CN110590680A - Preparation method of anagrelide ring-opening methyl esterification impurity - Google Patents
Preparation method of anagrelide ring-opening methyl esterification impurity Download PDFInfo
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- CN110590680A CN110590680A CN201910894326.6A CN201910894326A CN110590680A CN 110590680 A CN110590680 A CN 110590680A CN 201910894326 A CN201910894326 A CN 201910894326A CN 110590680 A CN110590680 A CN 110590680A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- 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
- C07D239/84—Nitrogen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to the technical field of medicinal chemical synthesis, in particular to a preparation method of anagrelide ring-opening methyl esterification impurities. Compared with the prior art, the invention adopts a one-pot method to realize the steps of ring opening and methyl esterification, has cheap and easily obtained raw materials, simple operation and post-treatment, mild reaction conditions, good stability of the technical process, high yield and good reproducibility. Therefore, the invention makes up the blank that the preparation method is not available at home and abroad, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of anagrelide ring-opening methyl esterification impurities.
Background
Anagrelide (Anagrelide, formula II), having the chemical name 6, 7-dichloro-1, 5-dihydroimidazo [2,1-b ] quinazolin-2 (3H) -one, was developed by Roberts, Inc., USA and was approved by the FDA in 1997 for marketing in the United states, under the name Agrylin, for use in essential thrombocythemia and polycythemia vera complicated with thrombocythemia. The medicine has the advantages of capability of treating thrombocytosis caused by various reasons, effective rate of more than 80 percent, less adverse reaction and the like.
The ring-opening methyl esterification impurity of anagrelide (formula I) is one of the impurities specified in the United states Pharmacopeia Standard (USP) for anagrelide hydrochloride, and has the chemical name of (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) methyl acetate. At present, no report on the synthesis research of the protein at home and abroad is found.
The quality of the medicine is directly related to the health and life safety of patients, is concerned with the social medical safety problem, and is the precondition guarantee of the safety, effectiveness and stability of the medicine. The research on impurities is an important content of the research on the quality of medicines, and the research and control on the impurities are one of the key elements for ensuring the quality of medicines. The anagrelide ring-opening methyl esterification impurity is one of the important impurities of anagrelide hydrochloride, the deep research on the anagrelide ring-opening methyl esterification impurity has great significance for developing the anagrelide hydrochloride product, the synthetic research on the anagrelide ring-opening methyl esterification impurity makes up the blank that the preparation method is not available at home and abroad, and the anagrelide ring-opening methyl esterification impurity provides convenience for pharmaceutical enterprises to develop the anagrelide.
Disclosure of Invention
The invention aims to provide a preparation method of ring-opening methyl esterification impurities of anagrelide aiming at the defects in the prior art, the method adopts a one-pot method to realize the steps of ring opening and methyl esterification, the raw materials are cheap and easy to obtain, the operation and the post-treatment are simple, the reaction condition is mild, the stability of the process is good, the yield is high, and the reproducibility is good.
The purpose of the invention is realized by the following technical scheme:
provides a preparation method of an anagrelide ring-opening methyl esterification impurity which is (2-amino-5, 6-dichloroquinazoline-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 for reaction for a certain time, cooling, concentrating, and separating out anagrelide ring-opening methyl esterification impurities.
In the above technical scheme, the ratio of the volume (V) of the added methanol to the mass (M) of anagrelide hydrochloride or anagrelide is V: and M is 5-20: 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 in the acid catalyst to the amount (mol) of 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 h.
The beneficial effects of the invention are as follows:
the invention relates to a preparation method of anagrelide ring-opening methyl esterification impurities, which is characterized in that anagrelide hydrochloride or anagrelide is subjected to ring opening under the action of an acid catalyst and is condensed with methanol to obtain the anagrelide ring-opening methyl esterification impurities. Compared with the prior art, the invention adopts a one-pot method to realize the steps of ring opening and methyl esterification, has cheap and easily obtained raw materials, simple operation and post-treatment, mild reaction conditions, good stability of the technical process, high yield and good reproducibility. Therefore, the invention makes up the blank that the preparation method is not available at home and abroad, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Drawings
FIG. 1 is an MS spectrum of the ring-opening methyl-esterified impurity of anagrelide example 1.
FIG. 2 is the ring opening methyl esterification of anagrelide as impurity salt of monomethyl sulfate of example 11HNMR spectrogram.
Figure 3 is an HPLC spectrum of anagrelide ring opening methyl esterification impurity of example 1.
Detailed Description
The invention is further described with reference to the following examples.
Example 1: preparation of anagrelide ring-opening methyl esterification impurity
Anagrelide hydrochloride (2.92g, 10mmol, 1.0eq) and methanol (29mL) were added to a 100mL three-necked flask, stirred at low temperature, and concentrated sulfuric acid (200mg, 2mmol, 0.2eq) was slowly added dropwise. After the dropwise addition, the temperature is raised to 85 ℃, reflux reaction is carried out for 20 hours, the temperature is lowered to 0 ℃, stirring is carried out for 1 hour, a large amount of white solid is separated out, and 3.47g of ring-opening methyl esterification impurity monomethyl sulfate salt of anagrelide is obtained by filtering, the yield is 86.8 percent, and the HPLC purity is 98.24 percent.
MS spectrogram of anagrelide ring-opening methyl esterification impurity and method for preparing anagrelide ring-opening methyl esterification impurity sulfuric acid monomethyl ester salt1The HNMR spectra are shown in FIG. 1 and FIG. 2, respectively, and the test conditions are as follows:
MS(m/z)：288.0(M+H)+；
1H NMR(400MHz,DMSO-d6)：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 anagrelide ring-opening methyl esterification impurity, an HPLC spectrogram is shown in figure 3, and the test conditions are as follows:
a chromatographic column: h & E C18A31 SPS 100-104.6X 250mm, 10 μm
Mobile phase:
a: methanol; b: 0.1% phosphoric acid aqueous solution
Mobile phase ratio: a, B and 70:30
Column temperature: 35 deg.C
Detection wavelength: 215nm
Flow rate: 0.7mL/min
Time: 15.00 min.
Example 2:
the preparation method and the test method of the ring-opening methyl esterification impurity of anagrelide in the embodiment are mainly the same as those of the embodiment 1, except that the method specifically comprises the following steps:
anagrelide hydrochloride (2.92g, 10mmol, 1.0eq) and methanol (15mL) were added to a 100mL three-necked flask, stirred at low temperature, and nitric acid (92mg, 1mmol, 0.1eq) was slowly added dropwise. After the dropwise addition, the temperature is raised to 50 ℃, the reflux reaction is carried out for 5 hours, the temperature is lowered to 0 ℃, the stirring is carried out for 1 hour, a large amount of white solid is separated out, and 2.72g of anagrelide ring-opening methyl esterification impurity nitrate is obtained by filtering, the yield is 77.5 percent, and the HPLC purity is 96.12 percent.
Example 3:
the preparation method and the test method of the ring-opening methyl esterification impurity of anagrelide in the embodiment are mainly the same as those of the embodiment 1, except that the method specifically comprises the following steps:
anagrelide hydrochloride (2.92g, 10mmol, 1.0eq) and methanol (29mL) were added to a 100mL three-necked flask, stirred at low temperature, and phosphoric acid (980mg, 10mmol, 1.0eq) was added slowly. After the dropwise addition, the temperature is raised to 80 ℃, reflux reaction is carried out for 18 hours, the temperature is lowered to 0 ℃, stirring is carried out for 1 hour, a large amount of white solid is separated out, and filtering is carried out to obtain 3.21g of anagrelide ring-opening methyl esterification impurity phosphate, wherein the yield is 83.2 percent, and the HPLC purity is 96.32 percent.
Example 4:
the preparation method and the test method of the ring-opening methyl esterification impurity of anagrelide in the embodiment are mainly the same as those of the embodiment 1, except that the method specifically comprises the following steps:
anagrelide hydrochloride (2.92g, 10mmol, 1.0eq) and methanol (58mL) were added to a 100mL three-necked flask, stirred at low temperature, and 40% hydrobromic acid (2.02g, 20mmol, 2.0eq) was slowly added dropwise. After the dropwise addition, the temperature is raised to 100 ℃, reflux reaction is carried out for 24 hours, the temperature is lowered to 0 ℃, stirring is carried out for 1 hour, a large amount of white solid is separated out, and filtration is carried out to obtain 2.79g of anagrelide ring-opening methyl esterification impurity hydrobromide, the yield is 75.8%, and the HPLC purity is 95.42%.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present invention.
Claims (6)
1. A preparation method of anagrelide ring-opening methyl esterification impurity which is (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) methyl acetate is characterized in that: the method comprises the following steps: dissolving anagrelide hydrochloride or anagrelide in methanol, adding an acid catalyst, heating for reaction for a certain time, cooling, concentrating, and separating out anagrelide ring-opening methyl esterification impurities.
2. A method of preparing anagrelide ring-opening methyl esterification impurities according to claim 1, wherein: the ratio of the volume (V) of methanol added to the mass (M) of anagrelide hydrochloride or anagrelide is V: and M is 5-20: 1.
3. A method of preparing anagrelide ring-opening methyl esterification impurities according to claim 1, wherein: the added acid catalyst is any one of sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid and hydrochloric acid.
4. A method of preparing anagrelide ring-opening methyl esterification impurities according to claim 3, wherein: the ratio of the amount (mol) of the substance added to the acid catalyst to the amount (mol) of anagrelide hydrochloride or anagrelide substance is 0.1-2: 1.
5. A method of preparing anagrelide ring-opening methyl esterification impurities according to claim 1, wherein: the reaction temperature is 50-100 ℃.
6. A method of preparing anagrelide ring-opening methyl esterification impurities according to claim 1, wherein: the reaction time is 5-24 h.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072575A (en) * | 2019-12-28 | 2020-04-28 | 深圳市祥根生物科技有限公司 | Preparation method of anagrelide impurity C |
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)
| Title |
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| ABD EL-AAL ET AL.: "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", 《ARKIVOC》 * |
| ACS.REGISTRY DATABASE: "RN号752151-24-9", 《STNEXT》 * |
| JUREMA SCHMIDT ET AL.: "Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| RICCARDO SALVIO ET AL.: "Organocatalytic Synthesis of Benzazetidines by Trapping Hemiaminals with Protecting Groups", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| 荣国斌 等: "《大学有机化学基础》", 31 August 2000, 华东理工大学出版社、化学工业出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072575A (en) * | 2019-12-28 | 2020-04-28 | 深圳市祥根生物科技有限公司 | Preparation method of anagrelide impurity C |
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Effective date of registration: 20230324 Address after: 518000 room 412, No.1 Park, Shenzhen Overseas Students (Longgang) Pioneer Park, Qinglin West Road, central city, Longcheng street, Longgang District, Shenzhen City, Guangdong Province Applicant after: Shenzhen Xianggen biomedical Co.,Ltd. Address before: 518000 room 412, No.1 Park, Shenzhen Overseas Students (Longgang) Pioneer Park, Qinglin West Road, central city, Longcheng street, Longgang District, Shenzhen City, Guangdong Province Applicant before: SHENZHEN SUNGENING BIOTECHNOLOGY CO.,LTD. |
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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 |