CN102757339A - Improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid - Google Patents
Improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid Download PDFInfo
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Abstract
The invention provides an improved preparation method of 4-(2-carboxybenzyloxy) phenylacetic acid. 6, 11-dihydro-11-oxo-dibenz (b, e) oxepin-2-acetic acid which is a raw material for producing the anti-allergic drug of olopatatadine can be obtained through a cyclization reaction of the 4-(2-carboxybenzyloxy) phenylacetic acid.
Description
Technical field
The present invention relates to as pharmaceuticals midbody 4-(2-carboxyl benzyloxy) toluylic acid and preparation method thereof.
Background technology
Preparing method as useful antihistamine H1 receptor antagonist Olopatatadine (olopatadine); In the openly flat 6-9606 of japanese; Described with 6, diene-2-acetate is the method for feedstock production Olopatatadine to 11-dihydro-11-oxo-dibenzo [b, e] oxepane; Technical process is suc as formula shown in (5)
Formula (5)
6,11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate makes through ring-closure reaction through being raw material with 4-(2-carboxyl benzyloxy) toluylic acid, for example at Chinese Journal of New Drugs, and 15 (23), 2045-2046; 2006 with USP 4082850 in 4-(2-carboxyl benzyloxy) toluylic acid its preparation method is disclosed.
At Chinese Journal of New Drugs, 15 (23), 2045-2046; The preparation method of 4-(2-carboxyl benzyloxy) toluylic acid of record is suc as formula shown in (6) in 2006, and 4-hydroxyl phenylacetic acid and sodium hydroxide solution reaction generate 4-hydroxyl phenylacetic acid disodium salt, and reactant is poured out reaction flask while hot; After the cooled and solidified hardening, grind oven dry, solvent-freely reacted 120 minutes at 200-240 ℃ with phthalide down; Be cooled to room temperature, add water and make reactants dissolved, using concentrated hydrochloric acid to transfer to the pH value is 1; Separate out solid, suction filtration, washing; The oven dry back obtains 4-(2-carboxyl benzyloxy) toluylic acid, yield 61% with ethyl alcohol recrystallization.
Formula (6)
The shortcoming of this technology is need be with aqueous 4-hydroxyl phenylacetic acid disodium through dry under the high temperature and two flow processs of pulverizing in generating 4-hydroxyl phenylacetic acid disodium process, and it is tediously long that treating processes becomes; Simultaneously, in the reaction of ensuing phthalide and 4-hydroxyl phenylacetic acid disodium salt, under molten state, react,, in actual production, be difficult to carry out because essential high temperature more than 200 ℃ is difficult to utilize the production of steam line as thermal source when considering suitability for industrialized production; Have, the yield of preparation 4-(2-carboxyl benzyloxy) toluylic acid is about 60% again.
Disclose in the USP 4082850 suc as formula the preparation method shown in (7); In tetracol phenixin; With the Lucidol is catalyzer; With 2-tolyl acid ethyl ester bromo, the sodium salt of 2-bromomethyl-benzoic acid ethyl ester that obtains and 4-hydroxyl phenylacetic acid ethyl ester reaction 16 hours obtains 4-(2-carboxyl benzyloxy) toluylic acid after the hydrolysis with N-bromosuccinimide.
Formula (7)
Yet because of the solvent tetracol phenixin that uses belongs to a kind solvent, dissolvent residual brings the problem of a series of secure contexts can for the finished product Olopatatadine in this technology; Have, use the price of N-bromosuccinimide higher, the factor of these several respects causes above-mentioned technology to be not suitable for scale operation.
In sum, there is following deficiency in synthetic 4-(2-carboxyl benzyloxy) the toluylic acid technology of disclosed preparation:
1. use dangerous high and expensive reagent such as tetracol phenixin, N-bromosuccinimide;
2. be reflected under the high temperature and carry out also, exacting terms causes enforcement scale operation to become unusual difficult;
3. adopt under the high temperature drying to dewater in the technology and pulverize, it is tediously long that treating processes becomes;
4. production cost is high;
5. yield is low, and purity is low.
Summary of the invention
The object of the present invention is to provide improving one's methods of produced in high yields 4-(2-carboxyl benzyloxy) toluylic acid, solve have in the prior art that cost is high, productive rate is low, poor stability, step are many etc. is unfavorable for the suitability for industrialized production problem.
The two lines of more having reported, Chinese Journal of New Drugs, 15 (23), 2045-2046; 2006 route advantages are bigger, concrete technology such as Chinese Journal of New Drugs, 15 (23), 2045-2046; 2006 is said, is example with the experimental section, and its synthesis technique is following:
The preparation of (1.4-2-carboxyl benzyloxy) toluylic acid
In churned mechanically there-necked flask is housed, add 4-hydroxyl phenylacetic acid, 4.4g (0.11 mole) sodium hydroxide of 15.2g (0.1 mole), add water and make it just all to dissolve; 80 ℃ were reacted 10 minutes, and reactant were poured out reaction flask while hot, after the cooled and solidified hardening; Grind oven dry, get white solid.This solid is added in the reaction flask, add phthalide 13.4g (0.1 mole), 200-240 ℃ of reaction 2h is cooled to room temperature; Add water and make reactants dissolved, using dense HCl to transfer to the pH value is 1, separates out solid, suction filtration; Washing, the oven dry back gets 17.5g with ethyl alcohol recrystallization, 182～184 ℃ of mp, yield 61%.
26, the preparation of 11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate
Add 4-(2-carboxyl benzyloxy) toluylic acid 14.3g, polyphosphoric acid 50g, Glacial acetic acid min. 99.5 50mL in the reaction flask, 80 ℃ of reaction 5h pour reaction solution in the trash ice into, use ethyl acetate extraction, and the ester layer is washed to slightly acidic, adds activated carbon decolorizing, leaches activated carbon.Use anhydrous sodium sulfate drying.Get solid 16.1g with the acetonitrile recrystallization behind the decompression and solvent recovery, yield 60%, mp:137 ℃.
The inventor is in repeating the process of this technology; Be surprisingly found out that and realize " one kettle way " preparation 4-(2-carboxyl benzyloxy) toluylic acid; In the process of preparation 4-hydroxyl phenylacetic acid disodium salt, adopt toluene or YLENE and water azeotropic can remove the water in the reaction system; And in the 4-hydroxyl phenylacetic acid disodium salt that in phthalide and last step, generates when reaction, adopt the polar aprotic solvent methyl-sulphoxide as solvent, can high yield obtain 4-(2-carboxyl benzyloxy) toluylic acid; 4-(2-carboxyl benzyloxy) toluylic acid dehydration condensation in the presence of polyphosphoric acid obtains 6,11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate.
The present invention provides a kind of improved 4-(2-carboxyl benzyloxy) the toluylic acid preparation method, it is characterized in that may further comprise the steps:
A. phthalide is dissolved in the mixed solvent of being made up of methyl-sulphoxide and a kind of varsol;
B. in methyl-sulphoxide, add the 4-hydroxyl phenylacetic acid, rising temperature for dissolving 4-hydroxyl phenylacetic acid stirs, and drips the aqueous solution of mineral alkali, controlled temperature; Add varsol, temperature rising reflux divides water, after branch water is complete, steams and removes varsol, obtains the dimethyl sulfoxide solution of PHB disodium salt;
C. obtain the half the phthalide solution that in step a, prepares, add in the 4-hydroxyl phenylacetic acid disodium salt dimethyl sulfoxide solution that obtains among the step b, varsol is steamed remove, temperature reaction reacts completely until phthalide; Add remaining phthalide solution once more, varsol is steamed remove, temperature reaction reacts completely until phthalide;
D. reaction solution is cooled to about 100 ℃, adds entry under stirring, when question response liquid is cooled to room temperature, add entry once more, with about concentrated hydrochloric acid adjust pH to 1, cooling obtains 4-(2-carboxyl benzyloxy) toluylic acid behind the filtration drying.
And with 6 of formula (4) expression, the method for manufacture of 11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate:
4-(2-carboxyl benzyloxy) toluylic acid cyclisation with formula (1) expression.
Further, the present invention provides a kind of 4-of preparation (2-carboxyl benzyloxy) method of toluylic acid, it is characterized in that may further comprise the steps:
A. phthalide is dissolved in the mixed solvent of being made up of methyl-sulphoxide and a kind of varsol;
B. in methyl-sulphoxide, add the 4-hydroxyl phenylacetic acid, be warming up to 40 ℃ of 4-hydroxyl phenylacetic acids and all dissolve, stir Dropwise 5 0% aqueous sodium hydroxide solution down, controlled temperature is no more than 95 ℃; Add varsol, temperature rising reflux divides water, after branch water is complete, steams and removes varsol, obtains the dimethyl sulfoxide solution of PHB disodium salt;
C. obtain the half the phthalide solution that in step a, prepares, add in the dimethyl sulfoxide solution of the 4-hydroxyl phenylacetic acid disodium salt that obtains among the step b, normal pressure steams and removes varsol, is warming up to 125 to 150 ℃, reacts completely until phthalide; Add remaining phthalide solution once more, normal pressure steams and removes varsol, rises to 125 to 150 ℃ of reactions once more and reacts completely until phthalide;
D. reaction solution is cooled to 100 ℃, adds entry, when reaction solution is cooled to room temperature, add entry once more, with about concentrated hydrochloric acid adjust pH to 1, stir, be cooled to 5 ℃, obtain 4-(2-carboxyl benzyloxy) toluylic acid behind the filtration drying.
And with 6 of formula (4) expression, the method for manufacture of 11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate:
With 4-(2-carboxyl benzyloxy) the toluylic acid cyclodehydration of formula (1) expression, this cyclization carries out under the polyphosphoric acid effect.
The used varsol of the said reaction of step a is selected from toluene, YLENE.
The used mineral alkali of the said reaction of step b is selected from sodium hydroxide, the consumption of sodium hydroxide be PHB 2 times more than the equivalent, 2 times of equivalents most preferably.
Among the step c consumption of phthalide be PHB 1 times more than the equivalent, 1 times of equivalent most preferably.
Phthalide and 4-hydroxyl phenylacetic acid disodium salt temperature of reaction are between 125-150 ℃ among the step c, and when toluene was solvent, most preferred temperature of reaction was between 125-140 ℃; When YLENE was solvent, most preferred temperature of reaction was between 125-140 ℃.
The reaction of phthalide and 4-hydroxyl phenylacetic acid disodium salt is a nucleophilic substitution reaction among the above-mentioned steps c; The existence of protic solvent will have a strong impact on the nucleophilicity of nucleophilic reagent; And the polar aprotic solvent can the solvation positive ion; But be difficult to the solvation negative ion, negative ion be in always be the solvation state, thereby make it have stronger nucleophilie nucleus ability; This reaction simultaneously will be carried out under comparatively high temps, and therefore, selecting boiling point is that 189 ℃ methyl-sulphoxide is as the solvent of this nucleophilic substitution reaction.
4-(2-carboxyl benzyloxy) toluylic acid cyclization carries out under the condition of common dehydration condensation, and dewatering agent commonly used comprises trifluoroacetic anhydride, polyphosphoric acid, Vanadium Pentoxide in FLAKES etc.Because there is the expensive of trifluoroacetic anhydride, and the difficult by force shortcoming of preserving and feeding intake of Vanadium Pentoxide in FLAKES water-absorbent, so select for use polyphosphoric acid to carry out ring-closure reaction as dewatering agent.
As an optimized technical scheme of the present invention, comprise the steps:
Phthalide is dissolved in methyl-sulphoxide and the toluene, and about 40 ℃ can dissolve entirely, subsequent use.
The 4-hydroxyl phenylacetic acid adds in the methyl-sulphoxide, stirs, when being heated to interior warm 48 ℃, and Dropwise 5 0% aqueous sodium hydroxide solution, exothermic heat of reaction, controlled temperature prevents to dash material below 95 ℃; Add toluene or YLENE again, temperature rising reflux begins branch water.After dividing water fully, toluene or YLENE are steamed, directly add the phthalide solution for preparing in advance of half amount approximately; Steam toluene or YLENE, be heated to 125-150 ℃ of reaction, after phthalide reacts completely basically; Add second half phthalide solution again; Steam toluene or YLENE, be heated to 125-150 ℃ of reaction, react to the effect of phthalide total overall reaction.Reaction system is cooled to add entry about 100 ℃, when treating that temperature is reduced to room temperature after, add entry, use again about concentrated hydrochloric acid adjust pH to 1, be cooled to obtain after the after-filtration drying below 5 ℃ 4-(2-carboxyl benzyloxy) toluylic acid.
Stir down, add 4-(2-carboxyl benzyloxy) toluylic acid in the reaction flask, polyphosphoric acid, Glacial acetic acid min. 99.5; Be heated to 80 ℃ of reactions, after reacting completely, reaction solution poured in the cold water; Use ethyl acetate extraction, water washing is to slightly acidic, behind the separatory; Ethyl acetate layer adds activated carbon decolorizing, reflux, filtering activated carbon while hot.Anhydrous sodium sulfate drying, remove solvent under reduced pressure after, again with obtaining 6 with the acetonitrile recrystallization, 11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate.
The invention has the advantages that:
1) adopts toluene or YLENE azeotropic water removing in the process of preparation 4-hydroxyl phenylacetic acid disodium salt; Substituted technological processs such as discharging while hot in the old technology, the dehydration of baking material, pulverizing, ethyl alcohol recrystallization bullion 4-(2-carboxyl benzyloxy) toluylic acid, shortened process step and cut down the consumption of energy.
2) preparation of 4-(2-carboxyl benzyloxy) toluylic acid needn't be used the technology in frit reaction more than 200 ℃ in the old technology, makes that reaction cost is lower and has reduced the danger of reacting, the security that has improved suitability for industrialized production.
3) adopt " one kettle way " technology high yield to make 4-(2-carboxyl benzyloxy) toluylic acid, make full use of raw material, practiced thrift cost.
Embodiment
In order to understand technical scheme of the present invention better, be described further below in conjunction with specific examples of the present invention, but it does not limit the present invention.
The preparation of embodiment one to eight 4-(2-carboxyl benzyloxy) toluylic acid
Phthalide is dissolved in methyl-sulphoxide and the toluene, and about 40 ℃ can dissolve entirely, subsequent use.
The 4-hydroxyl phenylacetic acid adds in the methyl-sulphoxide, stirs, when being heated to interior warm 48 ℃, and Dropwise 5 0% aqueous sodium hydroxide solution, exothermic heat of reaction, controlled temperature prevents to dash material below 95 ℃; Add toluene again, temperature rising reflux begins branch water.After dividing water fully, toluene is steamed, directly add the phthalide solution for preparing in advance of half amount approximately; Steam toluene, be heated to 125-140 ℃ of reaction, after phthalide reacts completely basically; Add second half phthalide solution again; Steam toluene, be heated to 125-140 ℃ of reaction, react to the effect of phthalide total overall reaction.Reaction system is cooled to add entry about 100 ℃, when treating that temperature is reduced to room temperature after, add entry, use again about concentrated hydrochloric acid adjust pH to 1, be cooled to below 5 ℃, obtain 4-(2-carboxyl benzyloxy) toluylic acid behind the filtration drying.Yellow solid, fusing point 182-184 ℃.
1H-NMR(DMS0-d
6)：3.49(s，2H)，5.43(s，2H)，6.91(d，2H，J＝8.7Hz)，7.18(d，2H)，7.39(t，1H)，7.55(t，1H)，7.69(d，1H)，8.00(d，1H)。
Concrete charging capacity and result see table 1:
Charging capacity and the detected result of table 1 embodiment one to eight
The preparation of embodiment nine to 16 4-(2-carboxyl benzyloxy) toluylic acid
Phthalide is dissolved in methyl-sulphoxide and the YLENE, and about 40 ℃ can dissolve entirely, subsequent use.
The 4-hydroxyl phenylacetic acid adds in the methyl-sulphoxide, stirs, when being heated to interior warm 48 ℃, and Dropwise 5 0% aqueous sodium hydroxide solution, exothermic heat of reaction, controlled temperature prevents to dash material below 95 ℃; Add YLENE again, temperature rising reflux begins branch water.After dividing water fully, YLENE is steamed, directly add the phthalide solution for preparing in advance of half amount approximately; Steam YLENE, be heated to 140-150 ℃ of reaction, after phthalide reacts completely basically; Add second half phthalide solution again; Steam YLENE, be heated to 140-150 ℃ of reaction, react to the effect of phthalide total overall reaction.Reaction system is cooled to add entry about 100 ℃, when treating that temperature is reduced to room temperature after, add entry, use again about concentrated hydrochloric acid adjust pH to 1, be cooled to below 5 ℃, obtain 4-(2-carboxyl benzyloxy) toluylic acid behind the filtration drying.Yellow solid, fusing point 182-184 ℃.Concrete charging capacity and result see table 2:
The charging capacity of table 2 embodiment two and detected result
Embodiment 17, the preparation preparation of 11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate
Stir down, add 28.6g 4-(2-carboxyl benzyloxy) toluylic acid, 100g polyphosphoric acid, 100ml Glacial acetic acid min. 99.5 in the reaction flask; Be heated to 80 ℃ of reactions 5 hours, after reacting completely, reaction solution poured in the cold water; With 100ml * 3 ethyl acetate extractions, with 200ml * 3 water washings to slightly acidic, behind the separatory; Ethyl acetate layer adds 3g activated carbon decolorizing, reflux 30 minutes, filtering activated carbon while hot.Anhydrous sodium sulfate drying removes ETHYLE ACETATE under reduced pressure behind the filtering siccative, uses 65ml1 again: 1 (v/v) ETHYLE ACETATE-normal hexane recrystallization obtains 6,11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate.It is light yellow to the off-white color solid to obtain 15.6 grams after the drying, and yield is 58%, and fusing point 137-139 ℃, HPLC purity 99.47%.
1H-NMR(DMSO-d
6)：3.69(s，2H)，5.19(s，2H)，7.03(d，1H)，7.36(d，1H)，7.45(m，2H)，7.55(d，1H)，7.88(d，1H)，8.12(s，1H)。
Claims (10)
1. 4-(2-carboxyl benzyloxy) toluylic acid of representing with formula (1),
2. with the method for manufacture of 4-(2-carboxyl benzyloxy) toluylic acid of formula (1) expression,
Wherein, make the 4-hydroxyl phenylacetic acid of formula (2) expression and the phthalide reaction of formula (3) expression,
3. an improved 4-(2-carboxyl benzyloxy) toluylic acid preparation method is characterized in that may further comprise the steps:
A. phthalide is dissolved in the mixed solvent of being made up of methyl-sulphoxide and a kind of varsol;
B. in methyl-sulphoxide, add the 4-hydroxyl phenylacetic acid, rising temperature for dissolving 4-hydroxyl phenylacetic acid stirs, and drips the aqueous solution of mineral alkali, controlled temperature; Add varsol, temperature rising reflux divides water, after branch water is complete, steams and removes varsol, obtains the dimethyl sulfoxide solution of PHB disodium salt;
C. obtain the half the phthalide solution that in step a, prepares, add in the 4-hydroxyl phenylacetic acid disodium salt dimethyl sulfoxide solution that obtains among the step b, varsol is steamed remove, temperature reaction reacts completely until phthalide; Add remaining phthalide solution once more, varsol is steamed remove, temperature reaction reacts completely until phthalide;
D. reaction solution is cooled to about 100 ℃, adds entry under stirring, when question response liquid is cooled to room temperature, add entry once more, with about concentrated hydrochloric acid adjust pH to 1, cooling obtains 4-(2-carboxyl benzyloxy) toluylic acid behind the filtration drying.
4. like the method for the said preparation of claim 2-(2-carboxyl benzyloxy) toluylic acid, it is characterized in that may further comprise the steps:
A. phthalide is dissolved in the mixed solvent of being made up of methyl-sulphoxide and a kind of varsol;
B. in methyl-sulphoxide, add the 4-hydroxyl phenylacetic acid, be warming up to 40 ℃ of 4-hydroxyl phenylacetic acids and all dissolve, stir Dropwise 5 0% aqueous sodium hydroxide solution down, controlled temperature is no more than 95 ℃; Add varsol, temperature rising reflux divides water, after branch water is complete, steams and removes varsol, obtains the dimethyl sulfoxide solution of PHB disodium salt;
C. obtain the half the phthalide solution that in step a, prepares, add in the dimethyl sulfoxide solution of the 4-hydroxyl phenylacetic acid disodium salt that obtains among the step b, normal pressure steams and removes varsol, is warming up to 125 to 150 ℃, reacts completely until phthalide; Add remaining phthalide solution once more, normal pressure steams and removes varsol, rises to 125 to 150 ℃ of reactions once more and reacts completely until phthalide;
D. reaction solution is cooled to 100 ℃, adds entry, when reaction solution is cooled to room temperature, add entry once more, with about concentrated hydrochloric acid adjust pH to 1, stir, be cooled to 5 ℃, obtain 4-(2-carboxyl benzyloxy) toluylic acid behind the filtration drying.
5. require 3 or 4 method according to aforesaid right, it is characterized in that the used varsol of the said reaction of step a is selected from toluene, YLENE.
6. require 3 or 4 method according to aforesaid right, it is characterized in that the mineral alkali among the step b is selected from sodium hydroxide, the consumption of sodium hydroxide be PHB 2 times of equivalents.
7. require 3 or 4 method according to aforesaid right, the consumption that it is characterized in that phthalide among the step c be PHB 1 times of equivalent.
8. require 3 or 4 method according to aforesaid right, it is characterized in that phthalide and 4-hydroxyl phenylacetic acid disodium salt temperature of reaction are between 125-150 ℃ among the step c.
9. with 6 of formula (4) expression, the method for manufacture of 11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate:
4-(2-carboxyl benzyloxy) toluylic acid cyclisation with formula (1) expression.
10. require 9 method according to aforesaid right, it is characterized in that using polyphosphoric acid to obtain 6,11-dihydro-11-oxo-dibenzo [b, e] oxepane diene-2-acetate as dewatering agent cyclisation 4-(2-carboxyl benzyloxy) toluylic acid.
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| CN114805302A (en) * | 2022-06-08 | 2022-07-29 | 北京联本医药化学技术有限公司 | Preparation method of 4- [ (4-chlorphenyl) -2-pyridylmethoxy ] -1-piperidine carboxylate |
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| CN106518833A (en) * | 2015-09-15 | 2017-03-22 | 江苏吉贝尔药业股份有限公司 | New method for preparation of 6,11-dihydro-11-oxo dibenzo [b, e] oxepin-2-acetic acid |
| CN114805302A (en) * | 2022-06-08 | 2022-07-29 | 北京联本医药化学技术有限公司 | Preparation method of 4- [ (4-chlorphenyl) -2-pyridylmethoxy ] -1-piperidine carboxylate |
| CN114805302B (en) * | 2022-06-08 | 2024-04-12 | 北京联本医药化学技术有限公司 | Preparation method of 4- [ (4-chlorophenyl) -2-pyridylmethoxy ] -1-piperidine carboxylic ester |
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