CN103058861A - New synthetic method of naproxcinod intermediate - Google Patents
New synthetic method of naproxcinod intermediate Download PDFInfo
- Publication number
- CN103058861A CN103058861A CN2013100059180A CN201310005918A CN103058861A CN 103058861 A CN103058861 A CN 103058861A CN 2013100059180 A CN2013100059180 A CN 2013100059180A CN 201310005918 A CN201310005918 A CN 201310005918A CN 103058861 A CN103058861 A CN 103058861A
- Authority
- CN
- China
- Prior art keywords
- vitriol oil
- reaction
- adds
- sodium hydroxide
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of the pharmaceutical chemistry, especially relates to an esterification and etherification method using concentrated sulfuric acid as a catalyst, and discloses a synthetic method of a naproxcinod intermediate (s-2-(6-methoxy-2-naphthyl)-4-chlorobutylpropionate). The synthetic method comprises the following steps: heating naproxen for dissolving naproxen in cyclohexane, adding 4-chloro-1-butanol, adding concentrated sulfuric acid at 0-5DEG C for the first time, carrying out refluxing and water separation, cooling to 5DEG C 1-4h later, adding the concentrated sulfuric acid for the second time, and carrying out refluxing and water separation for 1-2h; cooling to room temperature, adding 2% sodium hydroxide to the obtained reactant for washing 3 times, and washing with water 3 times; and drying through anhydrous magnesium sulfate, filtering, and carrying out reduced pressure drying of the obtained filtrate until there is no solvent in order to obtain white crystals. Cyclohexane used in the method is friendly to the environment and is harmless to the health of employee, so the method is very suitable for the mass production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, relate in particular to a kind of secondary and use the vitriol oil to do esterification and the etherification method of catalyzer, the method can reduce discharging, reduce Financial cost and bring strong upturn to industry energy conservation, simultaneously environment protection also is significant.
Background technology
Many drug molecules have esterified group or etherificate group, and these groups are improved the former drug side effect that stomach is stimulated that originally contains carboxyl or hydroxyl.This just needs esterification and etherificate to be translated into ester or ether, makes it to bring into play curative effect and no longer includes side effect.
The usefulness noxious solvent that existing esterification and etherification method have such as benzene, toluene, methyl-sulfate, the phase-transfer catalyst of using costliness that has etc.The most common most economical vitriol oil and cyclohexane and we adopt, both nuisanceless, very cheap be easy to get and cyclohexane can recycle again, a small amount of sulfuric acid can be with in the sodium hydroxide and discharging.
But abandoned the vitriol oil that convenience is easy to get because of the product impurity content exceeding index at a lot of classical esterification and etherification reactions, and the reaction that we propose there are 3 generations that can avoid impurity:
1, low temperature drips the overheated impurity that causes of local overrich that the vitriol oil can be avoided the vitriol oil;
2, drip at twice the vitriol oil, can impel the impact that originally reacts completely and avoided the vitriol oil;
3, use low boiling point solvent, make in can the situation of not high in temperature (80 ℃) to react completely, and can successfully remove wherein moisture, reaction yield and quality product are greatly improved, also can make industry energy conservation reduce discharging, reduce Financial cost.
College Of Pharmacy, Hebei Medical University Cao Liang, Li Hui in 2009 etc. the paper of Chinese Journal of Pharmaceuticals "
HCT 3012 synthetic " to have adopted benzene be the method esterification of solvent, only product fusing point and EMI-MS have been done and chemically examined that (melting range is longer, can only be qualitative, not not quantitatively), and its purity is not examined, and its solvent has larger toxicity to the human blood system, can't reach the requirement of large production.We test with reference to the document, and product purity only is 82%.This may be to produce all polymictic results owing to once add the relatively large vitriol oil in reaction.
Neat " development of nylon acid diethyl " of founding the state and delivering in Hebei chemical industry 2 phases in 2003 just groped general condition such as proportioning, the temperature etc. of esterification; " research of Synthesis of Benzyl Butyrate by Phase Transfer Catalysis " that chemical intermediate guide 23 phases in 2005 deliver, before test, also used the vitriol oil to make catalyzer, think that esterification yied is low, poor product quality, aftertreatment technology complexity, carry out esterification and have to make catalyzer, butyric acid and phenylcarbinol take the phase-transfer catalyst of costliness as raw material, this mainly is that the author uses the vitriol oil to do catalyzer institute extremely once; " research of silica gel load sulfuric acid catalysis esterification " that Li Jianwei, girth intelligence were delivered in application chemical industry 6 phases in 2005 has just found this problem, the vitriol oil is loaded on the silica gel, avoided esterification yied low, the series of problems of poor product quality, aftertreatment technology complexity, his yield is not high yet, only have 70%, and we comprise the Naproxen Base calculation of reclaiming with 2% sodium hydroxide, yield can reach 94-96%.
Our invention novelty is to use a kind of cheap cost, and simple technique can reach the effect of using expensive phase-transfer catalyst just can reach equally.At first, esterification and etherificate are a kind of reversible chemical reactions, and suitable activation energy is wanted in positive reaction.Experiment shows that reaction reaches a new balance behind minute water, continues reaction of propagation time and rising temperature of reaction, only can increase by product.In solvent, reach balance behind minute water during formation reaction thing 75%～80%, we will react when just reaching balance, increase catalyzer, esterification will obtain than before more completely catalysis, under relatively many catalyst actions, the reaction meeting is carried out to the positive reaction direction, and can reach gradually a new balance.Because it is shorter that reaction is subject to the influence time of larger sulfuric acid concentration, for the first time esterification acidity is not strong, and side reaction occurs less, and last whole reaction is tending towards complete.
Summary of the invention
The invention provides a process stabilizing, easy and simple to handle, yield is high, be fit to the vitriol oil esterification process of suitability for industrialized production, reduces discharging, reduces Financial cost to industry energy conservation and bring strong upturn, simultaneously environment protection also is significant.
A kind of HCT 3012 intermediate (s-2-(6-methoxyl group-2-naphthyl) propionic acid-4-neoprene ester) synthetic method may further comprise the steps:
1, the Naproxen Base heating is dissolved in hexanaphthene, adds 4-chloro-n-butyl alcohol, under 0-5 ℃ condition, add the vitriol oil for the first time, reflux and minute water;
2,1-4 hour afterreaction of reaction reaches balance, is cooled to 5 ℃, adds the vitriol oil for the second time, backflow and minute water 1 hour;
3, be chilled to room temperature, the sodium hydroxide washing of reactant adding 2% 3 times washes with water 3 times again.Through anhydrous magnesium sulfate drying, filter, the filtrate decompression dry solvent gets white crystals to doing.Then the 1st solution acid adding of 2% sodium hydroxide use the cyclohexane extracting to pH4, and solvent evaporated obtains the Naproxen Base raw material of about 6-8% charging capacity, with the more economic environmental protection of raw material recycling.
Chemical equation of the present invention is as follows:
The vitriol oil that the present invention mentions is industrial acids, content 〉=95%.
Cyclohexane mother liquor used in the present invention must recycling use.Its concrete steps are: vacuum and low temperature reclaims, and then measures out cut with Moisture Meter and reaches 95% and reclaim use when above.
Embodiment
The below sets forth the present invention with example:
1, the Naproxen Base heating with 100g is dissolved in the 600ml hexanaphthene, adds 4-chloro-n-butyl alcohol 50g, at the 0-5 ℃ of adding vitriol oil 7g first time, refluxes and minute water, is chilled to 5 ℃ after 2 hours, adds vitriol oil 3g for the second time, and backflow also divided water 1 hour.Be chilled to room temperature, reactant adds respectively 2% sodium hydroxide 200ml washing 3 times, more respectively water 200ml washing 3 times.Through anhydrous magnesium sulfate drying, filter, the filtrate decompression dry solvent gets white crystals 127g to doing.Sodium hydroxide with 3 times 2% after reaction finishes washs, and primary sodium hydroxide washing lotion adds dilute hydrochloric acid and is transferred to pH4, then uses the cyclohexane extracting, and solvent evaporated is recovered to the raw material Naproxen Base of 5g.Yield 95%, HPLC measures content 92%.
2, the Naproxen Base heating with 100g is dissolved in the 600ml hexanaphthene, adds 4-chloro-n-butyl alcohol 50g, at the 0-5 ℃ of adding vitriol oil 7g first time, refluxes and minute water, is chilled to 5 ℃ after 2 hours, adds vitriol oil 3g for the second time, and backflow also divided water 1 hour.Be chilled to room temperature, reactant adds respectively 2% sodium hydroxide 200ml washing 3 times, more respectively water 200ml washing 3 times.Through anhydrous magnesium sulfate drying, filter, the filtrate decompression dry solvent gets white crystals 126g to doing.Sodium hydroxide with 3 times 2% after reaction finishes washs, and primary sodium hydroxide washing lotion adds dilute hydrochloric acid and is transferred to pH4, then uses the cyclohexane extracting, and solvent evaporated is recovered to the raw material Naproxen Base of 8g.Yield 96%, HPLC measures content 90%.
3, the Naproxen Base heating with 100g is dissolved in the 600ml hexanaphthene, adds 4-chloro-n-butyl alcohol 50g, at the 0-5 ℃ of adding vitriol oil 7g first time, refluxes and minute water, is chilled to 5 ℃ after 2 hours, adds vitriol oil 3g for the second time, and backflow also divided water 1 hour.Be chilled to room temperature, reactant adds respectively 2% sodium hydroxide 200ml washing 3 times, more respectively water 200ml washing 3 times.Through anhydrous magnesium sulfate drying, filter, the filtrate decompression dry solvent gets white crystals 125g to doing.Sodium hydroxide with 3 times 2% after reaction finishes washs, and primary sodium hydroxide washing lotion adds dilute hydrochloric acid and is transferred to pH4, then uses the cyclohexane extracting, and solvent evaporated is recovered to the raw material Naproxen Base of 5g.Yield 94%, HPLC measures content 90%.
Claims (5)
1. a new preparation process HCT 3012 intermediate (s-2-(6-methoxyl group-2-naphthyl) propionic acid-4-neoprene ester) is characterized in that the operation steps of the method is as follows:
(1) the Naproxen Base heating is dissolved in hexanaphthene, adds 4-chloro-n-butyl alcohol, is cooled to low temperature, drips the vitriol oil, refluxes and minute water;
(2) after reaction reaches balance, be cooled to low temperature, drip again the vitriol oil, reflux and minute water;
(3) after reaction is finished, be cooled to room temperature, the sodium hydroxide washing of reactant adding 2% 3 times washes with water 3 times again, through anhydrous magnesium sulfate drying, filters, and filtrate decompression is dry, gets white crystals.
2. preparation method as described in claim 1 is characterized in that the weight ratio of Naproxen Base, 4-chloro-n-butyl alcohol, the vitriol oil is Naproxen Base: 4-chloro-n-butyl alcohol: the vitriol oil=2:1:0.2.
3. preparation method as described in claim 1, the amount that it is characterized in that the vitriol oil that adds in the step (1) be in the whole reaction vitriol oil amount 70%, the amount of the vitriol oil that adds in the step (2) be in the whole reaction vitriol oil amount 30%.
4. preparation method as claimed in claim 1 is characterized in that dripping in step (1) and the step (2) the front solution temperature of the vitriol oil and is 0-5 ℃.
5. preparation method as claimed in claim 1, it is characterized in that the sodium hydroxide washing of usefulness after reaction is finished in the step (3) 3 times 2%, primary sodium hydroxide washing lotion adds dilute hydrochloric acid and is transferred to pH4, then uses the cyclohexane extracting, solvent evaporated is recovered to the Naproxen Base raw material of 6-8% charging capacity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310005918.0A CN103058861B (en) | 2013-01-08 | 2013-01-08 | New synthetic method of naproxcinod intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310005918.0A CN103058861B (en) | 2013-01-08 | 2013-01-08 | New synthetic method of naproxcinod intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103058861A true CN103058861A (en) | 2013-04-24 |
| CN103058861B CN103058861B (en) | 2015-03-18 |
Family
ID=48101796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310005918.0A Active CN103058861B (en) | 2013-01-08 | 2013-01-08 | New synthetic method of naproxcinod intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103058861B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995009831A1 (en) * | 1993-10-06 | 1995-04-13 | Nicox S.A. | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| WO2009149053A2 (en) * | 2008-06-02 | 2009-12-10 | Dr. Reddy's Laboratories Ltd. | Naproxcinod process and solid dispersion |
| CN101874014A (en) * | 2008-06-20 | 2010-10-27 | 尼科克斯公司 | Method for purifying 4-(nitrooxy)butyl(2s)-2-(6-methoxy-2-naphthyl)propanoate |
| CN102442908A (en) * | 2010-10-14 | 2012-05-09 | 天津药物研究院 | Intermediate and method for preparing naproxcinod |
-
2013
- 2013-01-08 CN CN201310005918.0A patent/CN103058861B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995009831A1 (en) * | 1993-10-06 | 1995-04-13 | Nicox S.A. | Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation |
| WO2009149053A2 (en) * | 2008-06-02 | 2009-12-10 | Dr. Reddy's Laboratories Ltd. | Naproxcinod process and solid dispersion |
| CN101874014A (en) * | 2008-06-20 | 2010-10-27 | 尼科克斯公司 | Method for purifying 4-(nitrooxy)butyl(2s)-2-(6-methoxy-2-naphthyl)propanoate |
| CN102442908A (en) * | 2010-10-14 | 2012-05-09 | 天津药物研究院 | Intermediate and method for preparing naproxcinod |
Non-Patent Citations (1)
| Title |
|---|
| 曹亮等: "萘普西诺的合成", 《中国医药工业杂志》, vol. 40, no. 9, 31 December 2009 (2009-12-31) * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103058861B (en) | 2015-03-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101845362A (en) | Method for gathering oleic acid from tea-seed oil | |
| CN101863784B (en) | Methods for preparing and extracting betaine and betaine hydrochloride | |
| CN103274959B (en) | Synthetic method of cooling agent N-, 2, 3-trimethyl-2-isopropyl butyrylamide | |
| CN103613501A (en) | Method for preparing tributyl citrate by taking macroporous strong-acid cation exchange resin as catalyst | |
| CN101348451B (en) | Preparation of medicinal D,L-2-hydroxy-4-methylthio calcium butyrate | |
| CN111689878A (en) | Preparation process of trifluoromethanesulfonic anhydride | |
| CN104311413A (en) | Method for synthesis of ferulic acid ester by solid acid catalysis | |
| CN110527700A (en) | A kind of vitamin D3Method of purification | |
| CN102911235A (en) | Method for producing ursodesoxycholic acid by using chenodeoxycholic acid as raw material | |
| CN103554206A (en) | Method for separating hyocholic acid from pig's bile | |
| CN101307075A (en) | Method for preparing L-ascorbate-2-phosplate magnesium | |
| CN105294797A (en) | Preparation method for methyltestosterone | |
| CN101367722B (en) | Preparation of pyrethroid midbody | |
| CN103058861B (en) | New synthetic method of naproxcinod intermediate | |
| CN110885287B (en) | Synthetic method for synthesizing isooctyl salicylate from sodium salicylate | |
| CN103980481B (en) | The preparation method of watermiscible vitamin E | |
| CN107286218A (en) | A kind of preparation method of new oleanane-type triterpene saponin derivative | |
| CN104211674A (en) | Industrialized production method for producing high-content natural vitamin E by utilizing hydrolysis reduction process | |
| CN103665063A (en) | Method for preparing isopropyl-beta-D-isopropylthiogalactoside | |
| CN107129466B (en) | Synthesis method of 4-chloro-3-methoxy-2-methylpyridine-N-oxide | |
| CN103539829A (en) | Method for extracting ursodesoxycholic acid | |
| CN103408407A (en) | Isoeugenol synthetizing method | |
| CN103588825B (en) | A kind of method of benzaldehyde dimethyl acetal protection D-glucosamine derivant | |
| CN105294428A (en) | 2-adamantanecarboxylic acid and 1-adamantane methanol separation and purification method | |
| CN113200917B (en) | Purification method of 4-aminoantipyrine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: ANHUI SAINUO PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: ANHUI SAINUO PHARMACEUTICAL CHEMICALS CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 238251 Anhui Province, Ma'anshan city and county of Wujiang fine chemical base Anhui cinorch Pharmaceutical Chemical Co. Ltd. Patentee after: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee after: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. Address before: 238251 Anhui Province, Ma'anshan city and county of Wujiang fine chemical base Anhui cinorch Pharmaceutical Chemical Co. Ltd. Patentee before: FarmaSino Pharmaceuticals (Anhui) Co.,Ltd. Patentee before: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 238251 Anhui sanuo Pharmaceutical Chemical Co., Ltd., Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee after: FARMASINO PHARMACEUTICAL (ANHUI) Co.,Ltd. Patentee after: Jiangsu Kaiyuan Pharmaceutical Co.,Ltd. Address before: 238251 Anhui sanuo Pharmaceutical Chemical Co., Ltd., Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee before: FARMASINO PHARMACEUTICAL (ANHUI) Co.,Ltd. Patentee before: FARMASINO PHARMACEUTICALS (JIANGSU) Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210927 Address after: 210033 9th floor, F6 building, No.9, Weidi Road, Qixia District, Nanjing City, Jiangsu Province Patentee after: SKYRUN PHARMA Co.,Ltd. Address before: 238251 Anhui sanuo Pharmaceutical Chemical Co., Ltd., Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee before: FARMASINO PHARMACEUTICAL (ANHUI) Co.,Ltd. Patentee before: Jiangsu Kaiyuan Pharmaceutical Co.,Ltd. |
|
| TR01 | Transfer of patent right |