CN1077188A - The synthetic method of d1-Naproxen Base - Google Patents
The synthetic method of d1-Naproxen Base Download PDFInfo
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- CN1077188A CN1077188A CN 92102703 CN92102703A CN1077188A CN 1077188 A CN1077188 A CN 1077188A CN 92102703 CN92102703 CN 92102703 CN 92102703 A CN92102703 A CN 92102703A CN 1077188 A CN1077188 A CN 1077188A
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Abstract
The invention discloses a kind of method of d1-Naproxen Base.Adopting 2-methoxy naphthalene is starting raw material, generates 2-(5-halogen-6-methoxyl group) naphthyl vinylformic acid through halogenation, Veux-psoriasis reaction, phase-transfer-catalyzed reactions, preparation d1-Naproxen Base after process hydrogenation process, and overall yield of reaction is 81%.
Description
The present invention has narrated a kind of synthetic formula I compound (method of (dl-Naproxen Base).
The synthetic route of the disclosed Naproxen Base of people, as U.S.3,758; 544,3,873; 597,3,960; 957, G.B 2,098; 981, patents such as Chinese patent CN86100855 are described, all are from 2-methoxy naphthalene basically; earlier through Friedel-Crafts reaction Synthetic 2-ethanoyl-6-methoxy naphthalene, then through Darzens condensation reaction needed 7-8 step formality, the total recovery of calculating with the 2-methoxynaphthalene is less than 15%.
The clear 54-163561 of Ri Tekai, 56-16437, patents state such as 55-7225 use 2-methoxynaphthalene prepare intermediate 2-ethanoyl 6-methoxy naphthalene through Veux-psoriasis reaction, reaction preference is relatively poor, yield is only about 50%; Intermediate generates the 2-(6-methoxyl group through phase-transfer-catalyzed reactions again) naphthyl vinylformic acid, reaction conversion ratio low (about 60%), and by product is many, the separation and purification difficulty.
The objective of the invention is to avoid the deficiencies in the prior art and a kind of preparation method who begins synthetic Naproxen Base from the methoxy naphthalene is provided.
Purpose of the present invention realizes that by following measure process of the present invention comprises:
A) the present invention uses 2-methoxynaphthalene and N-halogenated succinimide imide (halogen is Cl, Br, I atom) to generate the formula II compound through the halogenating reaction process.
X is Cl, Br, I atom in the formula.
B) use the formula II compound to generate the formula III compound through Veux-psoriasis reaction;
C) use formula III compound and chloroform or bromofom under the phase-transfer catalyst effect, in alkaline medium, prepare formula IV compound [2-(5-halogen-6-methoxyl group) naphthyl vinylformic acid] through phase-transfer-catalyzed reactions.
At last under the effect of catalyzer, carry out heterogeneous hydrogenation (removing halogen in the hydrogenation reaction) and produce the d1-Naproxen Base.
The present invention can also realize by following measure:
A) adopting tetrachloromethane in the step is solvent, and reflux temperature quantitatively adds N-halogenated succinimide imide down, with the halogenation of 2-first chloro naphthalene, generates the formula II compound.
C) reaction solvent adopts halogenated alkane in the process, specifically is methylene dichloride, and 1,2-ethylene dichloride, 1,1-ethylene dichloride, sym.-tetrachloroethane.
Formula III compound and chloroform or bromofom carry out the phase-transfer catalyst of phase-transfer-catalyzed reactions use and represent with general formula (A);
R in the general formula
1, R
2, R
3Be C
1～C
8Alkyl (identical or different alkyl), R
4Be C
1～C
8Alkyl or benzyl, Y are Cl, Br, I, OH, SCH
3
C) after reaction process finishes, use the ethyl acetate separated product.
C) the used alkaline medium of reactions steps is the aqueous solution (weight percentage 40～55%) of sodium hydroxide or potassium hydroxide.
The mol ratio of formula III compound and chloroform or bromofom is 1: 2～10.
The preferred mol ratio of formula III compound and chloroform or bromofom is 1: 2～5.
The mol ratio of formula III compound and phase-transfer catalyst is 1: 0.3～3.8.
The mol ratio of the alkaline medium of formula III compound is 1: 5～10.
The preferred molar ratio of formula III compound and alkaline medium is 1: 9～10.
C) after phase-transfer-catalyzed reactions finishes in the step, add hydrochloric acid and carry out acidifying, making pH value is 2～3.
C) reaction of step is carried out at normal temperatures.
C) being reflected under the protection of inert gas of step carried out, and should select to be nitrogen.
C) reaction times of step was controlled at 4-30 hour.
A) after the halogenating reaction of step was finished, N-halogenated succinimide imide was converted into succinic diamide, and very easily with product formula II compound separation, succinic diamide can be used usual method regeneration N-halogenated succinimide imide.
B) adopt Veux-psoriasis reaction to carry out acetylize in the step, with the formula II compound dissolution 1, in the 2-ethylene dichloride; be added drop-wise to 1 of aluminum trichloride (anhydrous) and Acetyl Chloride 98Min. under 0 ℃, in the 2-dichloroethane solution, after reaction finishes; with hydrochloric acid hydrolysis, separate, promptly get the formula III compound.
The present invention generates (II) formula compound by 2-methoxynaphthalene halogenating reaction, and productive rate can reach 98%, and the product purity height can be directly used in next step reaction; Use 1-halogen-2-methoxynaphthalene [formula II] and can reach 98% through Veux-psoriasis reaction generation formula III compound productive rate; The phase-transfer-catalyzed reactions of step c), specificity ground generates 2-(5-halogen-6-methoxyl group) a kind of product of naphthyl vinylformic acid (TLC and ' H-NMR check show), productive rate is more than 90%.2-(5-halogen-6-methoxyl group) naphthyl vinylformic acid [formula IV compound], can be directly with asymmetric hydrogenation or carry out heterogeneous hydrogenation reaction with catalyzer such as Pd/C and produce the dl-Naproxen Base.By method of the present invention, to count from the 2-methoxynaphthalene, the total recovery of preparation dl-Naproxen Base is 81%.
The dl-Naproxen Base is non-steroidal anti-inflammatory, analgesia, antipyretic analgesics.
Below in conjunction with example the present invention is narrated in more detail:
Synthesizing of example 1 formula II compound
In the there-necked flask, add 47.4g(0.3mol) 2-methoxy naphthalene and the dry CCl of 300ml
4After being heated to backflow, stir adding 58.8g(0.33mol down), the N-bromo-succinimide, continued reflux 1 hour, reaction mixture is cooled to 0 ℃, filters, and filtrate is evaporated to dried, get the 74g light yellow crystal, in ethyl acetate/normal hexane behind the recrystallization the 69g white crystal, m.p.83～85 ℃, productive rate 97.9%.
Synthesizing of example 2 intermediate IV
The anhydrous AlCl of 43g
3And 24.6g(0.313mol) adding of acetyl oxygen fills 200ml1, in the there-necked flask of 2-ethylene dichloride, be cooled to 0 ℃, stir Dropwise 5 9.25g(0.250mol down) 1-bromo-2-methoxy naphthalene/150ml 1, the 2-dichloroethane solution, after dropwising, continue to stir 15 minutes, in 300ml water/100ml2N hydrochloric acid that the mixed solution impouring is cold, separate, organic phase is with 100ml1N hydrochloric acid and 100ml washing, evaporated under reduced pressure, recrystallization in the 2-butanols obtains the 68.11g crystal, m.p.133 ℃-135 ℃, yield 98%.
Example 3 is put into the 11.2g(0.045 mole in the 250ml there-necked flask) (5 '-bromo-6 '-methoxyl group)-2-acetylnaphthalene, the 38.2g(0.32 mole) CHCl
3, 15.3g benzyltrimethylammonium hydroxide (0.092 mole), stirring and dissolving under the room temperature slowly splashed into 55%KOH aqueous solution 41g(0.4 mole then at 8 hours).After dropwising, reaction mixture at room temperature continued to stir 6 hours, filtered, and the KCl crystal in the elimination reaction mixture after the adding 150ml ethyl acetate, uses 2N hydrochloric acid with the filtrate acidifying in filtrate.Leave standstill separatory, organic phase with 2N hydrochloric acid, each washing of water once, adds 20%NaOH solution again, stir, and separatory, organic phase is washed with 20%NaOH.Add 6N hydrochloric acid in the alkali lye after merging, regulate pH value to 3, and the usefulness ethyl acetate extraction (3 * 150ml), anhydrous sodium sulfate drying, reduction vaporization, get 12.4 gram faint yellow solids, recrystallization in the methyl alcohol gets the 11.1g white crystals, 1R, NMR be indicated as 2-(5 '-bromo-6 '-methoxyl group) naphthyl vinylformic acid, m.p.195～198 ℃, productive rate 90.1%.
The IR(KBr compressing tablet, cm
-1): 3400,2760～3280(Br), 1710,1682,1618(sh), 1590,1480,1430,1320,1260,1225,1055.
′H-NMR（400MHz，CO
3COCO
3，δ）：4.05（3H，S），6.14（1H，d），6.43（1H，d），7.12-7.86（5H，m）。
Above-mentioned product is dissolved in the 300ml20%NaOH aqueous solution, carries out shortening (reviewing normal pressure) on the 5%Pd/C catalyzer, filters with separating catalyst.After in filtrate, adding ethyl acetate, use hcl acidifying, get dl-Naproxen Base crude product 8.25g, behind the ethanol/water recrystallization, get white crystals 8.09 grams, productive rate 97.6%.
Example 4 adds the 5.6g(0.02 mole in the 250ml there-necked flask) 5-bromo-6-methoxyl group-2-acetylnaphthalene and 30gCH
2Cl
2After stirring makes into solution, add 36gCHCl again
3(0.3 mole) and 3.71g benzyl trimethyl ammonium chloride mix.In said mixture, in 4 hours, at room temperature drip 20.4g55%KOH solution (0.2 mole).After dropwising, at room temperature continue to stir 8 hours, filter, remove the KCl crystal that dereaction generates, in filtrate, add the 100ml ethyl acetate then, to PH=3, leave standstill separatory with the 6N hcl acidifying.Organic phase with 2N hydrochloric acid and water washing after, add 20%NaOH, vibration, separatory adds 6N hcl acidifying, ethyl acetate extraction in alkali lye, anhydrous sodium sulfate drying, reduction vaporization gets faint yellow solid, gets white crystal 5.6g behind the methanol recrystallization, productive rate 91%, products therefrom carries out shortening with the formality identical with example 1,4.09 gram dl-Naproxen Bases, productive rate 97.9%.
Example 5 adds the 5.6g(0.02 mole in the 250ml there-necked flask) 5-bromo-6-methoxyl group-2-acetylnaphthalene and 30 gram CH
2Cl after the stirring and dissolving, adds 7.7 gram benzyltriethylammoinium chlorides and 20.4 gram 55%KOH solution, mixes.In said mixture, in 6 hours, drip 7.17 gram (0.06 mole) CHCl
3, at room temperature continue to stir 6 hours after dropwising, handle by the formality identical afterwards with example 1 and example 2,5.7 gram products, yield 92.2%.
Above-mentioned product 2g is dissolved in 200ml methyl alcohol, adds 0.5g5%Pd/C, and hydrogenation under room temperature, normal pressure gets the 1.46gdl-Naproxen Base, productive rate 98%.
Example 6 in the 250ml there-necked flask, adds 11.2g(0.04mol) 5-bromo-6-methoxy naphthalene, 14.2g Tetrabutyl amonium bromide (0.044mol) the 40g40%NaOH aqueous solution, 50mlCH
2Cl
2, be stirred to fully dissolving after, room temperature dripped chloroform 12.0g(0.1mol in 6 hours), after dripping, stirring is spent the night.Filtration, filtrate are acidified to PH=2～3, with ethyl acetate extraction.Organic phase adds 20%NaOH after 2N hydrochloric acid and washing, sway, separate, alkali lye after ether is washed, acidifying, ethyl acetate extraction, reduction vaporization, solid after recrystallizing methanol, yellow crystals 10.9g, productive rate 88.5%.Through shortening, get the 7.9gdl-Naproxen Base, yield 97.0%.
Example 7, in the 250ml there-necked flask, add 9.42g(0.04mol) 5-chloro-6-methoxy naphthalene, 9.77g benzyl triethyl ammonium bromide (0.036mol), 40g40% aqueous sodium hydroxide solution, 50ml1, the 2-ethylene dichloride, be stirred to fully dissolving after, room temperature dripped chloroform 120g(0.1mol in 6 hours), after dripping, stirring is spent the night.After example 6 identical formalities processing, get light yellow crystal 9.3g, productive rate 88.2% through shortening, gets the 7.9gdl-Naproxen Base, yield 97.3%.
The invention is not restricted to above-mentioned example.
Claims (20)
1, the method for a kind of synthetic formula I compound (d1-Naproxen Base):
It is characterized in that:
A) use 2-methoxynaphthalene and W-halogenated succinimide imide (halogen is Cl, Br, l atom) to generate the formula II compound through the halogenating reaction process,
Wherein X is Cl, Br, l atom.
B) the formula II compound that is obtained by step a) generates the formula III compound through Veux-psoriasis reaction,
C) formula III compound that is obtained by step b) and chloroform or bromofom prepare the formula IV compound through phase-transfer-catalyzed reactions in alkaline medium under the phase-transfer catalyst effect | 2-(5-halogen-6-methoxyl group) naphthyl vinylformic acid |.
2, as claims 1 described method, it is characterized in that C) reaction solvent adopts halogenated alkane in the process.
3, method as claimed in claim 2 is characterized in that reaction solvent is a methylene dichloride, 1, and 2-ethylene dichloride, 1,1-ethylene dichloride, sym.-tetrachloroethane.
4, the method for claim 1 is characterized in that formula III compound and chloroform formula bromofom carry out the phase-transfer catalyst of phase-transfer-catalyzed reactions use with R in general formula (A) expression
1, R
2, R
3Be C
1～C
8The different alkyl of alkyl phase cotype), R
4Be C
1～C
8Alkyl or benzyl, Y are Cl, Br, I, OH, SCH
3
5, the method for claim 1 is characterized in that C) reactions steps ethyl acetate separated product.
6, the method for claim 1 is characterized in that C) the used alkaline medium of reactions steps is the aqueous solution (weight percentage 40～55%) of sodium hydroxide or potassium hydroxide.
7, the method for claim 1, the mol ratio that it is characterized in that formula III compound and chloroform or bromofom is 1: 2～10.
8, method as claimed in claim 7, the mol ratio that it is characterized in that formula III compound and chloroform or bromofom is 1: 2～5.
9, as claim 1 or 4 described methods, the mol ratio that it is characterized in that formula III compound and phase-transfer catalyst is 1: 0.3～3.8.
10, as claim 1 or 6 described methods, the mol ratio that it is characterized in that formula III compound and alkaline medium is 1～5: 10.
11, method as claimed in claim 10, the mol ratio that it is characterized in that formula III compound and alkaline medium is 1: 9～10.
12, the method for claim 1 is characterized in that C) phase-transfer-catalyzed reactions of step, need add hydrochloric acid and be hydrolyzed, making pH value is 2～3.
13, the method for claim 1 is characterized in that C) reaction of step carries out at normal temperatures.
14, the method for claim 1 is characterized in that C) being reflected under the protection of inert gas of step carry out.
15, method as claimed in claim 14 is characterized in that C) being reflected under the nitrogen protection of step carry out.
16, the method for claim 1 is characterized in that C) reaction times of step was controlled at 4～30 hours.
17, the method for claim 1 is characterized in that a) reaction solvent of step is a tetrachloromethane.
18, the method for claim 1 is characterized in that a) step is reacted under reflux temperature.
19, the method for claim 1 is characterized in that b) step formula II compound and aluminum trichloride (anhydrous) and Acetyl Chloride 98Min. react.
20, as claim 1 or 19 described methods, it is characterized in that b) reaction solvent of step is 1, the 2-ethylene dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92102703 CN1034661C (en) | 1992-04-08 | 1992-04-08 | Method of synthesis of dl-Naproxen |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92102703 CN1034661C (en) | 1992-04-08 | 1992-04-08 | Method of synthesis of dl-Naproxen |
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| Publication Number | Publication Date |
|---|---|
| CN1077188A true CN1077188A (en) | 1993-10-13 |
| CN1034661C CN1034661C (en) | 1997-04-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92102703 Expired - Fee Related CN1034661C (en) | 1992-04-08 | 1992-04-08 | Method of synthesis of dl-Naproxen |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309700C (en) * | 2005-05-27 | 2007-04-11 | 中国科学院上海有机化学研究所 | Prepn process of 2-ary lactate, naprosyn and ibuprofen |
| CN110183323A (en) * | 2019-07-09 | 2019-08-30 | 重庆医药高等专科学校 | The synthetic method of D, L- body naproxen |
-
1992
- 1992-04-08 CN CN 92102703 patent/CN1034661C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309700C (en) * | 2005-05-27 | 2007-04-11 | 中国科学院上海有机化学研究所 | Prepn process of 2-ary lactate, naprosyn and ibuprofen |
| CN110183323A (en) * | 2019-07-09 | 2019-08-30 | 重庆医药高等专科学校 | The synthetic method of D, L- body naproxen |
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| Publication number | Publication date |
|---|---|
| CN1034661C (en) | 1997-04-23 |
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