CN109384814B - Purification method of novel tenofovir prodrug - Google Patents
Purification method of novel tenofovir prodrug Download PDFInfo
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- CN109384814B CN109384814B CN201710691626.5A CN201710691626A CN109384814B CN 109384814 B CN109384814 B CN 109384814B CN 201710691626 A CN201710691626 A CN 201710691626A CN 109384814 B CN109384814 B CN 109384814B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention relates to a purification method of a novel tenofovir prodrug. Specifically comprises thatThe crude tenofovir prodrug shown as the formula Ia1 is recrystallized in acetonitrile, a mixed solvent of acetonitrile and an aromatic hydrocarbon solvent or a mixed solvent of acetonitrile and an ether solvent, so that the tenofovir prodrug shown as the formula Ia1 with the optical purity of more than 99.8 percent is prepared.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a purification method of a novel tenofovir prodrug.
Background
Tenofovir (tenofovir) is a novel nucleotide reverse transcriptase inhibitor, effective against various viruses, and useful for treating viral infectious diseases such as hepatitis B virus. Because tenofovir is a phosphonic acid group of a double anion under the physiological pH condition, the tenofovir is not easy to permeate a cell membrane for absorption, the bioavailability is very low, and dose-dependent nephrotoxicity exists, so that the treatment effect of the tenofovir is limited, and therefore, the phosphonate prodrug is prepared by means of esterification, salification and the like and can be clinically used. For example, Tenofovir disoproxil fumarate (Tenofovir fumarate) was the first generation of orally active Tenofovir prodrugs developed by giread Science, for the treatment of aids infections and hepatitis b.
Because tenofovir disoproxil fumarate is highly sensitive to a seroenzyme-mediated hydrolysis reaction, the concentration of a medicament at an action part cannot be effectively increased, two equivalents of potentially toxic formaldehyde are released in a metabolic process, and side effects such as lactic acidosis, severe hepatomegaly, lipodystrophy and the like are found in a clinical treatment process. In order to improve the stability of the tenofovir prodrug in plasma and reduce the concentration of a metabolite, namely tenofovir in plasma so as to reduce the drug toxicity, Girride company develops a tenofovir phosphoramidate prodrug (GS-7340) shown as a formula V and discloses a preparation method of GS-7340 (WO 2002008241).
On the basis of the research on GS-7340, Chinese patent application 2012100041647.4 reports that 9- [ (R) -2- [ [ (S) - [ [1- (isopropoxycarbonyl) -1-methyl ] ethyl ] amino ] phenoxyphosphinyl ] methoxy ] propyl ] adenine which is a compound shown as formula Ia1 is a novel nucleoside reverse transcriptase inhibitor and is a prodrug of tenofovir (PMPA). Compared with GS-7340, the novel prodrug is more stable in blood, and has higher concentration of tenofovir which is an active metabolite in Peripheral Blood Mononuclear Cells (PBMCs), so that the novel tenofovir prodrug has better curative effect and smaller toxic and side effect.
In the preparation of the compounds of the formula Ia1, a chiral center of phosphorus is formed during the reaction, so that a mixture of the compounds of the formula Ia1 and their diastereomers is obtained. The compound of formula Ia1 and its diastereoisomer are difficult to separate and purify by common recrystallization methods, and can be separated by preparative liquid phase to give the compound of formula Ia1, but this method is cumbersome and expensive and is not suitable for large scale preparation, as reported in Chinese patent application 2012100041647.4.
CN104558035A reports a process for isolating compounds of formula la 1 and mixtures of diastereomers thereof by salt-forming crystallization of D- (+) -dibenzoyltartaric acid followed by base neutralization to produce compounds of formula la 1 having an optical purity of 95% or greater. However, the above method fails to meet the requirement that the content of optical isomer in the compound represented by formula Ia1 is less than 0.1%, so that a purification method which is simple and convenient to operate is urgently needed to prepare the compound represented by formula Ia1 with high purity.
Disclosure of Invention
In order to solve the technical problems, the inventor successfully realizes the purification of the compound shown as the formula Ia1 by using a recrystallization method through repeated research, thereby preparing the compound shown as the formula Ia1 with the optical purity of more than 99.8%.
The invention aims to provide a method for purifying a compound shown as a formula Ia1, which specifically comprises the following steps: recrystallizing the crude product of the compound shown as the formula Ia1 by using acetonitrile, a mixed solvent of the acetonitrile and an aromatic hydrocarbon solvent or a mixed solvent of the acetonitrile and an ether solvent. The volume ratio of the acetonitrile to the aromatic hydrocarbon solvent is 1: 1-1: 10, can be 1: 1-1: 5, and can also be 1: 3.3; the volume ratio of the acetonitrile to the ether solvent is 1: 1-1: 10, 1: 1-1: 5 or 1: 3.3.
The aromatic hydrocarbon solvent is selected from benzene, toluene or xylene, and can be toluene; the ether solvent is selected from diethyl ether, isopropyl ether, methyl ethyl ether or methyl tert-butyl ether, and can be isopropyl ether.
In the recrystallization process, the heating and dissolving temperature is 30-90 ℃, and can be 40-50 ℃; the cooling crystallization temperature is-15 to 30 ℃, and can be 0 to 10 ℃.
In one embodiment of the present invention, a purification process is provided comprising the steps of:
1. heating and dissolving a crude compound shown as a formula Ia1 in any form in acetonitrile, a mixed solvent of acetonitrile and an aromatic hydrocarbon solvent or a mixed solvent of acetonitrile and an ether solvent;
2. cooling and crystallizing a dissolved solution of a crude compound shown as a formula Ia 1;
3. filtering and drying to obtain the compound shown as the formula Ia1 with high purity.
The preparation method is simple and is very suitable for industrial production, and the compound shown in the formula Ia1 prepared by the preparation method has the diastereoisomer content of 0.02-0.08%, related substances of 0.02-0.40% and the maximum unknown single impurity content of less than 0.10%, and reaches the use standard of raw material medicines.
Detailed Description
Example 1
(preparation of the Compound of formula Ia1 and its diastereoisomeric mixture, from Chinese patent application 2012100041647.4)
Step 1: trimethylchlorosilane (6.0g) was added dropwise to a solution of phenol (5g) and triethylamine (10.1mL) in dichloromethane (150mL) at 0 ℃ and, after completion of the addition, the reaction was stirred at 20 ℃ for 18 hours. The white solid was filtered off and the solid was washed with dichloromethane. The filtrates were combined and the solvent was distilled off to give 4.2g of phenoxytrimethylsilane as a colorless oil.
Step 2:
adding DMF (0.1mL) and thionyl chloride (0.73g) dropwise to a turbid solution of Tenofovir (1g, available from Heideson pharmaceutical science and technology Co., Ltd., Suzhou) in sulfolane (2.5mL) at 70 ℃, heating to 100 ℃, continuing to react the mixture at 100 ℃ for 1.5 hours until the mixture is totally clear, rapidly adding phenoxytrimethylsilane (0.70g), reacting the mixture at 100 ℃ for 1.5 hours, evaporating the solvent under reduced pressure to obtain a viscous yellow oily liquid, dissolving methanol, adjusting the pH to 3 with a 45% potassium hydroxide aqueous solution, filtering, and drying to obtain a white powdery solid IIa0.7 g. MS (M/z) 363.96(M + H)+)。
And step 3:
DMF (0.1mL) and thionyl chloride (343mg) were added to a sulfolane (1mL) mixture of IIa (600mg) at 60 ℃ and the mixture was stirred at 60 ℃ for 30 minutes until it was clear. The above solution was added to a solution of the amino acid ester IIIa (750mg, purchased from Shanghai Dairy Fine Chemicals, Ltd.) and diisopropylamine (452mg) in dichloromethane (7mL) at 0 ℃. The reaction mixture was heated to 20 ℃ and reacted for 2 hours, and the reaction mixture was washed with a 5% sodium dihydrogenphosphate aqueous solution and a saturated sodium chloride aqueous solution in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off to leave a crude product as a yellow oil, which was purified by column chromatography to give 150mg of the oily liquid product Ia (i.e., the compound represented by formula Ia1 and its diastereomer mixture, in which the optical purity of Compound Ia1 was 50.5%).
1H-NMR(400MHz,CDCl3):δ8.34(m,1H),8.05(m,1H),7.36～6.95(m,5H),6.49(b,2H),6.22～5.84(m,1H),5.01(m,1H),4.42(m,1H),4.40～3.60(m,3H),1.52～1.18(m,15H).MS(m/z):491.13(M+H+)。
Example 2 (preliminary purification of the Compound of formula Ia1 and its diastereoisomeric mixture, from Chinese patent application 201310499954.7)
A compound represented by the formula Ia1 obtained by the method of example 1 and a diastereomer mixture thereof (1.0g, optical purity of the compound represented by the formula Ia 1: 50.5%) were dissolved in ethyl acetate (10mL) and n-heptane (2mL), D- (+) -dibenzoyltartaric acid (0.35g) was added at 20 ℃ and stirred at 20 ℃ for 24 hours for crystallization, D- (+) -dibenzoyltartaric acid salt (0.8g) was obtained by filtration, the resulting salt was added to methylene chloride (10mL) and water (10mL), 2mL of an aqueous solution of sodium hydroxide was added to separate an organic layer, dried over anhydrous sodium sulfate and concentrated to obtain a product (0.42g) having an optical purity of 79.5% of the compound represented by the formula Ia 1.
Dissolving the compound represented by the formula Ia 1a1 (10.0g, optical purity 79.5%) obtained in the above step in ethyl acetate (100mL) and n-heptane (20mL), adding D- (+) -dibenzoyltartaric acid (2.9g) at 20 ℃, stirring at 20 ℃ for 24 hours for crystallization, and filtering to obtain D- (+) -dibenzoyltartaric acid salt (9.8g, optical purity of the compound represented by the formula Ia1 91.4%); dissolving the obtained salt in ethyl acetate (60mL) at 50 ℃, cooling to 20 ℃ and stirring for 18 hours for crystallization to obtain D- (+) -dibenzoyl tartrate (6.9g, the purity of the compound I is 97.1%); the resulting salt was dissolved in ethyl acetate (40mL) at 50 ℃ and cooled to 20 ℃ and stirred for 18 hours for crystallization to give D- (+) -dibenzoyl tartrate (5.2g), which was added to methylene chloride (50mL) and water (50mL) and 10mL of aqueous sodium hydroxide solution was added to separate the organic layer, dried over anhydrous sodium sulfate and concentrated to give the compound of formula Ia1 (3.6g) with an optical purity of 99.1%.
Example 3
10g of crude compound represented by the formula Ia1 (prepared according to Chinese patent application 2012100041647.4, purified twice according to Chinese patent application 201310499954.7, and containing 4.97% of related substances, 0.56% of maximum single impurities and 4.77% of non-corresponding isomers), 10ml of acetonitrile and 50ml of toluene are added into a 100ml reaction bottle, heated to 40-50 ℃, stirred, dissolved and cleared, cooled to 0-10 ℃, stirred, crystallized for 2h, filtered, a filter cake is washed by a small amount of mixed solution of acetonitrile and toluene, and dried in vacuum at 50 ℃ to obtain 8.59g of compound represented by the formula Ia1, the yield is 85.9%, the related substances are 0.11%, the maximum single impurities are 0.04% and the content of the non-corresponding isomers is 0.04%.
Example 4
10g of crude compound represented by the formula Ia1 (prepared according to Chinese patent application 2012100041647.4, purified twice according to Chinese patent application 201310499954.7, and containing 4.97% of related substances, 0.56% of maximum single impurities and 4.77% of non-corresponding isomers), 10ml of acetonitrile and 50ml of isopropyl ether are added into a 1L reaction bottle, heated to 40-50 ℃, stirred, dissolved and cleared, cooled to 0-10 ℃, stirred, crystallized for 2h, filtered, a filter cake is washed by a small amount of mixed solution of acetonitrile and isopropyl ether, 1:5, and dried in vacuum at 50 ℃ to obtain 8.86g of compound represented by the formula Ia1, the yield is 88.6%, the related substances are 0.21%, the maximum single impurities are 0.06% and the content of the non-corresponding isomers is 0.05%.
Example 5
10g of crude compound represented by the formula Ia1 (prepared according to Chinese patent application 2012100041647.4, purified twice according to Chinese patent application 201310499954.7, and containing 4.97% of related substances, 0.56% of maximum single impurities and 4.77% of non-corresponding isomers), 10ml of acetonitrile are added into a 50ml reaction bottle, heated to 40-50 ℃, stirred, dissolved and clear, cooled to 0-10 ℃, stirred and crystallized for 2h, filtered, a filter cake is washed by a small amount of acetonitrile, and dried in vacuum at 50 ℃ to obtain 4.89g of compound represented by the formula Ia1, wherein the yield is 48.9%, the related substances are 0.10%, the maximum single impurities are 0.04% and the content of the non-corresponding isomers is 0.03%.
Example 6
10g of crude compound represented by the formula Ia1 (prepared according to Chinese patent application 2012100041647.4, purified twice according to Chinese patent application 201310499954.7, and containing 4.97% of related substances, 0.56% of maximum single impurities and 4.77% of non-corresponding isomers), 15ml of acetonitrile and 50ml of isopropyl ether are added into a 100ml reaction bottle, heated to 40-50 ℃, stirred, dissolved and cleared, cooled to-10-0 ℃, stirred, crystallized for 2h, filtered, a filter cake is washed by a small amount of mixed solution of acetonitrile and isopropyl ether, 1:5, and dried in vacuum at 50 ℃ to obtain 8.92g of compound represented by the formula Ia1, the yield is 89.2%, the related substances are 0.30%, the maximum single impurities are 0.09%, and the content of the non-corresponding isomers is 0.10%.
Example 7
10g of crude compound represented by the formula Ia1 (prepared according to Chinese patent application 2012100041647.4, purified twice according to Chinese patent application 201310499954.7, and containing 4.97% of related substances, 0.56% of maximum single impurities and 4.77% of non-corresponding isomers), 15ml of acetonitrile and 50ml of isopropyl ether are added into a 100ml reaction bottle, heated to 40-50 ℃, stirred, dissolved and cleared, cooled to 10-20 ℃, stirred, crystallized for 2h, filtered, a filter cake is washed by a small amount of mixed solution of acetonitrile and isopropyl ether, 1:5, and dried in vacuum at 50 ℃ to obtain 7.32g of compound represented by the formula Ia1, the yield is 73.2%, the related substances are 0.15%, the maximum single impurities are 0.04% and the content of the non-corresponding isomers is 0.04%.
Claims (11)
1. A method for purifying a compound represented by formula Ia1, comprising the steps of,
the crude compound represented by formula Ia1 is recrystallized from acetonitrile, a mixed solvent of acetonitrile and toluene or a mixed solvent of acetonitrile and isopropyl ether.
2. The method according to claim 1, wherein the temperature of the heated dissolution during the recrystallization is 30 ℃ to 90 ℃.
3. The method according to claim 1, wherein the temperature of the heated dissolution during the recrystallization is 40 ℃ to 50 ℃.
4. The method according to claim 1, wherein the cooling crystallization temperature during recrystallization is from-15 ℃ to 30 ℃.
5. The method according to claim 1, wherein the cooling crystallization temperature during recrystallization is 0 ℃ to 10 ℃.
6. The method according to claim 1, wherein the volume ratio of acetonitrile to toluene is selected from 1:1 to 1: 10.
7. The method according to claim 1, wherein the volume ratio of acetonitrile to toluene is selected from 1:1 to 1: 5.
8. The process of claim 1, wherein the volume ratio of acetonitrile to toluene is 1: 3.3.
9. The method according to claim 1, wherein the volume ratio of acetonitrile to isopropyl ether is selected from 1:1 to 1: 10.
10. The method according to claim 1, wherein the volume ratio of acetonitrile to isopropyl ether is selected from 1:1 to 1: 5.
11. The process of claim 1, wherein the volume ratio of acetonitrile to isopropyl ether is 1: 3.3.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665043A (en) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | Tenofovir prodrug and medical application thereof |
| CN104558035A (en) * | 2013-10-22 | 2015-04-29 | 上海源力生物技术有限公司 | Method for purifying a tenofovir prodrug |
| CN106699812A (en) * | 2015-11-12 | 2017-05-24 | 江苏豪森药业集团有限公司 | Method for preparation and purification of tenofovir prodrug |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665043A (en) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | Tenofovir prodrug and medical application thereof |
| CN104558035A (en) * | 2013-10-22 | 2015-04-29 | 上海源力生物技术有限公司 | Method for purifying a tenofovir prodrug |
| CN106699812A (en) * | 2015-11-12 | 2017-05-24 | 江苏豪森药业集团有限公司 | Method for preparation and purification of tenofovir prodrug |
Non-Patent Citations (1)
| Title |
|---|
| 替诺福韦前药的设计、合成及初步代谢;刘浩等;《精细化工》;20170430;第34卷(第4期);437-443页 * |
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