CN1115320C - Process for synthesizing ketoibuprofen - Google Patents
Process for synthesizing ketoibuprofen Download PDFInfo
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- CN1115320C CN1115320C CN99116808A CN99116808A CN1115320C CN 1115320 C CN1115320 C CN 1115320C CN 99116808 A CN99116808 A CN 99116808A CN 99116808 A CN99116808 A CN 99116808A CN 1115320 C CN1115320 C CN 1115320C
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Abstract
The present invention provides a method for synthesizing ketoibuprofen. M-methyl benzoic acid serves as initial raw material, carries out chlorination, friedel-crafts reaction, halogenation, cyanidation and alpha-monomethylation to generate 2-(3-benzoylphenyl carbinol phenyl) propionitrile, and continuously carries out basic hydrolysis and acidification, and thus, ketoibuprofen is prepared. The total yield is 58%. The present invention has the advantages of easy obtaining of raw materials, moderate reaction condition, convenient operation, high product yield and good quality.
Description
The invention belongs to pharmaceutical chemistry technical field, is a kind of synthetic method of Ketoprofen BP 93.
Usually be that starting raw material has direct methylation method and indirect methylation method through the method for the method of the synthetic Ketoprofen BP 93 of 3-cyanogen methyldiphenyl ketone with the m-methyl benzoic acid.French Patent 2367728,2422619, Deutsches Reichs-Patent 2744833; English Patent 1515640; 2021562, belgian patent 616253,833266; the direct methylation method that 837624 grades are described; but its weak point also generates a certain amount of pair of methylate except that generating principal product 2-(3-benzoyl) benzenepropanenitrile (V), both physico-chemical properties are quite similar; separation difficulty and influence the quality of Ketoprofen BP 93 is lower than 30% with the m-methyl benzoic acid for the raw material total recovery.The indirect methylation method that United States Patent (USP) 3641127, south african patent 00524 grade are described, though can avoid two methyl products to form, reactions steps is long, anhydrous condition requires harshness, uses expensive methylating reagent methyl iodide, three take seriously polluted.Production cost height, total recovery only about 35%.
The objective of the invention is to propose a kind of total recovery height, what avoid serious three expense pollutions is the method for the synthetic Ketoprofen BP 93 of starting raw material with the m-methyl benzoic acid.
The method of the synthetic Ketoprofen BP 93 that the present invention proposes is a starting raw material with the m-methyl benzoic acid, and its synthetic route is as follows:
X in the compound (III) is Cl or Br.
Wherein the structural formula of (I), (II), (III), (IV), (V) is respectively Ketoprofen BP 93,3-methyldiphenyl ketone, 3-monochloromethyl benzophenone, 3-cyanogen methyldiphenyl ketone and 2-(3-benzoyl phenyl) propionitrile.
Corresponding to said synthesis route, concrete steps are as follows:
A) generate compound (II) with m-methyl benzoic acid through chlorination, friedel-crafts reaction one pot reaction;
B) obtain compound (II) by step a) and generate compound (III) through the side chain halogenating reaction;
C) obtain compound (III) by step b) and generate compound (IV) through cyanogenation;
D) obtain compound (IV) through α-monomethylation reacting generating compound (V) by step c);
E) obtain compound (V) by step d) and generate Ketoprofen BP 93 (I) through hydrolysis reaction.
Each step of this synthetic method specifically describes as follows:
Step a): m-methyl benzoic acid and chlorizating agent reflux in benzene with 1: 1.1～1.5 mol ratios and formed m-methyl benzoyl formyl chloride in 4～5 hours, this intermediate is without separation, the cooling back directly adds aluminum trichloride (anhydrous) and carries out one pot of friedel-crafts reaction, after reaction finishes, pour in the frozen water and decompose, underpressure distillation makes compound (II).(II) do not distill yet and be directly used in next step reaction.Used chlorizating agent can be used phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride, and preferred chlorizating agent is phosphorus trichloride and phosphorus pentachloride.
Step b): with compound (II) and halogenating agent, Diisopropyl azodicarboxylate or benzoyl peroxide carry out halogenating reaction in reflux temperature in the presence of solvent, make compound (III).Wherein the mol ratio of compound (II) and halogenating agent is 1: 1～1.5, and preferred mol ratio is 1: 1.2.Halogenating agent can be chlorine, sulfuryl chloride, bromine, N-chlorosuccinimide (NCS) or N-bromo-succinimide (NBS).Preferably chlorine, sulfuryl chloride or bromine.Suitable solvent can be tetracol phenixin, 1,2-ethylene dichloride, glycol dibromide, zellon and sym.-tetrachloroethane.Preferred solvent is: then first-selected 1 when making halogenating agent with chlorine or bromine, and 2-ethylene dichloride, glycol dibromide, zellon and sym.-tetrachloroethane; If when making halogenating agent, then select tetracol phenixin with NCS, sulfuryl chloride and NBS.
Step c): the cyanogenation of compound in the presence of phase-transfer catalyst or no phase-transfer catalyst (III) and potassium cyanide or sodium cyanide can carry out in solvent and make compound (IV).The solvent that is fit to is acetonitrile, water, benzene, toluene, N, dinethylformamide and methyl-sulphoxide.Preferred solvent is benzene/water, toluene, acetonitrile/water.The temperature of cyanogenation is a reflux temperature for well.The phase-transfer catalyst that adds catalytic amount in cyanogenation can shorten the reaction times, improves yield.Used phase-transfer catalyst can be polyethylene glycols (A) and quaternary ammonium salts (B),
A:HO (CH
2CH
2O)
nH molecular-weight average 200～4000 B:
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl; Y is Cl, Br, F.
Preferred phase-transfer catalyst is poly(oxyethylene glycol) 400, Polyethylene Glycol-600, benzyltriethylammoinium chloride or bromogeramine.Compound (III) is 1: 0.001～0.1 with the mol ratio of phase-transfer catalyst.Preferred mol ratio is 1: 0.005～0.1.Step d): compound (IV) adds phase-transfer catalyst with methylcarbonate (DMC) in mineral alkali or not with phase-transfer catalyst, the α-monomethylation that carries out of highly selective reacts, and makes key intermediate (V).Mineral alkali can be Anhydrous potassium carbonate, anhydrous sodium carbonate, Carbon Dioxide lithium and Carbon Dioxide caesium etc., and only alkali is Anhydrous potassium carbonate.The mol ratio of compound (IV), DMC and Anhydrous potassium carbonate is 1: 5～20: 1.5～8.The preferred mol ratio of three is 1: 16～19: 1.5～2.5.Temperature of reaction with 160～200 ℃ for well, preferred temperature is 170～190 ℃.The reaction period is 0.5～8 hour.Compound (IV) can be polyethylene glycols (A) and quaternary ammonium salts (B), A:HO (CH with the phase-transfer catalyst that the phase-transfer catalyst reaction of carrying out with methylcarbonate is used
2CH
2O)
nH molecular-weight average 300～6000B:
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl; Y is Cl, Br, F.
Preferred catalyzer is poly(oxyethylene glycol) 400 and bromogeramine.Compound (IV) is 1: 0.001～0.1 with the mol ratio of phase-transfer catalyst.
Step e): intermediate (V) is dissolved in toluene or the xylene solvent with 45% aqueous sodium hydroxide solution (w/v) in 110～135 ℃ of back hydrolysis 1.5～3 hours, and the sodium salt of a large amount of white solids (I) is separated out in cooling, gets (I) with glacial acetic acid and formic acid acidifying again.Isolated solid (I) sodium salt after (V) hydrolysis wherein, need colourless with toluene or xylene solvent repetitive scrubbing to solid, pure (I) sodium salt.And then its solid is dissolved in the deionized water, transfer to pH3～4 at 0～5 ℃ with glacial acetic acid or formic acid, promptly separate out white solid (I), need not recrystallization get final product elaboration, quality can reach 23 editions standards of British Pharmacopoeia.
The present invention, is paid through chlorination by a methylbenzene-Ke two steps one pot reaction generation compound (II), and yield reaches 90～95%; (II) generate compound (III) through halogenating reaction with 90～93% yields; Compound (HI) generates compound (IV) through cyanogenation, and yield reaches 80～90%; Make methylating reagent with this dimethyl phthalate of carbon and directly make (IV) to carry out monomethylation reacting generating compound (V), yield 90%, unparalleled methide generate (through GC and
1HNMR measures and shows); (V) generate Ketoprofen BP 93 (I), yield 90～95% through hydrolysis.By the method for the invention, to calculate from m-methyl benzoic acid, the total recovery of synthetic Ketoprofen BP 93 is greater than 58%, content 〉=98.5% (HPLC mensuration).
The invention has the advantages that: raw material is cheap and easy to get, reaction conditions is gentle, simple to operate, cost is low, three-waste pollution is few, compared with prior art total recovery has improved about 25%, product matter is good, is fit to suitability for industrialized production.
Embodiment: one, the preparation of 3-methyldiphenyl ketone (II)
Example 1 is with m-methyl benzoic acid (136g, 1mol), and dry-out benzene (443mL, 5mol) and phosphorus pentachloride (242g, 1.1mol) put in the dry reaction bottle, after the stirring and refluxing 4 hours, and the adding aluminum trichloride (anhydrous) (160g, 1.2mol), continue to reflux and stirred 8 hours, reaction is finished, and is cooled to room temperature, and reactant is poured in the frozen water, tell organic layer, the water layer benzene extraction, the combined benzene layer is behind the recovery benzene, underpressure distillation, collect bP180～182 ℃/14～15mmHg cut, faint yellow oily thing (II) 185g, yield 94%.
Example 2 with m-methyl benzoic acid (136g, 1mol), dry-out benzene (443mL, 5mol) and phosphorus trichloride (164g, 1.1mol) put in the dry reaction bottle, stirring and refluxing is after 5 hours, add aluminum trichloride (anhydrous) (160g, 1.2mol), continue to reflux and stirred 8.5 hours, reaction is finished, and is cooled to room temperature.Reactant is poured in the frozen water, is told organic layer, water layer with benzene extraction for several times, the combined benzene layer, reclaim benzene after, bP164～168 ℃/8mmHg cut is collected in underpressure distillation, colourless liquid 181g, yield 90%.Two, the preparation of 3-monochloromethyl benzophenone (III)
Example 3 with 3-methyldiphenyl ketone (170g, 0.87mol), anhydrous tetracol phenixin (600mL) and Diisopropyl azodicarboxylate (0.5g) are put in the reaction flask, after the stirring and refluxing, 300 or the 400W bulb irradiation under, drip bromine (168g, 1.05mol), finish for 8 hours, behind the recovery tetracol phenixin, be cooled to room temperature, separate out solid, use petroleum ether, in 40～45 ℃ of dryings, off-white powder 3-brooethyl benzophenone 253g, yield 92%, mp58～62 ℃.
Example 4 with 3-methyldiphenyl ketone (170g, 0.87mol), anhydrous zellon (550mL) and benzoyl peroxide (15g) put in the reaction flask, after the stirring and refluxing, (129g 0.96mol), dripped complete in 4.5 hours to drip sulfuryl chloride, continue to stir 2 hours, the reclaim under reduced pressure zellon is cooled to room temperature, separate out solid, use petroleum ether,, get off-white powder 3-chloromethyl benzophenone 207g in 40 ℃ of dryings, yield 90%, mp45～55 ℃.
Example 5 with 3-methyldiphenyl ketone (200g, 1.02mol), the N-bromo-succinimide (187g, 1.05mol) anhydrous tetracol phenixin (700ml) and Diisopropyl azodicarboxylate (1.5g) are put in the reaction flask, after the stirring and refluxing 13 hours, filter, filtrate is reclaimed tetracol phenixin, is cooled to room temperature, separate out solid, with ethanol/water (4: 1, V/V) recrystallization, white crystalline powder 3-brooethyl benzophenone 253g, yield 92%, mp55～62 ℃.Three, the preparation of 3-cyanogen methyldiphenyl ketone (IV)
Example 6 is with 3-chloromethyl benzophenone (231g, 1mol), toluene (45mL) puts in the reaction flask, stirring and refluxing treat 3-chloromethyl benzophenone complete molten after, drip potassium cyanide (78g, 1.2mol) be dissolved in the solution of water (220mL), 0.5 hour drip to finish, stirred 12 hours, be cooled to room temperature, tell organic layer, water layer merges organic layer with methylbenzene extraction several times, washing, after reclaiming toluene, bp221～226 ℃/3mmHg cut is collected in underpressure distillation, places to solidify to grind, in 45 ℃ of dryings, white powder 188.3g, yield 88%, mp58～60 ℃.
Example 7 is with 3-brooethyl benzophenone (275g, 1mol), benzene (600mL) puts in the reaction flask, after stirring and refluxing becomes homogeneous phase, drips potassium cyanide (61.3g, 1.25mol) be dissolved in the water (200mL), 1.5 hour drip to finish, stirred 15 hours, be cooled to room temperature, tell organic layer, water layer benzene extraction 3～4 times merge organic layer, washing, after reclaiming benzene, bp176～182 ℃/0.15mmHg cut is collected in underpressure distillation, places to solidify to grind, in 45 ℃ of dryings, white powder 188.3g, yield 90%, mp59～62 ℃.
Example 8 with 3-brooethyl benzophenone (275g, 1mol), toluene (550mL), Polyethylene Glycol-600 (2g) is put in the reaction flask, after the stirring and refluxing, (78g 1.2mol) is dissolved in the solution of water (210mL), drips in 2 hours to finish to drip potassium cyanide, stirring and refluxing 7.5 hours, be cooled to room temperature, in reaction mixture, add entry (150mL), refluxed 15 minutes in stirring at room, leave standstill and tell organic layer, water layer methylbenzene extraction 3～4 times merge organic layer, washing, after reclaiming toluene, bp220～225 ℃/3mmHg cut is collected in underpressure distillation, places to solidify and grinds essence, in 35～45 ℃ of dryings, white powder 190g, yield 88%, mp59～62 ℃.Four, 2-(3-benzoyl phenyl) propionitrile (V) preparation
Example 9 with 3-cyano group benzophenone (214g, 1mol), methylcarbonate (1.44kg, 16mol) and Anhydrous potassium carbonate (162g 1.8mol) puts in the voltage-resistant reactor, stirs 4 hours in 170 ℃.Be cooled to room temperature, filter, reclaim methylcarbonate after, bp202～204 ℃/3mmHg cut is collected in underpressure distillation, place to solidify to grind, in 35～40 ℃ of dryings, off-white powder 194g, yield 85%, mp52～54 ℃.
Example 10 with 3-cyano group benzophenone (214g, 1mol), methylcarbonate (1.44kg, 16mol) and Anhydrous potassium carbonate (162g, 1.8mol) and poly(oxyethylene glycol) 400 (3g) put in the voltage-resistant reactor, stirred 2.5 hours in 190 ℃.Be cooled to room temperature, filter, reclaim methylcarbonate after, bp204～205 ℃/6mmHg cut is collected in underpressure distillation, place to solidify to grind, in 35～40 ℃ of dryings, white powder 205g, yield 90%, mp52～54 ℃.Five, Ketoprofen BP 93 (I) is synthetic
(228g, 1mol), put in the reaction flask by toluene (450mL) with 2-(3-benzoyl phenyl) propionitrile for example 11.(48g 1.2mol) is dissolved in water (48mL) solution, stirring and refluxing 6 hours to dropping sodium, be cooled to 5 ℃ and separate out a large amount of white solids, in reaction mixture, add toluene (200ml) and stirred 15 minutes, filter,, drain till be entirely white with the toluene wash solid.Its solid is dissolved in the deionized water (500mL), be cooled under 0～5 ℃ of stirring and drip glacial acetic acid (the dropping time is 2.5 hours to pH3～4, separating out a large amount of white solids placed 5 hours in 0～5 ℃, filter, be washed till pH value of solution about 6, be dried to constant weight in 60 ℃ with deionized water, get white powder 241g, yield 95%, mp95～96 ℃, HPLC measured value content 99.78% ultimate analysis (Cl
16H
14O
3), calculated value C:75.57%, H:5.55%; Measured value C:75.46%, H:5.60%.IR(KBr)：2500～3300，1700，1655，1290，1230，970，715，690cm
-1。
1HNMR(CDCl
3)：1.52(d，J＝7.0Hz，3H)，3.77(q，J＝7.0Hz，1H)，7.29～7.80(m，9H)，11.5(br?s，1H)。
The invention is not restricted to above-mentioned example.
Claims (20)
1. the method for a synthetic Ketoprofen BP 93 (I)
It is characterized in that:
A): generate compound (II) through chlorination, friedel-crafts reaction one pot reaction with m-methyl benzoic acid:
B): obtain compound (II) by step a) and generate compound (III) through the side chain halogenating reaction:
X is Cl in the formula, Brc): obtain compound (III) by step b) and generate compound (IV) through cyanogenation:
D): obtain compound (IV) through a-monomethylation reacting generating compound (V) by step c):
E) obtain compound (V) by step d) and generate Ketoprofen BP 93 compound (I) through hydrolysis reaction.
2. the method for claim 1 is characterized in that compound (V) 1.5～3 hour makes Ketoprofen BP 93 sodium salt in 110～135 ℃ of hydrolysis with 45% sodium hydroxide solution in toluene or dimethylbenzene, becomes (I) with glacial acetic acid or formic acid acidifying again.
3. method as claimed in claim 2 is characterized in that isolating solid (I) sodium salt after compound (V) hydrolysis, makes pure (I) sodium salt with toluene or dimethylbenzene washing again.
4. method as claimed in claim 2, it is characterized in that pure (I) sodium salt is dissolved in deionized water after, transfer to pH3～4 with glacial acetic acid acid or formic acid and make elaboration (I).
5. the method for claim 1 is characterized in that compound (IV) and methylcarbonate add phase-transfer catalyst or do not carry out α-monomethylation reaction with phase-transfer catalyst in mineral alkali.
6. method as claimed in claim 5 is characterized in that mineral alkali is a kind of of Anhydrous potassium carbonate, anhydrous sodium carbonate, Carbon Dioxide lithium and Carbon Dioxide caesium.
7. method as claimed in claim 5 is characterized in that compound (IV), and the mol ratio of methylcarbonate and Anhydrous potassium carbonate is 1: 5～20: 1.5～8.
8. method as claimed in claim 5 is characterized in that 160～200 ℃ of temperature of reaction, and the reaction times was controlled at 0.5～8 hour.
9. method as claimed in claim 5 is characterized in that phase-transfer catalyst is polyethylene glycols (A) and quaternary ammonium salt (B).
A:HO (CH
2CH
2O)
nH molecular-weight average 300～6000 B:
R in the formula
1, R
2, R
3Be C
1-C
12Identical alkyl or different alkyl, R
4Be C
1-C
8Alkyl or benzyl;
Y is Cl, Br, F.
10. method as claimed in claim 5 is characterized in that compound (IV) and phase-transfer catalyst mol ratio are 1: 0.001-0.1.
11. the method for claim 1 is characterized in that compound (III) and potassium cyanide or sodium cyanide carry out cyanogenation under phase-transfer catalyst in solvent.
12. method as claimed in claim 11 is characterized in that reaction solvent is acetonitrile or acetonitrile/water, toluene or toluene, benzene or benzene/water, N, dinethylformamide, dimethyl sulfoxide (DMSO).
13. method as claimed in claim 11 is characterized in that the described phase-transfer catalyst of phase-transfer catalyst and claim 9 is identical.
14. method as claimed in claim 11 is characterized in that compound (III) and phase-transfer catalyst mol ratio are 1: 0.001-0.1.
15. the method for claim 1 is characterized in that compound (II) and halogenating agent, Diisopropyl azodicarboxylate or benzoyl peroxide are carrying out halogenating reaction under reflux temperature in the presence of the solvent.
16. method as claimed in claim 15 is characterized in that halogenating agent is a kind of of N-chlorosuccinimide, chlorine, N-bromo-succinimide, bromine, sulfuryl chloride.
17. method as claimed in claim 15 is characterized in that the compound (II) and the mol ratio of halogenating agent are 1: 1～1.5.
18. method as claimed in claim 15 is characterized in that solvent is zellon, tetracol phenixin, 1,2-ethylene dichloride, glycol dibromide and sym.-tetrachloroethane.
19. the method for claim 1, it is characterized in that m-methyl benzoic acid and chlorizating agent with 1: 1.1～1.5 mol ratios in benzene back flow reaction after 4～5 hours without separating, directly add aluminum trichloride (anhydrous) and carry out one pot of friedel-crafts reaction.
20. method as claimed in claim 19 is characterized in that chlorizating agent is a kind of of phosphorus trichloride, phosphorus oxychloride and phosphorus pentachloride.
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|---|---|---|---|
| CN99116808A CN1115320C (en) | 1999-08-20 | 1999-08-20 | Process for synthesizing ketoibuprofen |
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|---|---|---|---|
| CN99116808A CN1115320C (en) | 1999-08-20 | 1999-08-20 | Process for synthesizing ketoibuprofen |
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| CN1115320C true CN1115320C (en) | 2003-07-23 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2003236149A1 (en) * | 2002-04-22 | 2003-11-03 | Hualu Wang | Ibuprofen ribavirin ester, its method of preparation and use |
| CN101774945B (en) * | 2010-01-27 | 2013-05-29 | 巨化集团公司 | Method for synthesizing 4,4,4-trifluoro-butyronitrile |
| CN106631772B (en) * | 2016-12-14 | 2019-09-20 | 安徽省诚联医药科技有限公司 | The preparation method of Ketoprofen |
| CN107137387B (en) * | 2017-07-07 | 2020-05-12 | 中国科学技术大学 | Synthetic method of aryl propionic acid non-steroidal anti-inflammatory drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201870A (en) * | 1976-10-18 | 1980-05-06 | Lek Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of 2-(3-benzoylphenyl)-propionic acid |
| US4230884A (en) * | 1978-04-10 | 1980-10-28 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for preparing 2-(3-benzoylphenyl)-propionic acid |
-
1999
- 1999-08-20 CN CN99116808A patent/CN1115320C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201870A (en) * | 1976-10-18 | 1980-05-06 | Lek Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of 2-(3-benzoylphenyl)-propionic acid |
| US4230884A (en) * | 1978-04-10 | 1980-10-28 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for preparing 2-(3-benzoylphenyl)-propionic acid |
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