CN110590680B - Preparation method of anagrelide Lei Kaihuan methyl esterification impurity - Google Patents
Preparation method of anagrelide Lei Kaihuan methyl esterification impurity Download PDFInfo
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- CN110590680B CN110590680B CN201910894326.6A CN201910894326A CN110590680B CN 110590680 B CN110590680 B CN 110590680B CN 201910894326 A CN201910894326 A CN 201910894326A CN 110590680 B CN110590680 B CN 110590680B
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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Abstract
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a preparation method of anagrelide Lei Kaihuan methyl esterification impurities, which comprises the steps of dissolving anagrelide hydrochloride or anagrelide in methanol, adding an acid catalyst, heating to react for a certain time, then cooling, concentrating, and separating out anagrelide Lei Kaihuan methyl esterification impurities. Compared with the prior art, the method adopts a one-pot method to realize the steps of ring opening and methyl esterification, has the advantages of cheap and easily obtained raw materials, simple operation and post-treatment, mild reaction conditions, good stability of the technological process, high yield and good reproducibility. Therefore, the invention makes up the blank that no preparation method exists at home and abroad, can also reduce the cost of developing the medicine for pharmaceutical enterprises, and has very good industrialized application prospect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of anagrelide Lei Kaihuan methyl esterification impurities.
Background
Anagrelide (formula ii), chemical name 6, 7-dichloro-1, 5-dihydroimidazo [2,1-b ] quinazolin-2 (3H) -one, developed by Roberts corporation of united states, FDA approved in 1997, marketed in the united states under the trade name Agrylin for essential thrombocytosis and polycythemia vera complications. The medicine has the advantages of capability of treating platelet increase caused by various reasons, effective rate of more than 80%, less adverse reaction and the like.
The methyl esterification impurity of anagrelide Lei Kaihuan (formula i) is one of the impurities specified in the U.S. pharmacopoeia standards (USP) for anagrelide hydrochloride and has the chemical name methyl (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate. At present, no report on the synthesis research of the compound is found at home and abroad.
The quality of the medicine is directly related to the health and life safety of patients, the social medical safety problem is concerned, and the medicine is ensured on the premise of safety, effectiveness and stability. Impurity research is an important content of medicine quality research, and impurity research and control are one of key elements of medicine quality assurance. The anagrelide Lei Kaihuan methyl esterification impurity is taken as one of the important impurities of anagrelide hydrochloride, the deep research on the anagrelide hydrochloride is of great significance to the development of anagrelide hydrochloride products, and the synthesis research of anagrelide Lei Kaihuan methyl esterification impurity can make up the blank that no preparation method exists in China and abroad, thereby providing convenience for pharmaceutical enterprises to develop the products.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of anagrelide Lei Kaihuan methyl esterification impurities, which adopts a one-pot method to realize the steps of ring opening and methyl esterification, has the advantages of low-cost and easily obtained raw materials, simple operation and post-treatment, mild reaction conditions, good stability of the process, high yield and good repeatability.
The aim of the invention is achieved by the following technical scheme:
provided is a method for preparing anagrelide Lei Kaihuan methyl esterification impurity, wherein the impurity is (2-amino-5, 6-dichloro quinazoline-3 (4H) -group) methyl acetate, and the method is characterized in that: the method comprises the following steps: dissolving anagrelide hydrochloride or anagrelide in methanol, adding an acid catalyst, heating to react for a certain time, then cooling, concentrating, and separating out anagrelide Lei Kaihuan methyl esterification impurities.
In the technical scheme, the ratio of the volume (V) of the added methanol to the mass (M) of the anagrelide hydrochloride or the anagrelide is V: m=5 to 20:1.
In the technical scheme, the added acid catalyst is any one of sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid and hydrochloric acid.
In the technical scheme, the ratio of the amount (mol) of the substances added into the acid catalyst to the amount (mol) of the anagrelide hydrochloride or anagrelide substances is 0.1-2:1.
In the technical scheme, the reaction temperature is 50-100 ℃.
In the technical scheme, the reaction time is 5-24 hours.
The invention has the beneficial effects that:
according to the preparation method of the anagrelide Lei Kaihuan methyl esterification impurity, anagrelide hydrochloride or anagrelide is used for ring opening under the action of an acid catalyst and is condensed with methanol to obtain the anagrelide Lei Kaihuan methyl esterification impurity. Compared with the prior art, the method adopts a one-pot method to realize the steps of ring opening and methyl esterification, has the advantages of cheap and easily obtained raw materials, simple operation and post-treatment, mild reaction conditions, good stability of the technological process, high yield and good reproducibility. Therefore, the invention makes up the blank that no preparation method exists at home and abroad, can also reduce the cost of developing the medicine for pharmaceutical enterprises, and has very good industrialized application prospect.
Drawings
FIG. 1 is a MS spectrum of the methyl esterified impurity of anagrelide Lei Kaihuan of example 1.
FIG. 2 is a diagram of the methyl esterification impurity monomethyl sulfate salt of anagrelide Lei Kaihuan of example 1 1 HNMR spectra.
FIG. 3 is an HPLC chromatogram of the methyl esterification impurity of anagrelide Lei Kaihuan of example 1.
Detailed Description
The invention will be further described with reference to the following examples.
Example 1: preparation of methyl esterification impurity of anagrelide Lei Kaihuan
To a 100mL three-necked flask were added anagrelide hydrochloride (2.92 g,10mmol,1.0 eq) and methanol (29 mL), and the mixture was stirred at low temperature, followed by slow dropwise addition of concentrated sulfuric acid (200 mg,2mmol,0.2 eq). After the dripping, the temperature is raised to 85 ℃, the reflux reaction is carried out for 20 hours, the temperature is reduced to 0 ℃ and the stirring is carried out for 1 hour, a large amount of white solid is separated out, 3.47g of anager Lei Kaihuan methyl esterification impurity monomethyl sulfate salt is obtained by filtering, the yield is 86.8%, and the HPLC purity is 98.24%.
MS spectrum of methyl esterification impurity of anagrelide Lei Kaihuan and monomethyl sulfate salt of methyl esterification impurity of anagrelide Lei Kaihuan 1 HNMR spectra are shown in fig. 1 and 2, respectively, and the test conditions are as follows:
MS(m/z)：288.0(M+H) + ；
1 H NMR(400MHz,DMSO-d 6 )：δ10.91(s,1H),8.12(s,2H),7.59(d,J＝8Hz,1H),7.03(d,J＝8Hz,1H),4.68(s,2H),4.49(s,2H),3.75(s,3H),3.39(s,3H)。
HPLC detection is carried out on the prepared anagrelide Lei Kaihuan methyl esterification impurity, an HPLC spectrum is shown in figure 3, and the test conditions are as follows:
chromatographic column: h & E C A31 SPS 100-10.6X105 mm,10 μm
Mobile phase:
a: methanol; b:0.1% phosphoric acid aqueous solution
Mobile phase ratio: a: b=70:30
Column temperature: 35 DEG C
Detection wavelength: 215nm
Flow rate: 0.7mL/min
Time: 15.00min.
Example 2:
the preparation method and the test method of the methyl esterification impurity of anagrelide Lei Kaihuan in this embodiment are mainly the same as those in embodiment 1, except that the method is specifically as follows:
to a 100mL three-necked flask were added anagrelide hydrochloride (2.92 g,10mmol,1.0 eq) and methanol (15 mL), and the mixture was stirred at low temperature, followed by slow dropwise addition of nitric acid (92 mg,1mmol,0.1 eq). After the dripping, the temperature is raised to 50 ℃, the reflux reaction is carried out for 5 hours, the temperature is reduced to 0 ℃ and the stirring is carried out for 1 hour, a large amount of white solid is separated out, and 2.72g of anager Lei Kaihuan methyl esterification impurity nitrate is obtained by filtering, the yield is 77.5%, and the HPLC purity is 96.12%.
Example 3:
the preparation method and the test method of the methyl esterification impurity of anagrelide Lei Kaihuan in this embodiment are mainly the same as those in embodiment 1, except that the method is specifically as follows:
to a 100mL three-necked flask were added anagrelide hydrochloride (2.92 g,10mmol,1.0 eq) and methanol (29 mL), and the mixture was stirred at low temperature, followed by slow addition of phosphoric acid (480 mg,10mmol,1.0 eq). After the dripping, the temperature is raised to 80 ℃, the reflux reaction is carried out for 18 hours, the temperature is reduced to 0 ℃ and the stirring is carried out for 1 hour, a large amount of white solid is separated out, and 3.21g of anager Lei Kaihuan methyl esterified impurity phosphate is obtained by filtering, the yield is 83.2%, and the HPLC purity is 96.32%.
Example 4:
the preparation method and the test method of the methyl esterification impurity of anagrelide Lei Kaihuan in this embodiment are mainly the same as those in embodiment 1, except that the method is specifically as follows:
to a 100mL three-necked flask were added anagrelide hydrochloride (2.92 g,10mmol,1.0 eq) and methanol (58 mL), and the mixture was stirred at low temperature, followed by slow dropwise addition of 40% hydrobromic acid (2.02 g,20mmol,2.0 eq). After the dripping, the temperature is raised to 100 ℃, the reflux reaction is carried out for 24 hours, the temperature is reduced to 0 ℃ and the stirring is carried out for 1 hour, a large amount of white solid is separated out, and the filtration is carried out to obtain 2.79g of anager Lei Kaihuan methyl esterification impurity hydrobromide, the yield is 75.8 percent, and the HPLC purity is 95.42 percent.
The present embodiment is only for illustrating the technical scheme of the present invention, but not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiment, it should be understood by those skilled in the art that the technical scheme of the present invention may be modified or substituted without departing from the spirit and scope of the technical scheme of the present invention.
Claims (3)
1. A method for preparing anagrelide Lei Kaihuan methyl esterification impurity which is (2-amino-5, 6-dichloro quinazoline-3 (4H) -yl) methyl acetate, and is characterized in that: the method comprises the following steps: dissolving anagrelide hydrochloride or anagrelide in methanol, adding an acid catalyst, heating to react, then cooling, concentrating, and separating out anagrelide Lei Kaihuan methyl esterification impurities;
the ratio of the volume of methanol added to the mass of anagrelide hydrochloride or anagrelide is V: m=5-20:1;
the reaction temperature is 50-100 ℃; the reaction time is 5-24 h.
2. The method for preparing the methyl esterification impurity of anagrelide Lei Kaihuan as claimed in claim 1, wherein the method comprises the following steps: the added acid catalyst is any one of sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid and hydrochloric acid.
3. The method for preparing the methyl esterification impurity of anagrelide Lei Kaihuan as claimed in claim 2, wherein the method comprises the following steps: the ratio of the amount of the substance added to the acid catalyst to the amount of anagrelide hydrochloride or anagrelide substance is 0.1-2:1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005080398A1 (en) * | 2004-02-20 | 2005-09-01 | Aop Orphan Pharmaceuticals Ag | Method for the production of anagrelide hydrochloride |
| CN101463035A (en) * | 2007-12-19 | 2009-06-24 | 华生制药私人有限公司 | Improved method for producing anagrelide hydrochloride monohydrate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005080398A1 (en) * | 2004-02-20 | 2005-09-01 | Aop Orphan Pharmaceuticals Ag | Method for the production of anagrelide hydrochloride |
| CN101463035A (en) * | 2007-12-19 | 2009-06-24 | 华生制药私人有限公司 | Improved method for producing anagrelide hydrochloride monohydrate |
Non-Patent Citations (5)
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| Friedel-Crafts chemistry. Part 45: expedient new improved process for the synthesis of oxacarbazepine precursor 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine via Friedel-Crafts cycliacylations;Abd El-Aal et al.;《ARKIVOC》;20151231;第5卷;第230-241页 * |
| Organocatalytic Synthesis of Benzazetidines by Trapping Hemiaminals with Protecting Groups;Riccardo Salvio et al.;《The Journal of Organic Chemistry》;20190515;第84卷;第7395-7404页 * |
| RN号752151-24-9;ACS.REGISTRY DATABASE;《STNext》;20040926;第1页 * |
| Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists;Jurema Schmidt et al.;《Bioorganic & Medicinal Chemistry》;20180711;第26卷;第4240-4253页 * |
| 荣国斌 等.水解、醇解和氨解、酸解反应.《大学有机化学基础》.华东理工大学出版社、化学工业出版社,2000,(第2000年8月第一版),第421页. * |
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Denomination of invention: A Preparation Method of Anagrel Ring Opening Methylesterification Impurity Effective date of registration: 20230801 Granted publication date: 20230516 Pledgee: Bank of Communications Limited Shenzhen Branch Pledgor: Shenzhen Xianggen biomedical Co.,Ltd. Registration number: Y2023980050525 |