CN102442908A - Intermediate and method for preparing naproxcinod - Google Patents
Intermediate and method for preparing naproxcinod Download PDFInfo
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- CN102442908A CN102442908A CN2010105068657A CN201010506865A CN102442908A CN 102442908 A CN102442908 A CN 102442908A CN 2010105068657 A CN2010105068657 A CN 2010105068657A CN 201010506865 A CN201010506865 A CN 201010506865A CN 102442908 A CN102442908 A CN 102442908A
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- dibromobutane
- alkali metal
- xinuo
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- JYMHKEJDJZFUGD-KRWDZBQOSA-N C[C@H](C(OCCCCBr)=O)c1ccc(cc(c(C[BrH]CCCCBr)c2)OC)c2c1 Chemical compound C[C@H](C(OCCCCBr)=O)c1ccc(cc(c(C[BrH]CCCCBr)c2)OC)c2c1 JYMHKEJDJZFUGD-KRWDZBQOSA-N 0.000 description 1
- 0 C[C@](C(O*)=O)c1ccc(cc(cc2)OC)c2c1 Chemical compound C[C@](C(O*)=O)c1ccc(cc(cc2)OC)c2c1 0.000 description 1
Abstract
The invention provides an intermediate and a method for preparing naproxcinod. The method comprises the following steps: reacting naproxen or pharmaceutical acceptable salts thereof with dibromobutane to obtain (S) - 2 - (6 - methoxy - 2 - naphthyl) - propionic acid -4 - bromo butyl, and then preparing the naproxcinod by nitrate esterification. According to the method, the raw materials are easy to obtain, the operation is simple and convenient, the product yield is high and the purity is good. The method is suitable for mass production.
Description
Technical field
The present invention relates to the medical chemistry field, particularly, the present invention relates to a kind of preparation NSAIDs naphthalene Pu Xinuo midbody and method.
Background technology
Naphthalene Pu Xinuo (naproxc inod); Chemical name (S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-nitroxide butyl ester; Being the prodrug of Naproxen Base ((+)-Alpha-Methyl-6-methoxyl group-2-naphthylacetic acid), is first COX suppressor factor nitric oxide donors compound of French Nicox company.Naproxen Base is the nonsteroidal antiinflammatory and analgesic medicine, its anti-inflammatory, analgesic, analgesic activity is respond well, widespread use in the world at present becomes the main antipyretic and analgesic and one of the nonprescription drugs that is in great demand most in the whole world.But in recent years; The cardiovascular side effects of NSAIDs is by pay attention to day by day; U.S. FDA had been issued about careful warning with the anti-inflammatory drug Naproxen Base in 2004; Declare in the research process that enlarges indication about this medicine, to find, take cardiovascular diseases and the apoplexy probability that this medicine will increase the patient more than 10 days continuously, the restriction that this is very big its use.Naphthalene Pu Xinuo is Naproxen Base-NO compound donator, and NO is an endogenous compound, and it is gastrointestinal tract mucous to have significant protection, keeps antiotasis, suppresses thrombocyte, leukocytic gathering, prevents thrombosis and improves sanguimotor effect.Research shows that NO donor (promptly having the molecule or the group that discharge the NO ability) has the untoward reaction (like gi tract and cardiovascular adverse effects) of reduction NSAIDs and the characteristics of increase NSAIDs curative effect (increasing like anti-platelet activity) with the nitric oxide donors non-steroidal anti-inflammatory drugs (NO-NSAID) that the NSAIDs coupling generates.Research shows; Naphthalene Pu Xinuo is similar with Naproxen Base (naproxen) to the restraining effect of cyclooxygenase (COX); But there are not the latter's the gi tract infringement and untoward reaction (the Acta Pharmaceutica Sinica Acta Pharma-ceuticaSinica 2007,42 (4): 352-357) of cardiovascular aspect
Naphthalene Pu Xinuo metabolism in vivo is Naproxen Base and discharges NO, the performance anti-inflammatory action.Research shows that Naproxen Base has R and S configuration, and wherein the S configuration has pharmacologically active, therefore, and for guaranteeing anti-inflammatory activity and reduce the spinoff generation that the naphthalene Pu Xinuo for preparing high chiral purity becomes needs pharmaceutically.
The open naphthalene Pu Xinuo preparation method of WO95/09831; Comprise that Naproxen Base processes sodium salt; With synthetic (S)-2-(6-methoxyl group-2-naphthyl) the propionic acid 4-chlorobutyl ester of 1-bromo-4-chlorobutane reaction, then with Silver Nitrate prepared in reaction product, shortcoming is that chlorinated butyl ester activity is relatively poor then; Violent with the Silver Nitrate reaction conditions, be prone to produce the racemization product.And reaction not exclusively influences yield and quality product.
The open naphthalene Pu Xinuo preparation method of WO01/10814; Comprise that Naproxen Base or its acyl chlorides and 4-nitrooxy fourth-1-alcohol obtain product through the DCC condensation; Shortcoming is that very unstable being prone to of nitrooxy alkyl alcohol decomposed, and is not suitable for suitability for industrialized production, and Naproxen Base is when adopting the DCC condensation or be prepared into acyl chlorides; Chiral configuration all is prone to racemization takes place in the reaction process, thereby influences the chiral purity of finished product.
The open naphthalene Pu Xinuo preparation method of WO03/08698 comprises that Naproxen Base and the condensation under base catalysis of 4-brombutyl nitro ester obtain product, and this method shortcoming is that 4-brombutyl nitro ester need prepare at present, and is difficult for preserving.
The open naphthalene Pu Xinuo preparation method of WO03/45896 comprises Naproxen Base and 1, and the 4-butyleneglycol becomes ester to make (S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4--hydroxyl butyl ester, again through Tosyl chloride esterification and the nitrated product that makes of SODIUMNITRATE.It is all longer that this method of shortcoming respectively goes on foot the reaction times, and midbody must separate with column chromatography, operates more loaded down with trivial details.
Summary of the invention
The objective of the invention is to, a kind of preparation NSAIDs naphthalene Pu Xinuo midbody and method are provided.
Technical scheme provided by the invention is following:
Dibromobutane reaction shown in Naproxen Base shown in the formula (II) or its medicinal acceptable salt and the formula (III) obtains midbody (the S)-2-shown in the formula (I) (6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester.
The reaction formula of said reaction is as follows:
Formula (II) formula (III) formula (I)
Wherein, formula (II) R can be H, Na, K.
The midbody bromide that obtains carries out the nitre esterification with the Silver Nitrate reaction again, obtains naphthalene Pu Xinuo.
The Naproxen Base that the embodiment of the invention relates to and the reaction of dibromobutane, reaction under suitable base catalysis.Preferably described alkali is alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate and organic amine.Described alkali metal hydroxide comprises sodium hydroxide, Pottasium Hydroxide and Lithium Hydroxide MonoHydrate; Alkaline carbonate comprises salt of wormwood, yellow soda ash, verditer; Alkali metal hydrocarbonate comprises saleratus, sodium hydrogencarbonate; Organic amine comprises triethylamine, diisopropyl ethyl amine, N-methylmorpholine and pyridine.
The Naproxen Base pharmacologically acceptable salt that the embodiment of the invention relates to and the reaction of dibromobutane.Preferably described pharmaceutical salts is an an alkali metal salt.Described basic metal comprises sodium, potassium.
Preferably, the dibromobutane molar ratio shown in the Naproxen Base shown in the said formula (2) or its salt and the formula (3) is 1: 2～1: 20, is preferably 1: 5-1: 15.We find in the research, and dibromobutane must guarantee enough excessive, just can avoid the di-substituted generation of by product.
Preferably, the temperature of reaction of said method is 0-150 ℃, is preferably 20-100 ℃, is more preferably 40～70 ℃.
Compared with prior art, advantage of the present invention is:
The inventive method, raw material is easy to get, and is simple to operate, and cost is low, and good product quality is adapted to scale operation.The naphthalene Pu Xinuo that utilizes method of the present invention to obtain, yield is high, and purity is high.
Embodiment
The concrete embodiment of following reference explains the present invention.It will be appreciated by those skilled in the art that these embodiment only are used to explain the object of the invention, the scope that it does not limit the present invention in any way.
Embodiment 1(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with stirring, TM 1L flask, the adding Naproxen Base (23g, 0.1mol), and DMF300ml, add KHCO after the stirring and dissolving
3(10g, 0.1mol), room temperature reaction 4h, (43.2g 0.2mol) continues room temperature reaction 48h to add dibromobutane then.Add entry 200ml after reaction finishes, dichloromethane extraction, drying, distill light yellow oil, add the Virahol crystallization, obtain white solid 25g, yield 70%, mp32～36 ℃, HPLC >=82%.
1HNMR(CDCl
3)1.52(d，3H)，1.60～1.70(m，4H)，3.25～3.34(m，2H)，3.82(q，1H)，3.86(S，3H)，4.02～4.10(m，2H)，7.10～7.70(m，6H)。
Embodiment 2(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with the 1L flask of stirring, TM, reflux exchanger, add Naproxen Base (23g, 0.1mol) and acetone 200ml, add after the stirring and dissolving dibromobutane (64.8g, 0.3mol), triethylamine 5ml, 55～60 ℃ of reaction 8h.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 27g, yield 75%, mp32～36 ℃, HPLC >=85%.
Embodiment 3(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with the 1L flask of stirring, TM, reflux exchanger, (23g 0.1mol) and acetonitrile 300ml, adds K after the stirring and dissolving to add naproxen sodium
2CO
3(13.8g, 0.1mol), dibromobutane (216g, 1.0mol) back flow reaction 4h.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 32g, yield 89%, mp32～36 ℃, HPLC >=92%.
Embodiment 4(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with the 1L flask of stirring, TM, reflux exchanger, add Naproxen Base (23g, 0.1mol) and acetonitrile 200ml, Na
2CO
3(10.6g, 0.1mol), 55～60 ℃ of reaction 2h add dibromobutane (216g, 1.0mol) back flow reaction 2h then.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 34g, yield 95%, mp32～36 ℃, HPLC >=92%.
Embodiment 5(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with stirring, TM 1L flask, the adding naproxen sodium (25.2,0.1mol), and DMF300ml, adding dibromobutane (324g, 1.5mol) room temperature reaction 24h stirred.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 32g, yield 89%, mp32～36 ℃, HPLC >=95%.
Embodiment 6(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with stirring, TM, reflux exchanger 1L flask, add naproxen sodium (25.2,0.1mol) and acetonitrile 300ml, add dibromobutane (432g, 2.0mol) back flow reaction 2h.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 32g, yield 89%, mp32～36 ℃, HPLC >=98%.
Embodiment 7(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with the 1L flask of stirring, TM, the adding Naproxen Base (23g, 0.1mol), and DMF200ml, (5.6g, 0.1mol), stirring at room 4h adds dibromobutane (216g, 1.0mol) room temperature reaction 24h then to add KOH after the stirring and dissolving.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 32g, yield 89%, mp32～36 ℃, HPLC >=92%.
Embodiment 8(S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester
In being furnished with stirring, TM, reflux exchanger 1L flask, (23g, 0.1mol) with acetonitrile 200ml, (4.0g, 0.1mol), 55～60 ℃ of reaction 2h add dibromobutane (216g, 1.0mol) back flow reaction 2h to NaOH then to add Naproxen Base.Decompression steams solvent and excessive dibromobutane, light yellow oil, add the Virahol crystallization, obtain white solid 32g, yield 89%, mp32～36 ℃, HPLC >=92%.。
Embodiment 9Naphthalene Pu Xinuo
(S)-(36g 0.1mol) is dissolved in the acetonitrile (30ml) 2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester, adds Silver Nitrate (17g, acetonitrile solution 50ml 0.1mol), lucifuge stirring at room 2h, evaporated under reduced pressure solvent.Add methylene dichloride 90ml in the residuum, stir 10min, filter the filtrate decompression solvent evaporated.Virahol-THF-10 ℃ of crystallization, filter at low temperature obtains faint yellow solid.
1HNMR(CDCl
3)1.57(d，3H)，1.60～1.70(m，4H)，3.82(q，1H)，3.90(S，3H)，4.04～4.10(m，2H)，4.30(t，2H)，7.10～7.70(m，6H)。
Claims (5)
1. the method for naphthalene Pu Xinuo intermediate preparation shown in the formula (I); It is characterized in that; This method comprises reacts the dibromobutane shown in the Naproxen Base shown in the formula (II) or its salt and the formula (III); Obtain midbody (S)-2-(6-methoxyl group-2-naphthyl) propionic acid 4-brombutyl ester (I), the nitre esterification prepares naphthalene Pu Xinuo then.
Formula (II) formula (III) formula (I)
Wherein, formula (II) R
1And R
2Be hydrogen, sodium or potassium
2. method according to claim 1 is characterized in that, the dibromobutane molar ratio shown in the Naproxen Base shown in the said formula (II) or its salt and the formula (III) is 1: 2～1: 20, is preferably 1: 5～1: 15.
3. method according to claim 1 is characterized in that said being reflected in the non-protonic solvent reacted; The protic solvent of said reaction is amides, ketone, nitrile, comprises N, dinethylformamide, acetone, acetonitrile; Further preferably, said reaction solvent is an acetonitrile.
4. method according to claim 1 is characterized in that, preferably described alkali is alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate and organic amine.Described alkali metal hydroxide comprises sodium hydroxide, Pottasium Hydroxide and Lithium Hydroxide MonoHydrate; Alkaline carbonate comprises salt of wormwood, yellow soda ash, verditer; Alkali metal hydrocarbonate comprises saleratus, sodium hydrogencarbonate; Organic amine comprises triethylamine, diisopropyl ethyl amine, N-methylmorpholine and pyridine.
5. according to each described method among the claim 1-8, it is characterized in that the temperature of reaction of said method is 0-150 ℃, be preferably 20-100 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058861A (en) * | 2013-01-08 | 2013-04-24 | 安徽赛诺医药化工有限公司 | New synthetic method of naproxcinod intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780495A (en) * | 1993-10-06 | 1998-07-14 | Nicox S.A. | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| WO2000061537A2 (en) * | 1999-04-13 | 2000-10-19 | Nicox S.A. | Pharmaceutical compounds |
| WO2001012584A2 (en) * | 1999-08-12 | 2001-02-22 | Nicox S.A. | Pharmaceutical compounds |
| CN101255117A (en) * | 2008-04-03 | 2008-09-03 | 北京润德康医药技术有限公司 | Non-steroidal antiphlogiston prodrug with nitric oxide donor and preparation method thereof |
| WO2009149053A2 (en) * | 2008-06-02 | 2009-12-10 | Dr. Reddy's Laboratories Ltd. | Naproxcinod process and solid dispersion |
-
2010
- 2010-10-14 CN CN2010105068657A patent/CN102442908A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5780495A (en) * | 1993-10-06 | 1998-07-14 | Nicox S.A. | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| WO2000061537A2 (en) * | 1999-04-13 | 2000-10-19 | Nicox S.A. | Pharmaceutical compounds |
| WO2001012584A2 (en) * | 1999-08-12 | 2001-02-22 | Nicox S.A. | Pharmaceutical compounds |
| CN101255117A (en) * | 2008-04-03 | 2008-09-03 | 北京润德康医药技术有限公司 | Non-steroidal antiphlogiston prodrug with nitric oxide donor and preparation method thereof |
| WO2009149053A2 (en) * | 2008-06-02 | 2009-12-10 | Dr. Reddy's Laboratories Ltd. | Naproxcinod process and solid dispersion |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058861A (en) * | 2013-01-08 | 2013-04-24 | 安徽赛诺医药化工有限公司 | New synthetic method of naproxcinod intermediate |
| CN103058861B (en) * | 2013-01-08 | 2015-03-18 | 安徽赛诺医药化工有限公司 | New synthetic method of naproxcinod intermediate |
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Application publication date: 20120509 |