CN107903217B - Preparation method of anagrelide impurity B - Google Patents
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- CN107903217B CN107903217B CN201711139146.4A CN201711139146A CN107903217B CN 107903217 B CN107903217 B CN 107903217B CN 201711139146 A CN201711139146 A CN 201711139146A CN 107903217 B CN107903217 B CN 107903217B
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Abstract
The invention discloses a preparation method of an anagrelide impurity B, wherein the anagrelide impurity B has a structure shown as a formula I:
is prepared by carrying out nitration reaction, reduction reaction, halogenation reaction, condensation reaction and hydrolysis reaction on 2, 3-dichlorobenzaldehyde; the main reactions in the preparation method of the anagrelide impurity B are common reaction types, the operation and the post-treatment are simple, no special requirements are met, and the normal pressure operation is realized. The invention makes up the blank that the preparation method is not available at home and abroad, and can also reduce the cost of developing the variety by pharmaceutical enterprises.
Description
Technical Field
The invention relates to a preparation method of an anagrelide impurity B.
Background
Anagrelide hydrochloride is an adenosine cyclophosphate phosphodiesterase III inhibitor and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of essential thrombocythemia in 1997 to reduce platelet counts and prevent the risk of thrombosis, and was then marketed in canada and the european union, and is currently not marketed in china for a while. Anagrelide impurity B is one of the major impurities in Anagrelide hydrochloride United states Pharmacopeia Standard (USP) and European Pharmacopeia Standard (EP), and has the chemical name of (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetic acid. The molecular structure is shown in the following chart:
the anagrelide impurity B is one of the important impurities of anagrelide hydrochloride, the deep research on the anagrelide impurity B has great significance for developing the anagrelide hydrochloride product, the synthetic research on the anagrelide impurity B makes up the domestic and foreign literature reports without preparation methods, and the cost for developing the anagrelide product by pharmaceutical enterprises can be reduced.
Disclosure of Invention
Based on the defects of the prior art, the technical problem to be solved by the invention is to provide a preparation method of the anagrelide impurity B, wherein the main reactions in the preparation method of the anagrelide impurity B are common reaction types, including nitration reaction, reduction reaction, halogenation reaction, condensation reaction and hydrolysis reaction, and the reactions are characterized by simple operation and post-treatment, no special requirements and normal-pressure operation.
In order to solve the technical problem, the invention provides a preparation method of an anagrelide impurity B, wherein the anagrelide impurity B has a structure shown as a formula I:
the method is characterized by comprising the following steps:
step one, carrying out nitration reaction on the compound II to obtain a compound III;
secondly, carrying out reduction reaction on the compound III to obtain a compound IV;
thirdly, carrying out reduction reaction on the compound IV to obtain a compound V;
step four, performing chlorination and condensation reaction on the compound V to obtain a compound VI;
fifthly, carrying out cyclization reaction on the compound VI to obtain a compound VII;
sixthly, hydrolyzing the compound VII to obtain a compound I, namely the anagrelide impurity B;
wherein the compound I is anagrelide impurity B, the compound II is 2, 3-dichlorobenzaldehyde, the compound III is 2, 3-dichloro-6-nitrobenzaldehyde, the compound IV is 2, 3-dichloro-6-nitrobenzyl alcohol, the compound V is 2, 3-dichloro-6-aminobenzyl alcohol, the compound VI is N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester, and the compound VII is 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide.
As a preferred aspect of the above technical solution, the preparation method of anagrelide impurity B provided by the present invention further comprises a part or all of the following technical features:
as an improvement of the above technical scheme, in the first step, 2, 3-dichlorobenzaldehyde (II) undergoes a nitration reaction to obtain 2, 3-dichloro-6-nitrobenzaldehyde (III);
the nitration reaction is to drop concentrated nitric acid into a mixture of 2, 3-dichlorobenzaldehyde and concentrated sulfuric acid in a mass-to-volume ratio of 1:5-10, wherein the mass ratio of the 2, 3-dichlorobenzaldehyde to the concentrated nitric acid is 2-3: 1, then quenching, filtering and drying a filter cake to obtain the 2, 3-dichloro-6-nitrobenzaldehyde.
2, 3-dichloro-6-nitrobenzaldehyde (III) is subjected to reduction reaction to obtain 2, 3-dichloro-6-nitrobenzyl alcohol (IV);
as an improvement of the technical scheme, in the second step, the molar ratio of the 2, 3-dichloro-6-nitrobenzaldehyde to the reducing agent is 4-5: 1, the reducing agent and toluene are mixed according to the mass volume ratio of 1:30-50 to obtain a solution A, the 2, 3-dichloro-6-nitrobenzaldehyde and toluene are mixed according to the mass volume ratio of 1:5-10 to obtain a solution B, the solution B is dropwise added into the solution A to react for 3-5h, quenching and liquid separation are carried out, the organic phase is dried by anhydrous magnesium sulfate and then filtered, and the filtrate is subjected to reduced pressure concentration to obtain the 2, 3-dichloro-6-nitrobenzyl alcohol.
As an improvement of the above technical solution, in the second step, the reducing agent used in the reduction reaction is selected from sodium borohydride, lithium aluminum hydride or borane.
2, 3-dichloro-6-nitrobenzyl alcohol (IV) is subjected to reduction reaction to obtain 2, 3-dichloro-6-aminobenzyl alcohol (V);
as an improvement of the technical scheme, in the third step, the molar ratio of the 2, 3-dichloro-6-nitrobenzyl alcohol to the reducing agent is 1: 5-7; mixing and stirring 2, 3-dichloro-6-nitrobenzyl alcohol and concentrated hydrochloric acid according to the mass volume ratio of 1:5-10 to obtain a solution C, mixing stannous chloride and concentrated hydrochloric acid according to the mass volume ratio of 1:3-6 to obtain a solution D, dropwise adding the solution D into the solution C, stirring and reacting at room temperature for 1-3 hours after dropwise adding is finished, filtering, and drying a filter cake to obtain the 2, 3-dichloro-6-aminobenzyl alcohol.
As an improvement of the above technical solution, in the third step, a reducing agent is used in the reduction reaction and the reaction is carried out under an acidic condition; the reducing agent is selected from stannous chloride, iron powder or zinc powder; the acid is selected from hydrochloric acid, acetic acid or ammonium chloride.
2, 3-dichloro-6-aminobenzyl alcohol (V) is subjected to chlorination and condensation reaction to obtain N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester (VI);
in the fourth step, the molar ratio of the 2, 3-dichloro-6-aminobenzyl alcohol, the chlorinated reagent, the glycine tert-butyl ester hydrochloride and the acid-binding agent is 1: 1-3: 4-6: 6-9; mixing 2, 3-dichloro-6-aminobenzyl alcohol and benzene according to the mass-to-volume ratio of 1:7-10, slowly dropwise adding a chlorinated reagent, reacting at 70-80 ℃ for 1-2h after dropwise adding is finished, and concentrating the reaction solution under reduced pressure until the reaction solution is dried to obtain a reddish-brown solid; mixing the obtained red brown solid and benzene according to the mass volume ratio of 1:10-15 to obtain a solution E, mixing the tert-butyl glycinate hydrochloride, the acid binding agent and the benzene according to the mass volume ratio of 1:0.6-1.0:15-20 to obtain a solution F, dripping the solution E into the solution F, reacting at 40-50 ℃ for 3-5h after finishing dripping, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain the tert-butyl N- (2, 3-dichloro-6-amino-benzyl) glycinate.
In the fourth step, a chlorinating reagent used in the chlorination reaction is selected from thionyl chloride, oxalyl chloride or phosphorus oxychloride; the acid-binding agent used in the condensation reaction is selected from triethylamine, dimethylformamide or 4-dimethylaminopyridine.
Carrying out cyclization reaction on N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester (VI) to obtain 2- (2-amino-5, 6-dichloroquinazoline-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide (VII);
as an improvement of the technical scheme, in the fifth step, the molar ratio of N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester to cyanogen bromide is 1: 2-3; mixing N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester, an acid-binding agent and ethanol according to the mass volume ratio of 1:0.5-0.7:5-10, stirring for dissolving, adding cyanogen bromide, reacting for 3-4H, and concentrating under reduced pressure to obtain 2- (2-amino-5, 6-dichloroquinazoline-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide.
As an improvement of the technical scheme, an acid-binding agent used in the ring-closing reaction in the step five is selected from triethylamine, dimethylformamide or 4-dimethylaminopyridine.
2- (2-amino-5, 6-dichloroquinazoline-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide (VII) is hydrolyzed to obtain anagrelide impurity B (I).
In the sixth step, the molar ratio of tert-butyl 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate hydrobromide to hydrobromic acid is 1: 1-3; mixing tert-butyl 2- (2-amino-5, 6-dichloroquinazoline-3 (4H) -yl) acetate hydrobromide and benzene according to the mass-to-volume ratio of 1:15-20, dropwise adding hydrobromic acid while stirring, reacting for 2-3H, and concentrating under reduced pressure to obtain an anagrelide impurity B.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects: the invention provides a preparation method of the anagrelide impurity B, which makes up the blank that no preparation method exists at home and abroad, and can also reduce the cost of developing the anagrelide impurity B by pharmaceutical enterprises; the main reactions in the preparation method of the anagrelide impurity B are common reaction types, including nitration reaction, reduction reaction, halogenation reaction, condensation reaction and hydrolysis reaction, and the reactions are characterized by simple operation and post-treatment, no special requirements and normal pressure operation.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a nuclear magnetic resonance spectrum of a product obtained in step (1) of an example of the present invention;
FIG. 2 is a LCMS spectrum of the product obtained in step (2) of the example of the present invention;
FIG. 3 is a LCMS spectrum of the product obtained in step (3) of the example of the present invention;
FIG. 4 is a nuclear magnetic resonance spectrum of a product obtained in step (3) of an example of the present invention;
FIG. 5 is a LCMS spectrum of the product obtained in step (5) of the example of the present invention;
FIG. 6 is a LCMS spectrum of the product obtained in step (6) of the example of the present invention.
Detailed Description
Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.
Unless otherwise indicated, the materials and reagents used in the following examples are conventional in the art and may be purchased commercially; the methods used are also all routine experimental methods well known in the art.
Example (b):
the synthetic steps of the anagrelide impurity B are as follows:
step (1): adding 20.0g of 2, 3-dichlorobenzaldehyde (II) and 200ml of concentrated sulfuric acid into a three-necked bottle, slowly dropwise adding 10g of concentrated nitric acid, and reacting for 1-2h after dropwise adding. After the reaction, the reaction solution was poured into 2L of ice water to quench, filtered, and the filter cake was dried under reduced pressure to obtain 10.0g of 2, 3-dichloro-6-nitrobenzaldehyde (III);
1H NMR(400MHz,CDCl3)δ:7.78(d,1H),8.02(d,1H),10.36(s,1H)。
step (2): adding 0.35g of sodium borohydride and 15ml of toluene into a three-necked bottle, dissolving 10.0g of 2, 3-dichloro-6-nitrobenzaldehyde (III) into 50ml of toluene, dropwise adding the mixed solution into the three-necked bottle, reacting for 3-5h after dropwise adding, adding 10ml of water for quenching, separating liquid, drying an organic phase anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 9.2g of 2, 3-dichloro-6-nitrobenzyl alcohol (IV);
LC/MS(m/s)[ES-API]:204.0[M+1-H2O]+,206.1[M+3-H2O]+,208.1[M+5-H2O]+。
and (3): adding 80ml of concentrated hydrochloric acid and 9.0g of 2, 3-dichloro-6-nitrobenzyl alcohol (IV) into a three-necked bottle, stirring, dissolving 59.3g of stannous chloride into 200ml of concentrated hydrochloric acid, dropwise adding the mixed solution into the three-necked bottle, stirring and reacting at room temperature for 1-3h after dropwise adding, filtering, and drying a filter cake to obtain 6.3g of 2, 3-dichloro-6-aminobenzyl alcohol (V);
LC/MS(m/s)[ES-API]:174.1[M+1-H2O]+,176.1[M+3-H2O]+,178.2[M+5-H2O]+,192.0[M+1]+,193.9[M+3]+,196.1[M+5]+；
1H NMR(400MHz,CDCl3)δ:4.35(s,2H),4.94(s,2H),6.58(d,1H),7.20(d,1H)。
and (4): adding 6.0g of 2, 3-dichloro-6-aminobenzyl alcohol (V) and 60ml of benzene into a reaction bottle, slowly dropwise adding 5.6g of thionyl chloride, reacting at 70-80 ℃ for 1-2h after dropwise adding, and concentrating the reaction solution under reduced pressure until the reaction solution is dried to obtain a reddish brown solid; dissolving the obtained reddish brown solid with 100ml of benzene, dripping the mixed solution into 300ml of benzene solution of 21.0g of glycine tert-butyl ester hydrochloride and 20.0g of triethylamine, reacting at 40-50 ℃ for 3-5h after dripping is finished, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain 4.5g N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester VI);
and (5): adding 2.5g of triethylamine, 4.0g of 4.0g N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester (VI) and 20ml of ethanol into a three-necked flask, stirring to dissolve, adding 4.2g of cyanogen bromide, reacting for 3-4H, and concentrating under reduced pressure to obtain 4.0g of 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide (VII);
LC/MS(m/s)[ES-API]:330.1[M+1]+,332.1[M+3]+,334.1[M+5]+。
and (6): 50ml of benzene and 4.0g of tert-butyl 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate hydrobromide (VII) were added to a three-necked flask, and 1ml of hydrobromic acid was added dropwise with stirring, reacted for 2-3H, and concentrated under reduced pressure to obtain 1.0g of an impurity B (I) of anagrelide.
LC/MS(m/s)[ES-API]:274.0[M+1]+,276.1[M+3]+,278.1[M+5]+。
The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (1)
1. A preparation method of an anagrelide impurity B, wherein the anagrelide impurity B has a structure shown in a formula I:
the method is characterized by comprising the following steps:
step one, carrying out nitration reaction on the compound II to obtain a compound III; the nitration reaction comprises the steps of dropwise adding concentrated nitric acid into a mixture of 2, 3-dichlorobenzaldehyde and concentrated sulfuric acid in a mass-to-volume ratio of 1:5-10, wherein the mass ratio of the 2, 3-dichlorobenzaldehyde to the concentrated nitric acid is 2-3: 1, then quenching, filtering, and drying a filter cake to obtain 2, 3-dichloro-6-nitrobenzaldehyde;
secondly, carrying out reduction reaction on the compound III to obtain a compound IV; the molar ratio of the 2, 3-dichloro-6-nitrobenzaldehyde to the reducing agent is 4-5: 1, the reducing agent and toluene are mixed according to the mass volume ratio of 1:30-50 to obtain a solution A, the 2, 3-dichloro-6-nitrobenzaldehyde and toluene are mixed according to the mass volume ratio of 1:5-10 to obtain a solution B, the solution B is dropwise added into the solution A, the reaction is carried out for 3-5h, quenching and liquid separation are carried out, the organic phase anhydrous magnesium sulfate is dried and then filtered, and the filtrate is concentrated under reduced pressure to obtain the 2, 3-dichloro-6-nitrobenzyl alcohol; the reducing agent used in the reduction reaction is selected from sodium borohydride, lithium aluminum hydride or borane;
thirdly, carrying out reduction reaction on the compound IV to obtain a compound V; reducing agent is used in the reduction reaction and the reaction is carried out under the acidic condition; the reducing agent is selected from stannous chloride, iron powder or zinc powder; the acid is selected from hydrochloric acid, acetic acid or ammonium chloride;
step four, performing chlorination and condensation reaction on the compound V to obtain a compound VI; the chlorination reaction uses a chlorination reagent selected from thionyl chloride, oxalyl chloride or phosphorus oxychloride; the acid-binding agent used in the condensation reaction is selected from triethylamine, dimethylformamide or 4-dimethylaminopyridine;
fifthly, carrying out cyclization reaction on the compound VI to obtain a compound VII; an acid-binding agent used in the cyclization reaction is selected from triethylamine, dimethylformamide or 4-dimethylaminopyridine;
sixthly, hydrolyzing the compound VII to obtain a compound I, namely the anagrelide impurity B; the molar ratio of tert-butyl 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate hydrobromide to hydrobromic acid is 1: 1-3; mixing tert-butyl 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate hydrobromide and benzene at a mass-to-volume ratio of 1:15-20, dropwise adding hydrobromic acid while stirring, reacting for 2-3h, and concentrating under reduced pressure to obtain an anagrelide impurity B;
wherein the compound I is anagrelide impurity B, the compound II is 2, 3-dichlorobenzaldehyde, the compound III is 2, 3-dichloro-6-nitrobenzaldehyde, the compound IV is 2, 3-dichloro-6-nitrobenzyl alcohol, the compound V is 2, 3-dichloro-6-aminobenzyl alcohol, the compound VI is N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester, and the compound VII is 2- (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide;
in the third step, the molar ratio of the 2, 3-dichloro-6-nitrobenzyl alcohol to the reducing agent is 1: 5-7; mixing and stirring 2, 3-dichloro-6-nitrobenzyl alcohol and concentrated hydrochloric acid according to the mass volume ratio of 1:5-10 to obtain a solution C, mixing stannous chloride and concentrated hydrochloric acid according to the mass volume ratio of 1:3-6 to obtain a solution D, dropwise adding the solution D into the solution C, stirring and reacting at room temperature for 1-3 hours after dropwise adding is finished, filtering, and drying a filter cake to obtain 2, 3-dichloro-6-aminobenzyl alcohol;
in the fourth step, the molar ratio of the 2, 3-dichloro-6-aminobenzyl alcohol, the chlorinated reagent, the glycine tert-butyl ester hydrochloride and the acid-binding agent is 1: 1-3: 4-6: 6-9; mixing 2, 3-dichloro-6-aminobenzyl alcohol and benzene according to the mass-to-volume ratio of 1:7-10, slowly dropwise adding a chlorinated reagent, reacting at 70-80 ℃ for 1-2h after dropwise adding is finished, and concentrating the reaction solution under reduced pressure until the reaction solution is dried to obtain a reddish-brown solid; mixing the obtained red brown solid with benzene according to the mass volume ratio of 1:10-15 to obtain a solution E, mixing the tert-butyl glycinate hydrochloride, the acid binding agent and the benzene according to the mass volume ratio of 1:0.6-1.0:15-20 to obtain a solution F, dripping the solution E into the solution F, reacting at 40-50 ℃ for 3-5h after finishing dripping, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain the tert-butyl N- (2, 3-dichloro-6-amino-benzyl) glycinate;
in the fifth step, the molar ratio of the N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester to the cyanogen bromide is 1: 2-3; mixing N- (2, 3-dichloro-6-amino-benzyl) glycine tert-butyl ester, an acid-binding agent and ethanol according to the mass volume ratio of 1:0.5-0.7:5-10, stirring for dissolving, adding cyanogen bromide, reacting for 3-4H, and concentrating under reduced pressure to obtain 2- (2-amino-5, 6-dichloroquinazoline-3 (4H) -yl) acetic acid tert-butyl ester hydrobromide.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4146718A (en) * | 1978-04-10 | 1979-03-27 | Bristol-Myers Company | Alkyl 5,6-dichloro-3,4-dihydro-2(1h)-iminoquinazoline-3-acetate hydrohalides |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6388073B1 (en) * | 2000-07-26 | 2002-05-14 | Shire Us Inc. | Method for the manufacture of anagrelide |
| GB0808948D0 (en) * | 2008-05-16 | 2008-06-25 | Shire Llc | Substituted quinazolines |
| GB0822970D0 (en) * | 2008-12-17 | 2009-01-21 | Shire Llc | Process for the preparation of anagrelide and analogues |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4146718A (en) * | 1978-04-10 | 1979-03-27 | Bristol-Myers Company | Alkyl 5,6-dichloro-3,4-dihydro-2(1h)-iminoquinazoline-3-acetate hydrohalides |
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| Title |
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| RN：1194434-39-3;美国化学会;《STN ON THE WEB 》;20091130;第2-3页 * |
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