acid
- C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
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Abstract
一种制取对映异构过量高于或等于95%,优选高于或等于98%的2－(S)－(6－甲氧基－2－萘基)－丙酸硝基氧基烷基酯的方法,其特征在于,通式A－Hal的2－(S)－(6－甲氧基－2－萘基)－丙酸的酰卤,其中A是该酸的酰基残基,在惰性有机溶剂中、在无机碱存在下与脂族硝基氧基链烷醇HO－Y－ONO2起反应,其中Y是C2～C20亚烷基或者3～8个碳原子的亚环烷基,或者含有上述亚环烷基的如所规定的亚烷基。
Description
本发明涉及一种制备2-(S)-(6-甲氧基-2-萘基)-丙酸(萘普生(naproxene))的硝基氧基烷基酯的新方法，该产物具有大于或等于97％，优选高于或等于98％(S)形对映异构(体)过量，加之具有高收率，高于75～80％，优选高于85％。
现有技术中普遍知道，从上述产物的药理学观点来看，对映异构(体)形式(S)是活性形式。
在现有技术中，2-(S)-(6-甲氧基-2-萘基)-丙酸的硝基氧基烷基酯的合成方法是已知的。在专利申请WO 98/25,918中，描述了一种烷基链中含有饱和C3～C8环烷基残基的萘普生硝基氧基烷基酯的合成方法。在所述方法中，该酸或其官能衍生物之一，例如酰氯或酸酐，在惰性有机溶剂中与含上面规定的环烷基残基的硝基链烷醇起反应。反应在有机氮化碱如4-二甲氨基吡啶、吗啉、N-甲基吗啉或三乙胺的存在下进行。本申请人进行的试验表明，该现有技术方法不能获得具有超过55～80％对映异构过量的萘普生硝基氧基烷基酯，仅当采用一种特定有机碱，4-N，N-二甲氨基吡啶时，该过量数值才达到94％。
因此，感到需要制取对映异构过量较高的，至少97％，优选等于或高于98％的萘普生硝基氧基烷基酯。
本发明的目的是一种制取对映异构过量高于或等于97％，优选高于或等于98％的2-(S)-(6-甲氧基-2-萘基)-丙酸硝基氧基烷基酯的方法，其特征在于，通式A-Hal的2-(S)-(6-甲氧基-2-萘基)-丙酸的酰卤，其中A是所述酸的酰基残基，在惰性有机溶剂中、在无机碱存在下与脂族硝基氧基链烷醇HO-Y-ONO2起反应，其中Y具有下列含义之一：
-线型或任选地支化的C1～C20，优选C2～C5亚烷基；
-亚环烷基，其环具有3～8个碳原子，优选5～7个碳原子，所述亚环烷基任选地可被一个或两个上面规定的亚烷基，和/或一个或多个烷基基团所取代，其链中的碳原子数如同上面对亚烷基的规定；
-环上具有5或6个碳原子的芳族残基，所述芳族残基任选地可被一个或两个上面规定的亚烷基，和/或一个或多个烷基基团所取代，其链中的碳原子数如同上面对亚烷基的规定，或者被一个-COOH基团所取代；
-(T)p-(CH2-CH(ONO2)-CH2O)nf′-(T)-，T是上面规定的亚烷基，而p是等于0或1的整数，亚烷基具有上面提到的含义，nf′是1～6，优选1～4的整数；结果生成与通式A-O-Y-ONO2对应的2-(S)-(6-甲氧基-2-萘基)-丙酸硝基氧基烷基酯，其中A和Y如同上面的规定。
Y也可以是两个或更多个所提到基团的组合。
按摩尔计，脂族硝基氧基醇相对于酰卤的用量介于1～2，优选1.2～1.5。
所述无机碱指的是碱金属和碱土金属的氢氧化物、氧化物、碳酸盐和碳酸氢盐、硅酸盐、铝硅酸盐，或者属于族IIB，优选锌，或属于族IIIa或IVa，优选锡的金属的氢氧化物、氧化物、碳酸盐和碳酸氢盐。
无机碱的用量，按与酰卤的摩尔比计，一般介于1～2，优选1.2～1.5。
本发明的惰性有机溶剂是指芳烃，例如甲苯和二甲苯；氯化或氟化有机溶剂，例如二氯甲烷、氯苯；脂族酯如C1～C4酸与C1～C5醇的酯如乙酸乙酯和乙酸丁酯等。
溶剂的用量并不严格，一般使用1～10倍体积的溶剂，优选2～5倍体积，以酰卤重量为基准。
反应在-20℃～50℃，优选0℃～20℃的温度进行。
反应终点，在向有机相中加入水，发生相分离并蒸发出溶剂之后，回收到2-(S)-(6-甲氧基-2-萘基)-丙酸的硝基氧基烷基酯。必要的话，可利用硅胶柱色谱法做进一步提纯，以提高产物的脂酸冻点(titre)。
替代地，该化合物也可通过从适当溶剂中结晶来提纯。
脂族硝基氧基醇可按照现有技术中已知的方法制备。例如参见Gazzetta，《Chim.It.》1987，117、173，以及WO 98/25,918。
本申请人发现令人惊奇的是，无机碱的使用，相对于如所看到的采用有机碱的现有技术方法而言，可改善萘普生硝基氧基烷基酯的对映异构过量，同时又达到如上所述的高收率。
下面给出的实施例旨在说明本发明，无意对其做出限制。
例1(对比例)
按照WO 98/25918，2-(S)-(6-甲氧基-2-萘基)-丙酸的4-硝基氧基丁酯的制备
2-(S)-(6-甲氧基-2-萘基)-丙酸(0.32 g，1.4 mmol)、4-N，N-二甲氨基吡啶(16 mg，0.13mmol)、4-硝基氧基-1-丁醇(0.34g，2.5mmol)溶于二氯甲烷(6ml)中的混合物，在0℃～5℃的温度和搅拌下加入到N，N′-二环己基碳二亚胺(0.29 g，1.4mmol)溶于二氯甲烷(6ml)的溶液中。混合物在同一温度下维持搅拌3h，然后通过在真空下蒸发出溶剂而干燥。残余物通过硅胶柱色谱法(洗脱液二氯甲烷)提纯，产出2-(S)-(6-甲氧基-2-萘基)-丙酸的4-硝基氧基丁酯(0.41g，1.19mmol)，收率85％)，呈油状物形式。HPLC(高压液相色谱术)纯度：98％。1H NMR(CDCl3)δ(ppm)：1.59(d，3H，J＝7.5Hz)；1.65(m，4H)；3.85(q，1H，J＝7.5Hz)；3.91(m，2H)；4.10(m，2H)；7.1-7.7(m，芳族，8H).
对映异构过量：94％。
例2
在搅拌下向冷却至0℃～5℃的4-硝基氧基-1-丁醇(2.0 g；14.8mmol)溶于二氯甲烷(20ml)的溶液中，加入碳酸钾(3.21g，23.2mmol)。
向该混合物中加入2-(S)-(6-甲氧基-2-萘基)-丙酰氯(3.86g，15.5mmol；对映异构过量98％)溶于二氯甲烷(22ml)的溶液，其间温度维持在10℃～15℃。加料完毕时，升高温度，并在15℃～20℃的范围保持温度10h，然后溶液进行过滤。在真空下蒸发出溶剂。残余物通过硅胶柱色谱法(洗脱液二氯甲烷)提纯，产出2-(S)-(6-甲氧基-2-萘基)-丙酸的4-硝基氧基丁酯(4.4g，12.6mmol，收率85％)，呈油状物形式。HPLC纯度：99％。1H NMR(CDCl3)δ(ppm)：1.59(d，3H，J＝7.5Hz)；1.65(m，4H)；3.85(q，1H，J＝7.5Hz)；3.91(m，2H)；4.10(m，2H)；7.1-7.7(m，芳族，8H).
对映异构过量：98％。
例3
采用甲苯作为溶剂重复例2。硝基氧基酯的收率是76％，(HPLC)纯度＞99％。对映异构过量等于98％。
例4
采用碳酸钙作为碱重复例2。获得4.6g，等于13.3mmol的硝基氧基酯(收率90％)，HPLC纯度＞99％，对映异构过量98％。
例5
采用铝硅酸钙作为碱重复例2。获得4.6g，等于13.3mmol的硝基氧基酯(收率90％)，HPLC纯度＞99％，对映异构过量98％。
例6
在搅拌下向冷却至0℃～5℃温度的4-硝基氧基-1-丁醇(2.0g；14.8mmol)溶于二氯甲烷(20ml)的溶液中，加入碳酸钾(3.21g，23.2mmol)。
向该混合物中加入2-(S)-(6-甲氧基-2-萘基)-丙酰氯(3.86g，15.5mmol；对映异构过量98％)溶于二氯甲烷(22ml)的溶液，其间温度维持在10℃～15℃。加料完毕时，升高温度，并在15℃～20℃的范围保持温度10h，然后溶液进行过滤。向溶液中加入水(1ml)和N，N-二甲基甲酰胺(2ml)并在室温下维持搅拌3h。结束时分离出有机相，以水洗涤并通过碳酸钾板进行过滤。在真空下蒸发出溶剂，获得4.1g，相当于11.8mmol酯(收率80％)，呈油状物形式，HPLC纯度＞99％，对映异构过量：98％。
例7(对比例)
采用三乙胺作为碱重复例2。反应后获得的混合物进行分析以评估对映异构过量，结果是80％。
例8(对比例)
采用二异丙基乙胺作为碱重复例2。反应后获得的混合物进行分析以评估对映异构过量，结果是76％。
例9(对比例)
采用N-甲基吗啉作为碱重复例2。反应后获得的混合物进行分析以评估对映异构过量，结果是56％。
Claims (5)
1.一种制取对映异构过量高于或等于97％，优选高于或等于98％的2-(S)-(6-甲氧基-2-萘基)-丙酸硝基氧基烷基酯的方法，其特征在于，通式A-Hal的2-(S)-(6-甲氧基-2-萘基)-丙酸的酰卤，其中A是该酸的酰基残基，在惰性有机溶剂中、在无机碱存在下与脂族硝基氧基链烷醇HO-Y-ONO2起反应，其中Y具有下列含义之一：
-线型或任选地支化的C1～C20，优选C2～C5亚烷基，或
-亚环烷基，其环具有3～8个碳原子，优选5～7个碳原子，所述亚环烷基任选地被一个或两个上面规定的亚烷基，和/或一个或多个烷基基团所取代，其链中的碳原子数如同上面对亚烷基的规定；
-环上具有5或6个碳原子的芳族残基，所述芳族残基任选地被一个或两个上面规定的亚烷基，和/或一个或多个烷基基团所取代，其链中的碳原子数如同上面对亚烷基的规定，或者被一个-COOH基团所取代；
-(T)p-(CH2-CH(ONO2)-CH2O)nf′-(T)-，T是上面规定的亚烷基，而p是等于0或1的整数，亚烷基具有上面提到的含义，nf′是1～6，优选1～4的整数；
结果生成与通式A-O-Y-ONO2对应的2-(S)-(6-甲氧基-2-萘基)-丙酸硝基氧基烷基酯，其中A和Y如同上面的规定。
2.权利要求1的方法，其中按摩尔计，脂族硝基氧基醇的用量相对于酰卤用量介于1～2，优选1.2～1.5。
3.权利要求1和2的方法，其中无机碱是碱金属和碱土金属的氢氧化物、氧化物、碳酸盐和碳酸氢盐、硅酸盐、铝硅酸盐，或者属于族IIB，优选锌，或属于族IIIa或IVa，优选锡的金属的氢氧化物、氧化物、碳酸盐和碳酸氢盐。
4.权利要求1～3的方法，其中无机碱用量，按与酰卤用量的摩尔比计介于1～2，优选1.2～1.5。
5.权利要求1～4的方法，其中反应在-20℃～50℃，优选0℃～20℃的温度进行。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1999MI001753A IT1313596B1 (it) | 1999-08-04 | 1999-08-04 | Processo per la preparazione di nitrossialchil esteri del naproxene |
| ITMI99A001753 | 1999-08-04 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100427475C (zh) * | 2006-11-30 | 2008-10-22 | 华南理工大学 | 萘普生-2-芳基吗啉乙酯及其制备方法与应用 |
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| CA2348741C (en) | 1998-10-30 | 2010-04-20 | Nitromed Inc. | Nitrosasted and nitrosylated nonsteroidal antiinflammatory compounds, comositions and methods of use |
| CA2432642A1 (en) | 2000-12-21 | 2002-08-08 | Subhash P. Khanapure | Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use |
| US20050234123A1 (en) * | 2001-11-27 | 2005-10-20 | Aldo Belli | Process |
| US7220749B2 (en) | 2002-06-11 | 2007-05-22 | Nitromed, Inc. | Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use |
| US7163958B2 (en) | 2002-07-03 | 2007-01-16 | Nitromed Inc. | Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use |
| AU2003261281A1 (en) | 2002-07-29 | 2004-02-16 | Nicox S.A. | Cyclooxygenase- 2 selective inhibitors, compositions and methods of use |
| ITMI20021861A1 (it) * | 2002-08-29 | 2004-02-29 | Nicox Sa | Procedimento di sintesi di nitrossialchilesteri di acidi carbossilici, intermedi impiegabili in detto procedimento e loro preparazione. |
| ITMI20022409A1 (it) * | 2002-11-14 | 2004-05-15 | Dinamite Dipharma S P A | Procedimento per la purificazione di 1, 4-butandiolo mononitrato. |
| CA2641816C (en) * | 2006-02-03 | 2016-01-05 | Nicox S.A. | Use of nitrooxyderivative of drug for the treatment of muscular dystrophies |
| EP2170803A1 (en) * | 2007-06-28 | 2010-04-07 | Nicox S.A. | Process for preparing 1,4-butandiol mononitrate |
| WO2009149053A2 (en) * | 2008-06-02 | 2009-12-10 | Dr. Reddy's Laboratories Ltd. | Naproxcinod process and solid dispersion |
| ITRM20080325A1 (it) * | 2008-06-20 | 2009-12-21 | Nicox Sa | Metodo per purificare 4-(nitroosi)butil(2s)-2-(6-metossi-2-naftil) propanoato |
| TW201139337A (en) | 2010-03-31 | 2011-11-16 | Lonza Ag | Process for the production of esters of nitric acid |
| TWI417276B (zh) | 2011-03-01 | 2013-12-01 | Everlight Chem Ind Corp | ２-（ｓ）-（６-甲氧基-２-萘基）-丙酸之酸酐衍生物、其製法暨及其用途 |
| CA2897571C (en) | 2013-01-21 | 2018-12-18 | Apparao Satyam | Nitric oxide releasing prodrugs of therapeutic agents containing at least one carboxylic acid group |
| EP4103171A1 (en) | 2020-02-10 | 2022-12-21 | Nicox S.A. | Method for treating vaso occlusive crises associated with sickle cell disease |
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| JPS57145841A (en) * | 1981-03-05 | 1982-09-09 | Nissan Chem Ind Ltd | L-menthyl naphthylpropionate and its preparation |
| IT1243367B (it) | 1990-07-26 | 1994-06-10 | Italfarmaco Spa | Derivati acidi benzoici sostituiti ad attivita' cardiovascolare |
| ATE168986T1 (de) * | 1993-10-06 | 1998-08-15 | Nicox Sa | Salzetersaüreester mit entzündungshemmender und/oder schmerzlindernder wirkung und verfahren zu deren herstellung |
| WO1995030641A1 (en) | 1994-05-10 | 1995-11-16 | Nicox S.A. | Nitro compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic acitivities |
| US5703073A (en) * | 1995-04-19 | 1997-12-30 | Nitromed, Inc. | Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs |
| CN1144092A (zh) * | 1995-08-25 | 1997-03-05 | 蔡雄 | 可释放一氧化氮的新型非类固醇类抗炎药、它们的制备方法和用途 |
| WO1997013519A1 (en) * | 1995-10-09 | 1997-04-17 | Russinsky Limited | Esters of cyclooxygenase inhibitors and terpene derivatives as pharmaceutical products |
| IT1276071B1 (it) * | 1995-10-31 | 1997-10-24 | Nicox Ltd | Compositi ad attivita' anti-infiammatoria |
| FR2757159B1 (fr) | 1996-12-12 | 1999-12-17 | Hoechst Marion Roussel Inc | Nouveaux derives nitres analgesiques, anti-inflammatoires et anti-thrombotiques, leur procede de preparation, leur application comme medicaments |
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