CN105218351A - A kind of synthetic method of loxoprofen sodium - Google Patents
A kind of synthetic method of loxoprofen sodium Download PDFInfo
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- CN105218351A CN105218351A CN201510743097.XA CN201510743097A CN105218351A CN 105218351 A CN105218351 A CN 105218351A CN 201510743097 A CN201510743097 A CN 201510743097A CN 105218351 A CN105218351 A CN 105218351A
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- loxoprofen sodium
- synthetic method
- dimethyl adipate
- cyclization
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention discloses a kind of synthetic method of loxoprofen sodium, comprise the steps: a) to be starting raw material with dimethyl adipate; B) adding certain alkali makes described dimethyl adipate cyclization generate 2-oxocyclopentyl methyl-formiate intermediate; C) dimethyl adipate after adding certain organic solvent involutive ring carries out agitation and dilution; D) adopt the methyl alcohol produced during underpressure distillation removing cyclization, and promote that cyclization reaction forward is carried out; E) after the complete cyclization reaction of dimethyl adipate, add 2-(4-2-bromomethylphenyl) propionic acid, react completely to it at a certain temperature, after extraction drying, then obtain loxoprofen sodium through decarboxylation and quaternization.The intermediate that the present invention generates is without aftertreatment and separation and purification, directly react with 2-(4-2-bromomethylphenyl) propionic acid added, easy and simple to handle, reaction scheme simply, safety, environmental protection, with low cost, reaction conditions is gentle, regioselectivity is good, and conversion rate of products is higher.
Description
Technical field
The present invention relates to a kind of medical synthetic method, particularly relate to a kind of synthetic method of loxoprofen sodium.
Background technology
Loxoprofen sodium (LoxoprofenSodium) is a kind of novel non-steroidal arylprop acids actasal, has the advantages such as little, efficient, the low toxicity, side effect of oral consumption is low.Be widely used in the alleviation of osteoarthritis, rheumatoid arthritis, multiple heating and various pain symptom clinically.
Loxoprofen sodium (LoxoprofenSodium) is the novel phenylpropionic acid non-steroid antiinflammatory drug of one developed by Japanese Sankyo Co., Ltd, clinical experiment shows that it is that in current known arylprop acids medicine, analgesic effect is best, there is stronger anti-inflammatory, analgesia, antipyretic left and right, oral dosage is few, absorb fast, digestive tract side effects is little, curative effect is obviously better than other arylprop acids medicines, having listed country's 95 and 2010 years new product developments in and recommended trial-production kind, is a kind of medicine having very much development potentiality.
Synthetic method report both at home and abroad about loxoprofen sodium is more, but mainly contains following several:
Method one: with 2-(4 bromomethyl phenyl) propionic acid for raw material, by obtaining by series of steps such as condensation, hydrolysis, acidifying and neutralizations with 2-oxocyclopentyl methyl-formiate or ethyl ester.The domestic and international research method about this route is more at present, and Tian Cheng Chemical Co., Ltd. in granary realizes suitability for industrialized production at home.
Method two: be that 2-benzyl rings pentanone first prepared by raw material with cyclopentanone; again under Using Aluminium Trichloride as Catalyst with Acetyl Chloride 98Min. generation Friedel-Crafts reaction; introduce ethanoyl in benzyl contraposition, and then cyaniding obtains cyano group phosphoric acid ester, finally obtains loxoprofen sodium through the step such as hydro-reduction, hydrolysis again.There is more problem in the method, one is have ortho position by product in acetylation to produce; Two is there is the series of problems such as yield is low, condition is harsh, material toxicity is large in cyaniding and hydrogenation process.
Method three: cyclopentanone and Pyrrolidine are obtained by reacting enamine intermediates, then prepare loxoprofen sodium with 2 (4-bromomethyl phenyl) propionic acid by condensation.The subject matter that this route exists is take cyclopentanone as the complicacy that raw material prepares that enamine intermediates adds synthetic route.
Existing loxoprofen sodium synthetic method reaction scheme is comparatively complicated, and comparatively responsive to reaction conditions, regioselectivity is poor, and conversion rate of products is lower, therefore, is necessary to improve existing loxoprofen sodium synthetic method.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of synthetic method of loxoprofen sodium, and reaction scheme is simple, safety, environmental protection, with low cost, reaction conditions is gentle, and regioselectivity is good, and conversion rate of products is higher.
The present invention solves the problems of the technologies described above the synthetic method that the technical scheme adopted is to provide a kind of loxoprofen sodium, comprises the steps: a) to be starting raw material with dimethyl adipate; B) adding certain alkali makes described dimethyl adipate cyclization generate 2-oxocyclopentyl methyl-formiate intermediate; C) dimethyl adipate after adding certain organic solvent involutive ring carries out agitation and dilution; D) adopt the methyl alcohol produced during underpressure distillation removing cyclization, and promote that cyclization reaction forward is carried out; E) after the complete cyclization reaction of dimethyl adipate, add 2-(4-2-bromomethylphenyl) propionic acid, react completely to it at a certain temperature, after extraction drying, then obtain loxoprofen sodium through decarboxylation and quaternization.
The synthetic method of above-mentioned loxoprofen sodium, wherein, the alkali in described step b) is organic bases, mineral alkali or alkali metal compound.
The synthetic method of above-mentioned loxoprofen sodium, wherein, the mass ratio of described alkali, dimethyl adipate and organic solvent is 0.5:1:1 ~ 3:1:10.
The synthetic method of above-mentioned loxoprofen sodium, wherein, in described step c), organic solvent is one in methyl alcohol, ethanol, ether, methyl tertiary butyl ether, methylene dichloride, ethyl acetate, acetone, toluene, dimethylbenzene, DMF and dimethyl sulfoxide (DMSO) or its combination.
The synthetic method of above-mentioned loxoprofen sodium, wherein, the temperature of underpressure distillation in described step d) controls to be 10 DEG C ~ 100 DEG C.
The synthetic method of above-mentioned loxoprofen sodium, wherein, the temperature of described step d) underpressure distillation controls to be 30 DEG C ~ 80 DEG C, and it is 30 DEG C ~ 80 DEG C that the temperature of reaction in described step e) controls.
The synthetic method of above-mentioned loxoprofen sodium, wherein, described step e) add 20mL concentration be the dilute hydrochloric acid adjust ph of 6 moles often liter to 6-7, utilize toluene to extract.
The present invention contrasts prior art following beneficial effect: the synthetic method of loxoprofen sodium provided by the invention, reaction scheme is simple, safety, environmental protection, with low cost, reaction conditions is gentle, regioselectivity is good, conversion rate of products is higher, the 2-oxocyclopentyl methyl-formiate intermediate generated is without aftertreatment and separation and purification, directly react with 2-(4-2-bromomethylphenyl) propionic acid added, easy and simple to handle.
Accompanying drawing explanation
Fig. 1 is loxoprofen sodium building-up process schematic diagram of the present invention.
Embodiment
Below in conjunction with drawings and Examples, the invention will be further described.
Fig. 1 is loxoprofen sodium building-up process schematic diagram of the present invention.
Refer to Fig. 1, the synthetic method of loxoprofen sodium provided by the invention, comprises the steps:
Step S1: take dimethyl adipate as starting raw material;
Step S2: add certain alkali and make described dimethyl adipate cyclization generate 2-oxocyclopentyl methyl-formiate intermediate; As organic bases, mineral alkali or alkali metal compound;
Step S3: the dimethyl adipate added after certain organic solvent involutive ring carries out agitation and dilution; The mass ratio of alkali and dimethyl adipate and organic solvent is preferably between 0.5:1:1 to 3:1:10; The selection outbalance of organic solvent, can not be removed during underpressure distillation boiling point lower causing, can not boiling point is higher not easily reclaims separation when aftertreatment, had better not introduce required other the outer solvents of reaction in addition, increase cost recovery; Through many experiments, organic solvent is preferably MeOH(methyl alcohol), EtOH(ethanol), Et
2o(ether), MTBE(methyl tertiary butyl ether), DCM(methylene dichloride), EtOAc(ethyl acetate), acetone, toluene, dimethylbenzene, DMF(N, dinethylformamide) and DMSO(dimethyl sulfoxide (DMSO)) in one or its combination;
Step S4: adopt the methyl alcohol produced during underpressure distillation removing cyclization, and promote that cyclization reaction forward is carried out; During underpressure distillation, temperature controls outbalance, not easily distills too fast or excessively slow; Too fastly cause system foaming thickness, not easily stir; Cross and then cause reaction to generate 2-oxocyclopentyl methyl-formiate intermediate time lengthening slowly; The temperature of underpressure distillation controls to be 10 DEG C ~ 100 DEG C, is preferably 30 DEG C ~ 80 DEG C;
Step S5: after the complete cyclization reaction of dimethyl adipate, add 2-(4-2-bromomethylphenyl) propionic acid, make to react completely between 2-oxocyclopentyl methyl-formiate intermediate and 2-(4-2-bromomethylphenyl) propionic acid added at 30 DEG C ~ 80 DEG C temperature, obtain the precursor of loxoprofen sodium after extraction drying, then can loxoprofen sodium be obtained after decarboxylation and alkalization two-step reaction; Before extraction, adjustable system pH value is to slightly acidic, and the precursor of the loxoprofen sodium of generation is existed with carboxylic acid form; The analysis found that, if system is alkalescence, then precursor exists soluble in water with carboxylic acid sodium salt form, can not be extracted completely totally, cause yield losses by toluene; If instead PH is adjusted to strongly-acid, then other carboxylic acid impurities are had also to be extracted by toluene; The present invention through many experiments, add 20mL concentration be the dilute hydrochloric acid adjust ph of 6 moles often liter to 6-7, recycling toluene extraction, now yield is higher, and other carboxylic acid impurities's content are lower.
The synthetic method of loxoprofen sodium provided by the invention, the 2-oxocyclopentyl methyl-formiate intermediate of generation does not need purifying, but directly input is reacted with 2-(4-2-bromomethylphenyl) propionic acid added.Main consideration is as follows: in treating processes before, 1, pass through the adjustment of pH value by most of Impurity removal, and other impurity can be removed after directly carrying out next step reaction after overweight crystallization and purification; If carry out reaction after 2 purifying again to waste time and energy; 3, the precursor boiling point generated is higher, also not easily purifying.
Embodiment 1
1000mL tetra-mouthfuls of vials, temperature thermometer in being equipped with, condenser and mechanical stirring, 130g dimethyl adipate is loaded under room temperature, toluene 450mL is added under stirring, add sodium Metal 99.5 17.2g under mixing rear stirring in batches, intensification underpressure distillation is except the methyl alcohol generated in dereaction, 2-(4-2-bromomethylphenyl) 121g is added after dimethyl adipate reacts completely, temperature reaction reacts completely to it, be down to room temperature, add 300mL water, adding 20mL concentration is that dilute hydrochloric acid (6MHCl) regulation system of 6 moles often liter is to about PH=6-7, toluene extracts, drying obtains yellow oil 191g after being concentrated into and doing, namely the precursor of loxoprofen sodium is obtained, purifying is not needed directly to drop into next step decarboxylic reaction.
Embodiment 2
1000mL tetra-mouthfuls of vials, temperature thermometer in being equipped with, condenser and mechanical stirring, 130g dimethyl adipate is loaded under room temperature, toluene 200mL is added under stirring, add sodium Metal 99.5 17.2g under mixing rear stirring in batches, intensification underpressure distillation is except the methyl alcohol generated in dereaction, 2-(4-2-bromomethylphenyl) 121g is added after dimethyl adipate reacts completely, temperature reaction reacts completely to it, be down to room temperature, add 300mL water, add 20mL6MHCl regulation system to about PH=6-7, toluene extracts, drying obtains yellow oil 182g after being concentrated into and doing, purifying is not needed directly to drop into next step reaction.
Embodiment 3
1000mL tetra-mouthfuls of vials, temperature thermometer in being equipped with, condenser and mechanical stirring, 130g dimethyl adipate is loaded under room temperature, MTBE(methyltert-butylether is added under stirring, methyl tertiary butyl ether) 450mL, add sodium Metal 99.5 17.2g under mixing rear stirring in batches, intensification underpressure distillation is except the methyl alcohol generated in dereaction, 2-(4-2-bromomethylphenyl) 121g is added after dimethyl adipate reacts completely, temperature reaction reacts completely to it, be down to room temperature, add 300mL water, add 20mL6MHCl regulation system to about PH=6-7, toluene extracts, drying obtains yellow oil 185g after being concentrated into and doing, purifying is not needed directly to drop into next step reaction.
Although the present invention discloses as above with preferred embodiment; so itself and be not used to limit the present invention, any those skilled in the art, without departing from the spirit and scope of the present invention; when doing a little amendment and perfect, therefore protection scope of the present invention is when being as the criterion of defining with claims.
Claims (7)
1. a synthetic method for loxoprofen sodium, is characterized in that, comprises the steps:
A) take dimethyl adipate as starting raw material;
B) adding certain alkali makes described dimethyl adipate cyclization generate 2-oxocyclopentyl methyl-formiate intermediate;
C) dimethyl adipate after adding certain organic solvent involutive ring carries out agitation and dilution;
D) adopt the methyl alcohol produced during underpressure distillation removing cyclization, and promote that cyclization reaction forward is carried out;
E) after the complete cyclization reaction of dimethyl adipate, add 2-(4-2-bromomethylphenyl) propionic acid, react completely to it at a certain temperature, after extraction drying, then obtain loxoprofen sodium through decarboxylation and quaternization.
2. the synthetic method of loxoprofen sodium as claimed in claim 1, it is characterized in that, the mass ratio of described alkali, dimethyl adipate and organic solvent is 0.5:1:1 ~ 3:1:10.
3. the synthetic method of loxoprofen sodium as claimed in claim 1, it is characterized in that, the alkali in described step b) is organic bases, mineral alkali or alkali metal compound.
4. the synthetic method of loxoprofen sodium as claimed in claim 1, it is characterized in that, in described step c), organic solvent is one in methyl alcohol, ethanol, ether, methyl tertiary butyl ether, methylene dichloride, ethyl acetate, acetone, toluene, dimethylbenzene, DMF and dimethyl sulfoxide (DMSO) or its combination.
5. the synthetic method of loxoprofen sodium as claimed in claim 1, is characterized in that, the temperature of underpressure distillation in described step d) controls to be 10 DEG C ~ 100 DEG C.
6. the synthetic method of loxoprofen sodium as claimed in claim 1, is characterized in that, the temperature of described step d) underpressure distillation controls to be 30 DEG C ~ 80 DEG C, and it is 30 DEG C ~ 80 DEG C that the temperature of reaction in described step e) controls.
7. the synthetic method of loxoprofen sodium as claimed in claim 1, is characterized in that, described step e) add 20mL concentration be the dilute hydrochloric acid adjust ph of 6 moles often liter to 6-7, utilize toluene to extract.
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| CN201510743097.XA CN105218351A (en) | 2015-11-05 | 2015-11-05 | A kind of synthetic method of loxoprofen sodium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109725074A (en) * | 2018-12-14 | 2019-05-07 | 康美（北京）药物研究院有限公司 | A kind of method of separating and assaying of related substance contained by loxoprofen acid and its salt |
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2015
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109725074A (en) * | 2018-12-14 | 2019-05-07 | 康美（北京）药物研究院有限公司 | A kind of method of separating and assaying of related substance contained by loxoprofen acid and its salt |
| CN109725074B (en) * | 2018-12-14 | 2021-07-13 | 康美（北京）药物研究院有限公司 | Method for separating and measuring related substances contained in loxoprofen acid and salt thereof |
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Application publication date: 20160106 |