CN106146308A - Alpha, alpha-dimethyl-4-(2-halogen acetyl group) purification process of phenylacetate - Google Patents
Alpha, alpha-dimethyl-4-(2-halogen acetyl group) purification process of phenylacetate Download PDFInfo
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- CN106146308A CN106146308A CN201510166640.4A CN201510166640A CN106146308A CN 106146308 A CN106146308 A CN 106146308A CN 201510166640 A CN201510166640 A CN 201510166640A CN 106146308 A CN106146308 A CN 106146308A
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- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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Abstract
The invention discloses a kind of α; the purification process of alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate; use alkane solvents or alcohols solvent or both mixed solvents that α, alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate is carried out recrystallization.This method is used to prepare α; alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate, can remove the impurity such as its position isomer α, alpha-alpha-dimethyl-3-(2-halogen acetyl group) phenylacetate completely; products obtained therefrom chemical purity is high, is suitable as intermediate and prepares bilastine.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the purification process of α, alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate.
Background technology
Bilastine (Bilastine) is that 2nd generation is administered orally non-sedating histamine H 1 receptor antagonist, FAES drugmaker of Spain develop, and in 2010 Nian Huo European Union, approval is used for treating allergic rhinitis and chronic idiopathic urticaria.This product required dosage is little, safety range is big, variable with antihistamine drug exist to maincenter neuroleptic effect and the toxic and side effects to cardiovascular system.Its chemical constitution is as shown in Formula II:
Patent application CN102675101A, CN104326909A disclose bilastine intermediate α; the preparation method of alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate; use following reaction, i.e. alpha-alpha-dimethyl phenyl acetic acid ester and halogen acetyl halide generation friedel-crafts acylation:
Friedel-crafts acylation is a class Reaction of Aromatic Electrophilic Substitution, under lewis acidic catalytic condition, and carboxylic acid halides and phenyl ring generation acylation reaction.According to the difference of seeking group on phenyl ring, the site that acylation reaction occurs is the most different.But inevitably, have a small amount of position isomer to generate.Such as in above-mentioned reaction, we just observe the generation of meta-isomer α, alpha-alpha-dimethyl-3-(2-halogen acetyl group) phenylacetate.Owing to para-position product and metacompaund polarity are close, separate the most difficult.And due to the existence of impurity, product presents grease, bring very big inconvenience to storage and transport.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of purification of alpha, the method for alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate (Formulas I), removes impurity therein, the position isomer especially introduced in friedel-crafts acylation.
R is the alkyl of C1～C6, and X is halogen.
Purification process of the present invention is to use alkane solvents or alcohols solvent or its mixed solvent that alpha, alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate crude product is carried out recrystallization.
Preferably, R is methyl or ethyl.
Preferably, X is chlorine or bromine.
Described alkane solvents is normal hexane, hexamethylene, normal heptane, petroleum ether.
Described alcohols solvent is methanol, ethanol, normal propyl alcohol, isopropanol.
In described mixed solvent, alkane solvents is preferably 1:1～10:1 with the volume ratio of alcohols solvent.
The inventive method specifically comprise the following steps that 1) in alpha, alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate crude product add recrystallization solvent；2) return stirring, until dissolving；3) room temperature crystallize it is cooled to；4) filter, wash, be vacuum dried.
Beneficial effects of the present invention: the purification of alpha that the present invention provides; the method of alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate can remove its position isomer α the most completely; the impurity such as alpha-alpha-dimethyl-3-(2-halogen acetyl group) phenylacetate; and yield is higher; the α obtained; alpha-alpha-dimethyl-4-(2-halogen acetyl group) its chemical purity of phenylacetate is all more than 99.5%; this product synthesizes bilastine as intermediate; it is effectively reduced the kind of bilastine lmpurities, improves crude drug quality；And obtained α, alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate improves due to purity, and product presents solid rather than grease, convenient storage and transport.
Accompanying drawing explanation
The HPLC collection of illustrative plates of Fig. 1: alpha, alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product
The HPLC collection of illustrative plates of products obtained therefrom after Fig. 2: embodiment 1 recrystallization
The HPLC collection of illustrative plates of products obtained therefrom after Fig. 3: reference example 1 recrystallization
Specific embodiment
Following embodiment is preferred embodiment in order to demonstrate the invention, the protection domain being not meant to limit the present invention.
The crude product of alpha, alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate uses the method in patent application CN102675101A or CN104326909A to prepare.
Embodiment 1
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product 25g, add 200mL normal hexane; return stirring 3-5 hour, until being completely dissolved, is cooled to room temperature; stirring and crystallizing 5-7 hour; filtering product, and wash with 20mL normal hexane, it is vacuum dried at 40 DEG C; obtain white crystal 18.7g; productivity 75%, HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate is 100%.
Embodiment 2
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product 25g, add 200mL hexamethylene; return stirring 3-5 hour, until being completely dissolved, is cooled to room temperature; stirring and crystallizing 5-7 hour; filtering product, and wash with 20mL hexamethylene, it is vacuum dried at 40 DEG C; obtain white crystal 19.2g; productivity 77%, HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate is 99.8%.
Embodiment 3
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product 25g, add 200mL normal heptane; return stirring 3-5 hour; until being completely dissolved, it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product; and wash with 20mL normal heptane; it is vacuum dried at 50 DEG C, obtains white crystal 19.1g, productivity 76%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate is 100%.
Embodiment 4
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate crude product 25g, add 200mL petroleum ether; return stirring 3-5 hour; until being completely dissolved, it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product; and use 20mL petroleum ether; it is vacuum dried at 40 DEG C, obtains white crystal 18.3g, productivity 73%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate is 99.8%.
Embodiment 5
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate crude product 25g, add 150mL methanol; return stirring 3-5 hour; until being completely dissolved, it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product; and wash with 10mL methanol; it is vacuum dried at 40 DEG C, obtains white crystal 17.8g, productivity 71%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate is 99.8%.
Embodiment 6
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate crude product 25g, add 150mL ethanol; return stirring 3-5 hour; until being completely dissolved, it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product; and use 10mL washing with alcohol; it is vacuum dried at 40 DEG C, obtains white crystal 18.8g, productivity 75%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate is 99.9%.
Embodiment 7
Take α, alpha-alpha-dimethyl-4-(2-chloracetyl) ethyl phenylacetate crude product 25g, add 150mL isopropanol; return stirring 3-5 hour; until being completely dissolved, it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product; and wash with 10mL isopropanol; it is vacuum dried at 40 DEG C, obtains white crystal 18.2g, productivity 73%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-chloracetyl) ethyl phenylacetate is 99.8%.
Embodiment 8
Take α; alpha-alpha-dimethyl-4-(2-chloracetyl) ethyl phenylacetate crude product 25g; add 200mL normal hexane and the mixed solvent (v:v=1:1) of methanol; return stirring 3-5 hour; until being completely dissolved; it is cooled to crystallize is stirred at room temperature 5-7 hour; filtering product; and wash with 20mL normal hexane; it is vacuum dried at 40 DEG C, obtains white crystal 17.7g, productivity 71%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-chloracetyl) ethyl phenylacetate is 99.9%.
Embodiment 9
Take α; alpha-alpha-dimethyl-4-(2-chloracetyl) methyl phenylacetate crude product 25g; add 200mL hexamethylene and the mixed solvent (v:v=10:1) of ethanol; return stirring 3-5 hour; until being completely dissolved; it is cooled to crystallize is stirred at room temperature 5-7 hour; filtering product; and wash with 20mL normal hexane; it is vacuum dried at 40 DEG C, obtains white crystal 17.5g, productivity 70%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-chloracetyl) methyl phenylacetate is 99.8%.
Embodiment 10
Take α; alpha-alpha-dimethyl-4-(2-chloracetyl) methyl phenylacetate crude product 25g; add 200mL petroleum ether and the mixed solvent (v:v=5:1) of isopropanol; return stirring 3-5 hour; until being completely dissolved; it is cooled to crystallize is stirred at room temperature 5-7 hour; filtering product; and wash with 20mL normal hexane; it is vacuum dried at 40 DEG C, obtains white crystal 17.9g, productivity 72%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-chloracetyl) methyl phenylacetate is 100%.
Embodiment 11
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) phenylacetic acid own ester crude product 25g, add 200mL petroleum ether; return stirring 3-5 hour; until being completely dissolved, it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product; and use 20mL petroleum ether; it is vacuum dried at 40 DEG C, obtains white crystal 18.1g, productivity 72%; HPLC shows that the purity of α, alpha-alpha-dimethyl-4-(2-acetyl bromide) the own ester of phenylacetic acid is 99.8%.
Reference example 1
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product 25g, add 200mL dichloromethane; return stirring 3-5 hour is until dissolving; it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product, and washs with 20mL dichloromethane; it is vacuum dried at 40 DEG C; obtaining white crystal 15.7g, productivity 63%, HPLC shows α; the purity of alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate is 98.9%, and meta-isomer content is 1.1%.
Reference example 2
Take α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product 25g, add 200mL acetone; return stirring 3-5 hour is until dissolving; it is cooled to crystallize is stirred at room temperature 5-7 hour, filtering product, and uses 20mL washing with acetone; it is vacuum dried at 40 DEG C; obtaining white crystal 15.0g, productivity 60%, HPLC shows α; the purity of alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate is 97.5%, and meta-isomer content is 2.50%.
Reference example 3
Taking α, alpha-alpha-dimethyl-4-(2-acetyl bromide) ethyl phenylacetate crude product 25g, add 200mL ethyl acetate, return stirring 3-5 hour, until dissolving, is cooled to be stirred at room temperature 5-7 hour, separates out without crystal.
Claims (9)
1. the purification process of the α shown in Formulas I, alpha-alpha-dimethyl-4-(2-halogen acetyl group) phenylacetate, it is characterised in that to α, alpha-alpha-dimethyl-4-
(2-halogen acetyl group) phenylacetate crude product carries out recrystallization, recrystallization solvent selected from alkane solvents or alcohols solvent or both
Mixed solvent,
R is the alkyl of C1～C6, and X is halogen.
Purification process the most according to claim 1, it is characterised in that R is methyl.
Purification process the most according to claim 1, it is characterised in that R is ethyl.
Purification process the most according to claim 1, it is characterised in that X is chlorine.
Purification process the most according to claim 1, its feature is bromine at X.
Purification process the most according to claim 1, it is characterised in that described alkane solvents preferably is selected from normal hexane, hexamethylene, just
One or more in heptane, petroleum ether.
Purification process the most according to claim 1, it is characterised in that described alcohols solvent preferably be selected from methanol, ethanol, normal propyl alcohol,
One or more in isopropanol.
Purification process the most according to claim 1, it is characterised in that alkane solvents and the body of alcohols solvent in described mixed solvent
Long-pending ratio preferably 1:1～10:1.
9. according to the purification process described in any one of claim 1～8, it is characterised in that comprise the following steps: 1) at α, alpha-alpha-dimethyl-4-
(2-halogen acetyl group) phenylacetate crude product adds recrystallization solvent；2) return stirring, until dissolving；3) room temperature analysis it is cooled to
Brilliant；4) filter, wash, be vacuum dried.
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| CN201510166640.4A CN106146308A (en) | 2015-04-09 | 2015-04-09 | Alpha, alpha-dimethyl-4-(2-halogen acetyl group) purification process of phenylacetate |
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| CN201510166640.4A CN106146308A (en) | 2015-04-09 | 2015-04-09 | Alpha, alpha-dimethyl-4-(2-halogen acetyl group) purification process of phenylacetate |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5322850A (en) * | 1992-07-20 | 1994-06-21 | Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. | Antiallergic piperidine derivatives of benzimidazole |
| ES2151442A1 (en) * | 1999-01-11 | 2000-12-16 | Espanola Prod Quimicos | Benzene ethanol derivative for antihistamine products consists of a composition based on a methyl bromo benzene acetate |
| CN101952273A (en) * | 2008-02-12 | 2011-01-19 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
| CN102675101A (en) * | 2012-05-16 | 2012-09-19 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
| CN104276952A (en) * | 2013-07-11 | 2015-01-14 | 南京华威医药科技开发有限公司 | Preparation method of bilastine key intermediate |
-
2015
- 2015-04-09 CN CN201510166640.4A patent/CN106146308A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5322850A (en) * | 1992-07-20 | 1994-06-21 | Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. | Antiallergic piperidine derivatives of benzimidazole |
| ES2151442A1 (en) * | 1999-01-11 | 2000-12-16 | Espanola Prod Quimicos | Benzene ethanol derivative for antihistamine products consists of a composition based on a methyl bromo benzene acetate |
| CN101952273A (en) * | 2008-02-12 | 2011-01-19 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
| CN102675101A (en) * | 2012-05-16 | 2012-09-19 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
| CN104276952A (en) * | 2013-07-11 | 2015-01-14 | 南京华威医药科技开发有限公司 | Preparation method of bilastine key intermediate |
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Application publication date: 20161123 |