CN111072575A - Preparation method of anagrelide impurity C - Google Patents
Preparation method of anagrelide impurity C Download PDFInfo
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- CN111072575A CN111072575A CN201911383430.5A CN201911383430A CN111072575A CN 111072575 A CN111072575 A CN 111072575A CN 201911383430 A CN201911383430 A CN 201911383430A CN 111072575 A CN111072575 A CN 111072575A
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- 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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Abstract
The invention provides a preparation method of an anagrelide impurity C, wherein the anagrelide impurity C is (2-amino-5, 6-dichloroquinazoline-3 (4H) -yl) ethyl acetate, and the preparation method comprises the following steps: dissolving anagrelide hydrochloride or anagrelide in ethanol, adding an acid catalyst, heating for reaction, cooling, concentrating and purifying to obtain an anagrelide impurity C. By adopting the technical scheme of the invention, the anagrelide hydrochloride or the anagrelide reacts with ethanol to obtain the anagrelide impurity C under the action of an acid catalyst, the steps of ring opening and ethyl esterification are realized by adopting a one-step method, the raw materials are cheap and easy to obtain, the operation and aftertreatment are simple, the reaction conditions are mild, the stability of the technological process is good, the yield is high, and the reproducibility is good.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of anagrelide impurity C.
Background
Anagrelide (formula I), 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 to be marketed in the United states under the name Agrylin, and was used for 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.
Anagrelide impurity C (formula II) is one of the major impurities specified in the United states Pharmacopeia standards (USP) and European Pharmacopeia standards (EP) for anagrelide hydrochloride, and is chemically named ethyl (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate.
The patent US3932407 reports a synthetic method of a compound (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) ethyl acetate, the route of the synthetic method takes 1, 2, 3-trichlorotoluene as a raw material, and the synthesis of the compound (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) ethyl acetate is completed through six steps of nitration, nucleophilic substitution, cyano reduction, secondary nucleophilic substitution and nitro reduction, and secondary substitution. The route adopts organic highly toxic compound ethyl bromoacetate and extremely toxic cyanogen bromide with active property as synthetic materials, and a large amount of waste acid is generated in the first step, which is not favorable for environmental protection, and the second step is easy to generate a large amount of byproducts, has the defects of complicated steps, low yield and the like, and is not suitable for industrialized production.
In addition, patent WO0208228a2 reports another method for synthesizing ethyl (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) acetate, the synthetic route is substantially the same as that of patent US3932407, only the starting materials are different, but cyanogen bromide which is extremely toxic and active in nature is also used as the synthetic material in the synthetic process, so that the method has the defects of complicated steps, low yield and the like, and is not suitable for industrial production.
The research on impurities in medicines is an important content of the research on the quality of medicines, and the research and control on impurities are one of the key elements for ensuring the quality of medicines. The anagrelide impurity C is one of the important impurities of anagrelide hydrochloride, and the deep research on the anagrelide impurity C has great significance for developing the anagrelide hydrochloride product, and the existing synthetic method of the anagrelide impurity C has the problems of complicated steps, low yield and the like.
Disclosure of Invention
Aiming at the technical problems, the invention discloses a preparation method of anagrelide impurity C, which has the advantages of simple reaction steps, simple operation and post-treatment, mild reaction conditions, good stability of the technological process, high yield and good reproducibility.
In contrast, the technical scheme adopted by the invention is as follows:
a preparation method of anagrelide impurity C, wherein the anagrelide impurity C is (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) ethyl acetate, and the preparation method of the anagrelide impurity C comprises the following steps:
dissolving anagrelide hydrochloride or anagrelide in ethanol, adding an acid catalyst, heating for reaction, cooling, concentrating and purifying to obtain an anagrelide impurity C.
The technical scheme realizes the steps of ring opening and ethyl esterification by a one-step method, and has the advantages of cheap and easily obtained raw materials and convenient implementation.
In a further improvement of the invention, the ratio of the amount of the substance of the acid catalyst to the amount of anagrelide hydrochloride or anagrelide substance is 0.1-2: 1.
As a further improvement of the invention, the acid catalyst is at least one of sulfuric acid, potassium bisulfate, phosphoric acid, nitric acid, hydrobromic acid and hydrochloric acid.
As a further development of the invention, the ratio of the volume V of ethanol to the mass M of anagrelide hydrochloride or anagrelide satisfies V: and M is 5-25: 1.
As a further improvement of the method, the reaction temperature is 50-100 ℃.
As a further improvement of the method, the reaction time is 5-24 h.
Compared with the prior art, the invention has the beneficial effects that:
by adopting the technical scheme of the invention, the anagrelide hydrochloride or the anagrelide reacts with ethanol under the action of an acid catalyst to obtain the anagrelide impurity C. Compared with the prior art, the invention adopts a one-step method to realize the steps of ring opening and ethyl esterification, has 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 the preparation method is not available in China, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Drawings
Figure 1 is an MS spectrum of anagrelide impurity C of example 1 of the present invention.
FIG. 2 shows the preparation of Anagrelide impurity C of example 1 of the present invention1HNMR spectrogram.
Figure 3 is an HPLC profile of anagrelide impurity C of example 1 of the present invention.
Detailed Description
Preferred embodiments of the present invention are described in further detail below.
Example 1
The anagrelide impurity C is prepared by the following steps:
anagrelide hydrochloride (2.92g, 10mmol, 1.0eq) and ethanol (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, ethanol is removed by concentration, water is added, the pH is adjusted to 9-10 by using 2N NaOH aqueous solution, EA (20mL) is used for extraction for 2 times, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, purifying by silica gel column chromatography to obtain 2.52g of anagrelide impurity C, the yield is 83.4%, and the HPLC purity is 97.92%.
MS(m/z)：302.1(M+H)+；
1H NMR(400MHz,DMSO-d6)：δ8.11(s,2H),7.59(d,J＝8Hz,1H),7.03(d,J＝12Hz,1H),4.67(s,2H),4.48(s,2H),4.20(q,2H),1.25(t,3H)。
MS spectrogram of anagrelide impurity C and method for preparing anagrelide impurity C1The HNMR spectra are shown in FIG. 1 and FIG. 2, respectively.
And (3) carrying out HPLC detection on the anagrelide impurity C obtained by the preparation, wherein 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 60:40
Column temperature: 35 deg.C
Detection wavelength: 215nm
Flow rate: 0.7mL/min
Time: 21.00 min.
Example 2
The preparation method and the test method of the anagrelide impurity C in the embodiment are mainly the same as those in the embodiment 1, except that the method specifically comprises the following steps:
anagrelide hydrochloride (2.92g, 10mmol, 1.0eq) and ethanol (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 ℃, reflux reaction is carried out for 5 hours, ethanol is removed by concentration, water is added, the pH is adjusted to 9-10 by using 2N NaOH aqueous solution, EA (20mL) is used for extraction for 2 times, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, purifying by silica gel column chromatography to obtain 2.41g of anagrelide impurity C, yield 79.8%, and HPLC purity 96.24%.
Example 3
The preparation method and the test method of the anagrelide impurity C in the embodiment are mainly the same as those in the embodiment 1, except that the method specifically comprises the following steps:
anagrelide (2.56g, 10mmol, 1.0eq) and ethanol (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 85 ℃, reflux reaction is carried out for 18 hours, ethanol is removed by concentration, water is added, the pH is adjusted to 9-10 by using 2N NaOH aqueous solution, EA (20mL) is used for extraction for 2 times, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, purifying by silica gel column chromatography to obtain 2.34g of anagrelide impurity C, with yield of 77.5% and HPLC purity of 97.11%.
Example 4
The preparation method and the test method of the anagrelide impurity C in the embodiment are mainly the same as those in the embodiment 1, except that the method specifically comprises the following steps:
hydrochloric acid was added to a 100mL three-necked flaskAnagrelide (2.92g, 10mmol, 1.0eq) and ethanol (75mL) were 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, ethanol is removed by concentration, water is added, the pH is adjusted to 9-10 by using 2N NaOH aqueous solution, EA (20mL) is used for extraction for 2 times, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, purifying by silica gel column chromatography to obtain anagrelide impurity C2.46g, yield 81.4%, HPLC purity 97.45%.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (6)
1. A preparation method of anagrelide impurity C, wherein the anagrelide impurity C is (2-amino-5, 6-dichloroquinazolin-3 (4H) -yl) ethyl acetate, and is characterized by comprising the following steps: dissolving anagrelide hydrochloride or anagrelide in ethanol, adding an acid catalyst, heating for reaction, cooling, concentrating and purifying to obtain an anagrelide impurity C.
2. A method of preparing anagrelide impurity C according to claim 1, wherein: the ratio of the amount of the acid catalyst substance to the amount of anagrelide hydrochloride or anagrelide substance is 0.1-2: 1.
3. A method of preparing anagrelide impurity C according to claim 2, wherein: the acid catalyst is at least one of sulfuric acid, potassium bisulfate, phosphoric acid, nitric acid, hydrobromic acid and hydrochloric acid.
4. A method of preparing anagrelide impurity C according to any one of claims 1 to 3, wherein: the ratio of the volume V of the ethanol to the mass M of the anagrelide hydrochloride or anagrelide satisfies V: and M is 5-25: 1.
5. A method of preparing anagrelide impurity C according to any one of claims 1 to 3, wherein: the reaction temperature is 50-100 ℃.
6. A method of preparing anagrelide impurity C according to any one of claims 1 to 3, wherein: the reaction time is 5-24 h.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3932407A (en) * | 1973-11-19 | 1976-01-13 | Bristol-Myers Company | Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones |
| US6388073B1 (en) * | 2000-07-26 | 2002-05-14 | Shire Us Inc. | Method for the manufacture of anagrelide |
| AT412873B (en) * | 2004-02-20 | 2005-08-25 | Aop Orphan Pharmaceuticals Ag | Preparation of anagrelide hydrochloride, useful for thrombocyte suppression, using 2,3-dichlorobenzaldehyde as starting material, avoids use of toxic reagents |
| CN102076668A (en) * | 2008-06-02 | 2011-05-25 | 夏尔有限责任公司 | Substituted quinazolines |
| CN110590680A (en) * | 2019-09-20 | 2019-12-20 | 深圳市祥根生物科技有限公司 | Preparation method of anagrelide ring-opening methyl esterification impurity |
-
2019
- 2019-12-28 CN CN201911383430.5A patent/CN111072575A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3932407A (en) * | 1973-11-19 | 1976-01-13 | Bristol-Myers Company | Optionally substituted 1,2,3,5-tetrahydroimidezo(2,1-b)-quinazolin-2-ones and 6(H)-1,2,3,4-tetrahydropyimido(2,1-b)quinazolin-2-ones |
| US6388073B1 (en) * | 2000-07-26 | 2002-05-14 | Shire Us Inc. | Method for the manufacture of anagrelide |
| AT412873B (en) * | 2004-02-20 | 2005-08-25 | Aop Orphan Pharmaceuticals Ag | Preparation of anagrelide hydrochloride, useful for thrombocyte suppression, using 2,3-dichlorobenzaldehyde as starting material, avoids use of toxic reagents |
| CN102076668A (en) * | 2008-06-02 | 2011-05-25 | 夏尔有限责任公司 | Substituted quinazolines |
| CN110590680A (en) * | 2019-09-20 | 2019-12-20 | 深圳市祥根生物科技有限公司 | Preparation method of anagrelide ring-opening methyl esterification impurity |
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Application publication date: 20200428 |