CN113980012A - Purification method of emtricitabine - Google Patents
Purification method of emtricitabine Download PDFInfo
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- CN113980012A CN113980012A CN202111361242.XA CN202111361242A CN113980012A CN 113980012 A CN113980012 A CN 113980012A CN 202111361242 A CN202111361242 A CN 202111361242A CN 113980012 A CN113980012 A CN 113980012A
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- emtricitabine
- benzoate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention provides a purification method of emtricitabine, which separates the emtricitabine from aqueous solution in the form of emtricitabine benzoate, and dissociates the benzoate to obtain high-purity emtricitabine with high yield.
Description
The present application is a divisional application of the following applications: application date 2015, 11 month 18; application No.: 201580060548.8, respectively; the invention name is as follows: "purification method of emtricitabine".
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a purification method of emtricitabine.
Background
Emtricitabine (formula I), chemically (2R,5S) -5-fluoro-1- [2- (hydroxymethyl) -1, 3-oxathiolan-5-yl ] cytosine, is used in combination with other antiretroviral drugs for the treatment of HIV-1 infection.
Emtricitabine is an optically pure compound with two chiral centers of configuration (2R,5S), which is generally prepared by stereoselective synthesis. Because emtricitabine has higher solubility in water, how to efficiently separate and purify the reaction product emtricitabine from a complex reaction system containing water becomes a difficult problem which needs to be solved for realizing industrial mass production.
WO2011095987 discloses the formation of salts by reacting emtricitabine with organic acids such as 2-fluorobenzoic acid, halobenzoic acid, 2-methoxybenzoic acid, 3-hydroxy-2-naphthoic acid, L-pyroglutamic acid or aspartic acid. However, the method uses a large amount of reagents, has complicated operation steps and an unsatisfactory separation effect, and is not suitable for industrial production.
CN103833741A discloses a method for separating the reaction product by crystallization by reacting emtricitabine with salicylic acid to form a salt. However, applicants have found that the process for purifying emtricitabine by its salicylate does not achieve the yields described in this patent application and that the final product has a high level of impurities.
The purification process of emtricitabine in the prior art has a plurality of defects, so a simple and efficient method for purifying emtricitabine is still needed, and the method is provided by the application.
Summary of The Invention
In one aspect, the present application provides a method for purifying emtricitabine (formula i), comprising: emtricitabine is reacted with benzoic acid to form emtricitabine benzoate (formula iii).
The purification method of the emtricitabine further comprises the following steps: reacting emtricitabine benzoate (formula III) to produce emtricitabine,
in another aspect, the present application provides emtricitabine benzoate (formula III),
in yet another aspect, the present application provides a method of preparing emtricitabine comprising:
(1) reacting 5- (4-amino-5-fluoro-2-oxo-1 (2H) -pyrimidine) -1, 3-oxathiolane-2-carboxylic acid 5-methyl-2-isopropylcyclohexanol ester (formula II) in the presence of a reducing agent,
(2) reacting the reaction product obtained in the step (1) with benzoic acid to prepare emtricitabine benzoate (formula III)
The method for preparing emtricitabine further comprises (3) reacting emtricitabine benzoate (formula iii) to prepare emtricitabine (formula i):
the inventor of the present application has unexpectedly found that by adding benzoic acid to form emtricitabine as a benzoate and then reacting the benzoate to free emtricitabine, high purity emtricitabine can be obtained in high yield, and the preparation is simple and easy to operate, and is particularly suitable for industrial production and refining of emtricitabine.
Detailed Description
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to be open-ended, inclusive meaning that "includes but is not limited to".
Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a reaction comprising "a catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
One aspect of the present application provides a method for purifying emtricitabine (formula i), comprising: reacting emtricitabine with benzoic acid to form emtricitabine benzoate (formula III),
the emtricitabine is either a reaction product containing emtricitabine obtained during the preparation of emtricitabine or emtricitabine of lower purity which requires further refinement. Preferably, the emtricitabine is in the form of an aqueous solution containing emtricitabine, such that emtricitabine benzoate can be precipitated from the aqueous solution.
In a particular embodiment, the method of purifying emtricitabine of the present application comprises: separating the emtricitabine out of the aqueous solution in the form of emtricitabine benzoate.
The method of purifying emtricitabine of the present application further comprises: reacting emtricitabine benzoate (formula III) to produce emtricitabine,
in the step of reacting the emtricitabine benzoate to prepare emtricitabine, the solvent for the reaction is selected from acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, isopropyl ether, 1, 4-dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or any mixture thereof, preferably acetone. Optionally, the emtricitabine benzoate may be reacted under heated conditions, such as heated reflux conditions, to produce emtricitabine. The emtricitabine benzoate may be reacted in the absence of a base or in the presence of an appropriate base to produce emtricitabine.
In another aspect, the present application provides emtricitabine benzoate, which has a structure shown in formula III,
yet another aspect of the present application provides a method of preparing emtricitabine comprising:
(1) reacting 5- (4-amino-5-fluoro-2-oxo-1 (2H) -pyrimidine) -1, 3-oxathiolane-2-carboxylic acid 5-methyl-2-isopropylcyclohexanol ester (formula II) in the presence of a reducing agent,
(2) reacting the reaction product obtained in the step (1) with benzoic acid to prepare emtricitabine benzoate (formula III),
the compounds of formula ii can be obtained commercially or can be prepared by synthetic methods known to the person skilled in the art, for example CN101066971A or PCT patent application WO 2007077505.
The reducing agent used in said step (1) is a commonly used reducing agent known to those skilled in the art, and includes, but is not limited to, sodium borohydride, potassium borohydride, lithium borohydride or lithium aluminum hydride, preferably sodium borohydride or potassium borohydride, more preferably sodium borohydride.
In the step (1), the solvent used in the reduction reaction is selected from C1～C8Alcohol of (1, 4-dioxane), diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMSO or any mixture thereof, preferably C1～C8More preferably methanol, ethanol or a mixture of methanol and ethanol in any proportion, most preferably methanol.
Optionally, before carrying out step (2), the reaction product obtained in step (1) is subjected to the following steps:
i) the reaction product is concentrated and then dissolved by adding water,
ii) washing with a water-immiscible organic solvent.
The water-immiscible organic solvent comprises but is not limited to one or more of benzene, toluene, xylene, cyclohexane, petroleum ether, diethyl ether, isopropyl ether, ethyl acetate or butyl acetate, and is preferably toluene;
optionally, the pH of the reaction product obtained in said step (1) is adjusted to 1-6, preferably to 5, with an acid commonly used in the art, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid, before carrying out step i). A suitable acid concentration can be determined by one skilled in the art based on the desired pH, for example, 6mol/L hydrochloric acid.
In the step (2), the emtricitabine benzoate may be precipitated by heating, dissolving, and then cooling. In one embodiment, the heating temperature is from 70 ℃ to 80 ℃.
The method for preparing emtricitabine further comprises (3) reacting emtricitabine benzoate (formula iii) to prepare emtricitabine (formula i):
in step (3), the solvent for the reaction is selected from acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, isopropyl ether, 1, 4-dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or any mixture thereof, preferably acetone. Optionally, the emtricitabine benzoate may be reacted under heated conditions, such as heated reflux, to produce emtricitabine. The emtricitabine benzoate may be reacted in the absence of a base or in the presence of an appropriate base to produce emtricitabine.
Examples
The present application is described in detail by the following examples, which are only examples and do not limit the present application, and all the technologies realized by the present application belong to the scope of the present application.
Example 1 preparation of emtricitabine benzoate
5- (4-amino-5-fluoro-2-oxo-1 (2H) -pyrimidine) -1, 3-oxathiolane-2-carboxylic acid 5-methyl-2-isopropylcyclohexanol ester (40g, 0.1mol) was added to 200ml of methanol, followed by sodium borohydride (9g, 0.24mol), and reacted at room temperature. After completion of the reaction was monitored by TLC, the reaction solution was adjusted to pH 5 with 6mol/L hydrochloric acid and concentrated under reduced pressure. To the concentrate was added 60ml of water, followed by washing twice with 100ml of toluene. Adding benzoic acid (20g, 0.16mol) into the water layer, heating to 70-80 ℃, dissolving into a clear solution, cooling to room temperature, and precipitating. And (3) filtering, washing the filter cake twice with 40ml of water, filtering, drying, washing with 40ml of isopropyl ether, filtering and drying to obtain 30g of emtricitabine benzoate with the yield of 81%.
Example 2 preparation of emtricitabine
Adding 30g of emtricitabine benzoate into 300ml of acetone, carrying out reflux reaction for 2 hours, filtering while the emtricitabine benzoate is hot, and drying to obtain 17.4g of emtricitabine, wherein the yield is 87%, and the HPLC purity is 99.9% (area normalization method).
1H NMR (500MHz, DMSO-d6) < delta > 6.16(1H, m), < 5.41(1H, t, disappearance after heavy water exchange), < 5.20(1H, t), < 3.82(1H, m), < 3.74(1H, m), < 3.44(1H, dd), < 3.14(1H, dd),
ESI-MS m/z[M+Na]+:270、ESI-MS m/z[M-H]-：246，
IR(HBr)cm-1:3422、2957、2903、2856、1442、1408、1169、1093、1045。
EXAMPLE 3 preparation of emtricitabine by other organic acid salts
Emtricitabine organic acid salt was prepared by substituting benzoic acid with p-fluorobenzoic acid, salicylic acid, oxalic acid, maleic acid or fumaric acid, and emtricitabine was prepared according to the method of example 1 and the method of example 2, and the results are shown in table 1.
TABLE 1 results of yield/purity of emtricitabine organic acid salt and emtricitabine
| Organic acids | Yield of emtricitabine organic acid salt | Emtricitabine HPLC purity | Yield of emtricitabine |
| Benzoic acid | 86％ | 99.9％ | 87％ |
| P-fluorobenzoic acid | 85％ | 99.7％ | 55％ |
| Salicylic acid | 56％ | 99.7％ | 59％ |
| Oxalic acid | Does not separate out | / | / |
| Maleic acid | 16％ | / | / |
| Fumaric acid | 15％ | / | / |
Note: the purity/content was measured by high performance liquid chromatography (appendix V D of the second part of the pharmacopoeia 2010 edition).
Claims (10)
1. A method of purifying emtricitabine comprising: reacting the emtricitabine with benzoic acid to form emtricitabine benzoate (formula III),
2. the method of purifying emtricitabine of claim 1, further comprising: reacting the emtricitabine benzoate (formula III) to produce the emtricitabine,
3. the process for purifying emtricitabine according to claim 2, wherein the solvent for the reaction is selected from the group consisting of acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, isopropyl ether, 1, 4-dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or any mixture thereof, preferably acetone.
4. The method for purifying emtricitabine of claim 3 wherein the emtricitabine benzoate salt (formula III) is reacted under heating to produce the emtricitabine.
5. The structure of the emtricitabine benzoate is shown as a formula III,
6. a method of preparing emtricitabine comprising:
(1) reacting 5- (4-amino-5-fluoro-2-oxo-1 (2H) -pyrimidine) -1, 3-oxathiolane-2-carboxylic acid 5-methyl-2-isopropylcyclohexanol ester (formula II) in the presence of a reducing agent,
(2) reacting the reaction product obtained in the step (1) with benzoic acid to prepare emtricitabine benzoate (formula III),
(3) reacting the emtricitabine benzoate (formula III) to produce the emtricitabine,
7. the process for preparing emtricitabine according to claim 6, wherein the solvent for the reaction is selected from acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, diethyl ether, isopropyl ether, 1, 4-dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or any mixture thereof, preferably acetone.
8. The method of preparing emtricitabine according to claim 6 or 7, wherein the emtricitabine benzoate (formula III) is reacted under heating to prepare the emtricitabine.
9. The process for the preparation of emtricitabine according to any one of claims 6 to 8, wherein the reducing agent used in step (1) is selected from sodium borohydride, potassium borohydride, lithium borohydride or lithium aluminum hydride, preferably sodium borohydride or potassium borohydride, more preferably sodium borohydride.
10. The process for preparing emtricitabine according to any one of claims 6 to 8, wherein the reaction product obtained in step (1) is reacted with benzoic acid at a temperature of 70 ℃ to 80 ℃.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410660872.0A CN105585564A (en) | 2014-11-18 | 2014-11-18 | Purifying method of emtricitabine |
| CN2014106608720 | 2014-11-18 | ||
| CN201580060548.8A CN107074834A (en) | 2014-11-18 | 2015-11-18 | The purification process of emtricitabine |
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| CN201580060548.8A Division CN107074834A (en) | 2014-11-18 | 2015-11-18 | The purification process of emtricitabine |
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| CN202111361242.XA Pending CN113980012A (en) | 2014-11-18 | 2015-11-18 | Purification method of emtricitabine |
| CN201580060548.8A Pending CN107074834A (en) | 2014-11-18 | 2015-11-18 | The purification process of emtricitabine |
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| CN106496208A (en) * | 2016-10-19 | 2017-03-15 | 上海博志研新药物技术有限公司 | The preparation method of emtricitabine |
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| US8350030B2 (en) * | 2007-12-07 | 2013-01-08 | Matrix Laboratories Limited | Process for producing 5-fluoro-1-(2R, 5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine |
| EP2542551B1 (en) * | 2010-03-04 | 2014-08-27 | Ranbaxy Laboratories Limited | A process for stereoselective synthesis of 5-fluoro-1-(2r,5s)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine |
| WO2012137227A2 (en) * | 2011-04-08 | 2012-10-11 | Laurus Labs Private Limited | Solid forms of antiretroviral compounds, process for the preparation and their pharmaceutical composition thereof |
| CN103833741A (en) * | 2012-11-22 | 2014-06-04 | 上海医药工业研究院 | Emtricitabine salicylate and preparation method and application thereof |
| CN105130972B (en) * | 2015-08-04 | 2018-04-20 | 中孚药业股份有限公司 | Benzoic acid emtricitabine salt, its preparation method and the method for preparing emtricitabine with benzoic acid emtricitabine salt |
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