CN105294762A - Preparation method of adefovir dipivoxil impurities - Google Patents
Preparation method of adefovir dipivoxil impurities Download PDFInfo
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Abstract
The invention relates to a brand-new synthetic method of three adefovir dipivoxil impurities. The synthetic method is of great significance for synthesis of high-quality adefovir dipivoxil. The invention mainly studies synthesis of adefovir dipivoxil methyl ester impurity [[2-(6-amino-9H-purine-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl)(methyl)ester (III), adefovir dipivoxil ethyl ester impurity [[2-(6-amino-9H-purine-9-yl)-ethoxy]methyl]phosphonic acid (pivaloyloxymethyl)(ethyl)ester (IV), adefovir dipivoxil amide impurity [[2-(6-pivaloylamido-9H-purine-9-yl)-ethoxy]methyl]phosphonic acid bi(pivaloyloxymethyl)ester (V). The specific synthetic route of the impurities is as shown in the specification.
Description
Technical field
The present invention relates to the preparation method of adefovir ester impurity.
Background technology
Adefovir ester (AdefovirDipivoxil), chemistry [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester by name, it is the acyclic analog of 5 '-monophosphate deoxidation vidarabine, it is the precursor of Adefovir, under the effect of cell kinase, activation is for Adefovir diphosphate, is suppressed HBVDNA polymerase by the mode of competing with natural substrate deoxyadenosine triphosphate and cause DNA chain extension to stop after being incorporated into viral DNA thus is played antivirus action.This compound is researched and developed by GileadSciences company of the U.S., and within 2002, ratified by FDA, specification is 10mg/ sheet, and commodity are called Hepsera, is clinically used for the treatment of Adult chronic's hepatitis B.2003, European Union ratified the listing of this medicine, and this medicine is in the listing of multiple countries at present.Domestic in 2003 first by Tianjin Inst. of Materia Medica pharmaceutcal corporation, Ltd submission adefovir ester raw material and tablet new drug application, obtained first class national new drug certificate in 2005 and produce official written reply.Current domestic existing 30 Yu Jia manufacturing enterprises obtain the production permit of this medicine raw material and preparation.
The principal reaction route that adefovir ester (I) synthesizes is as follows:
(1) take ethylene chlorhydrin as raw material, [[2-(6-amino-9H-purine-9-base) oxyethyl group] methyl] phosphonic acids diisopropyl ester is reacted through paraformaldehyde, triisopropyl phosphite and VITAMIN B4, take off sec.-propyl through bromotrimethylsilane and obtain Adefovir, obtain adefovir ester finally by esterification.
(2) take oxyethane as raw material, with VITAMIN B4 condensation, under sodium reagent effect, carry out alkylated reaction with tolysulfonyl oxygen ylmethyl diethyl phosphonate obtain [[2-(6-amino-9H-purine-9-base) oxyethyl group] methyl] diethyl phosphonate, finally be hydrolyzed to obtain Adefovir with bromotrimethylsilane or trimethylchlorosilane, again through esterification, obtain adefovir ester.
(3) take NSC 11801 as raw material, 9-(2-hydroxyethyl) VITAMIN B4 is generated with VITAMIN B4 condensation under the effect of alkali, under sodium reagent effect, carry out alkylated reaction with tolysulfonyl oxygen ylmethyl diethyl phosphonate obtain [[2-(6-amino-9H-purine-9-base) oxyethyl group] methyl] diethyl phosphonate, obtain Adefovir with bromotrimethylsilane or the de-ethyl of trimethylchlorosilane hydrolysis again, obtain adefovir ester finally by esterification.
The key of Adefovir Lipase absobed is the control of its impurity, and therefore the study on the synthesis of adefovir ester impurity is significant.Document points out that the impurity that adefovir ester research needs comprises: adefovir ester methyl ester impurity, chemical name: [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester; Adefovir ester ethyl ester impurity, chemical name: [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester; Adefovir ester amide impurities, chemical name: [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester etc.Synthesis report document both at home and abroad for adefovir ester impurity is few, is especially showed no bibliographical information at present to the synthesis of adefovir ester methyl ester impurity (III), adefovir ester ethyl ester impurity (IV) and adefovir ester amide impurities (V).
Summary of the invention
The present invention relates to adefovir ester three impurity: adefovir ester methyl ester impurity (III), adefovir ester ethyl ester impurity (IV), the synthetic method of adefovir ester amide impurities (V), synthetic route of the present invention is as follows:
Impurity (III) and impurity (IV) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, impurity (V) with adefovir ester (I) for raw material.
The preparation method of impurity (III) (IV) and (V) has not yet to see bibliographical information so far.
Synthesis step of the present invention is as follows:
(1) preparation of [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester (III)
1. the preparation of adefovir ester methyl ester (III) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, drip at a slow speed oxalyl chloride under catalyzer existence condition and carry out chloro, then esterification is carried out, temperature of reaction with methyl alcohol: room temperature after first cryosel bath.
In the preparation method of 2. adefovir ester methyl ester (III), solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, pyridine, N-methylpyrrole piperazine ketone.
In the preparation method of adefovir ester methyl ester (III), Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.0 ~ 1.5 with the mol ratio of oxalyl chloride, Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.5 ~ 2.0 with the mol ratio of methyl alcohol, and Adefovir list trimethylacetic acid methyl esters (II) is 1: 15 ~ 25 with the mass volume ratio of solvent.
Chloride is carried out, this catalyzer mainly DMF, DMA and pyridine under needing catalyzer to exist in the preparation method of 3. adefovir ester methyl ester (III).
In the preparation method of 4. adefovir ester methyl ester (III), with the larger solvent extraction of polarity, solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF), toluene, acetone.The preferred methylene dichloride range of solvents of the present invention.
In the preparation method of 5. adefovir ester methyl ester (III), it is refining adopts silica gel column chromatography method, and eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 25 ~ 35.
(2) preparation of [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester (IV)
1. the preparation of adefovir ester ethyl ester impurity (IV) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, drip at a slow speed oxalyl chloride under catalyzer existence condition and carry out chloro, then esterification is carried out, temperature of reaction with ethanol: room temperature after first cryosel bath.
In the preparation method of 2. adefovir ester ethyl ester impurity (IV), solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, pyridine, N-methylpyrrole piperazine ketone.
In the preparation method of adefovir ester ethyl ester impurity (IV), Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.0 ~ 1.5 with the mol ratio of oxalyl chloride, Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.5 ~ 2.5 with the mol ratio of ethanol, and Adefovir list trimethylacetic acid methyl esters (II) is 1: 15 ~ 25 with the mass volume ratio of solvent.
Chloride is carried out, this catalyzer mainly DMF, DMA and pyridine under needing catalyzer to exist in the preparation method of 3. adefovir ester ethyl ester impurity (IV).
In the preparation method of 4. adefovir ester ethyl ester impurity (IV), with the larger solvent extraction of polarity, solvent for use be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, ethyl acetate, methylene dichloride, chloroform, tetrahydrofuran (THF), toluene, acetone.The preferred methylene dichloride range of solvents of the present invention.
In the preparation method of 5. adefovir ester ethyl ester impurity (IV), it is refining adopts silica gel column chromatography method, and eluent adopts ethanol/methylene system, particular methanol: methylene dichloride=1: 25 ~ 35.
(3) preparation of [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester (V)
1. adefovir ester amide impurities (V) is with adefovir ester (I) for raw material, drips pivaloyl chloride and carries out amidation and obtain, amidate action temperature: room temperature after the bath of first cryosel under acid binding agent existence condition.
In the preparation method of 2. adefovir ester amide impurities (VI), solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, N-Methyl pyrrolidone, DMF.
In the preparation method of adefovir ester amide impurities (V), adefovir ester (I) with the mol ratio of pivaloyl chloride is: 1: 1.0 ~ 1.5; Adefovir ester (I) is 1: 15 ~ 25 with the mass volume ratio of solvent.
3. drip pivaloyl chloride under acid binding agent existence condition and obtain adefovir ester amide impurities (V), wherein, described acid binding agent is selected from triethylamine and pyridine, and adefovir ester (I) is 1: 1.2 ~ 1.8 with the mol ratio of acid binding agent.
In the preparation method of 4. adefovir ester amide impurities (V), directly except desolventizing obtains adefovir ester amide impurities (VI) crude product after reaction to terminal, its refining employing silica gel column chromatography method, eluent adopts methanol/ethyl acetate system, particular methanol: ethyl acetate=1: 40 ~ 50.
Embodiment
Following Examples further illustrates the present invention, but the present invention is not limited.
Embodiment:
The preparation of embodiment 1 [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester
By Adefovir list trimethylacetic acid methyl esters (3.0g, 7.75mmol) be placed in 100mL three-necked bottle, add 50mL methylene dichloride, add 7 ~ 8 N again, dinethylformamide makees catalyzer, oxalyl chloride (1.47g, the 11.57mmol) solution being dissolved in 10ml methylene dichloride is slowly dripped under cryosel bath condition.After dropwising, dislocation room temperature continues reaction 2 hours, and some plate judges terminal; TLC condition: methylene chloride-methanol (8: 1).After reacting completely, immediately solvent is revolved and steam to dry, then dissolve with 10ml methylene dichloride, use to get step ready.
Measure methyl alcohol (0.50g, 15.63mmol) and be placed in 100mL three-necked bottle, add 50ml methylene dichloride, under cryosel bath condition, slowly drip above-mentioned solution; Dropwise, dislocation room temperature reaction 3 hours, some plate judges terminal; TLC condition: methylene chloride-methanol (8: 1).After reaction terminates, revolved by solvent and steam to dry, be cooled to room temperature, add 40ml methylene dichloride and dissolve, stratification, suction filtration removing solid obtains filtrate, and filtrate concentrates, and enriched material obtains white solid 1.21g through column chromatography for separation, yield 38.93%.
Its Structural Identification data are as follows:
1H-NMR(300Mz，DMSO-d
6)δ：8.13(s，1H，H-2)，8.07(s，1H，H-8)，7.20(s，1H，N
H 2)，5.52(d，J＝12.81Hz，2H，OC
H 2O)，4.31～4.34(t，J＝5.01，2H，NC
H 2CH
2)，3.87～3.99(m，7H，OC
H 2P，CH
2C
H 2O，OC
H 3)，1.13～1.18(m，9H，3×C
H 3)。
ESI-MS(m/z)：424[M+Na]
+。
The preparation of embodiment 2 [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester
By Adefovir list trimethylacetic acid methyl esters (3.0g, 7.75mmol) be placed in 100mL three-necked bottle, add 50mL methylene dichloride, add 7 ~ 8 N again, dinethylformamide makees catalyzer, oxalyl chloride (1.47g, the 11.57mmol) solution being dissolved in 10ml water methylene dichloride is slowly dripped under cryosel bath condition.After dropwising, dislocation room temperature continues reaction 2 hours, and some plate judges terminal; TLC condition: methylene chloride-methanol (8: 1).After reacting completely, immediately solvent is revolved and steam to dry, then dissolve with 10ml methylene dichloride, use to get step ready.
Measure ethanol (0.72g, 15.65mmol) and be placed in 100mL three-necked bottle, add 50ml methylene dichloride, under cryosel bath condition, slowly drip above-mentioned solution; Dropwise, dislocation room temperature reaction 3 hours, some plate judges terminal; TLC condition: methylene chloride-methanol (8: 1).After reaction terminates, revolved by solvent and steam to dry, be cooled to room temperature, add 40ml methylene dichloride and dissolve, stratification, suction filtration removing solid obtains filtrate, and filtrate concentrates, and enriched material obtains white solid 1.18g through column chromatography for separation, yield 36.69%.
Its Structural Identification data are as follows:
1H-NMR(300Mz，DMSO-d
6)δ：8.13(s，1H，H-2)，8.07(s，1H，H-8)，7.20(s，2H，N
H 2)，5.52(d，J＝12.45，OC
H 2O)，4.30～4.34(t，J＝5.07，NC
H 2CH
2)，3.87～3.94(m，4H，OC
H 2P，CH
2C
H 2O)，3.60(d，J＝10.95，2H，OC
H 2CH
3)，1.23(s，3H，CH
2C
H 3)，1.14(s，9H，3×C
H 3)。·
ESI-MS(m/z)：415[M+H]
+。
The preparation of embodiment 3 [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester
By adefovir ester (I) (2.0g, 3.99mmol) be placed in 100mL three-necked bottle, triethylamine (0.60g is added under room temperature, 5.94mmol), add methylene dichloride 40ml again, pivaloyl chloride (0.62g, 5.19mmol) is slowly dripped under cryosel bath condition; Dropwise, dislocation room temperature continues reaction 8 hours, and some plate judges terminal; TLC condition: methanol-ethyl acetate (1: 18).After reaction terminates, revolved by solvent and steam to dry, enriched material obtains white oil thing 1.78g through column chromatography for separation.Yield 76.13%.
Its Structural Identification data are as follows:
1H-NMR(300Mz，DMSO-d
6)δ：10.08(s，1H，N
H)，8.66(s，1H，H-2)，8.37(s，1H，H-8)，5.53(d，J＝12.75Hz，4H，2×OC
H 2O)，4.43～4.46(t，J＝4.47，2H，NC
H 2CH
2)，3.92～3.98(m，4H，OC
H 2P，CH
2C
H 2O)，1.27(s，9H，3×C
H 3)，1.13(s，18H，6×C
H 3)。
ESI-MS(m/z)：587[M+H]
+。
Claims (10)
1. the preparation method of adefovir ester impurity, is characterized in that comprising following three synthetic routes:
(1) Adefovir list trimethylacetic acid methyl esters (II) obtains [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester (III) (being called for short adefovir ester methyl ester impurity) through chloro, esterification;
(2) Adefovir list trimethylacetic acid methyl esters (II) obtains [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester (IV) (being called for short adefovir ester ethyl ester impurity) through chloro, esterification;
(3) adefovir ester (I) and pivaloyl chloride carry out amidation and obtain [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester (V) (being called for short adefovir ester amide impurities).
。
2. the preparation method of [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (methyl) ester (III) according to claim 1, it is characterized in that the preparation of adefovir ester methyl ester impurity (III) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, drip at a slow speed oxalyl chloride under catalyzer existence condition and carry out chloro, then esterification is carried out, temperature of reaction with methyl alcohol: room temperature after first cryosel bath; Solvent for use be selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, pyridine, N-methylpyrrole piperazine ketone.
3. carry out chlorination under catalyzer existence condition according to claim 2, it is characterized in that used catalyst is selected from DMF, DMA and pyridine, preferred DMF; Chlorinating agent used is sulfur oxychloride and oxalyl chloride, preferred oxalyl chloride.
4. in the preparation method of adefovir ester methyl ester impurity (III) according to claim 2, it is characterized in that Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.0 ~ 1.5 with the mol ratio of oxalyl chloride, Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.5 ~ 2.0 with the mol ratio of methyl alcohol, and Adefovir list trimethylacetic acid methyl esters (II) is 1: 15 ~ 25 with the mass volume ratio of solvent.
5. the preparation method of [[2-(6-amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids (oxy acid methyl neopentyl) (ethyl) ester (IV) according to claim 1, it is characterized in that the preparation of adefovir ester ethyl ester impurity (IV) with Adefovir list trimethylacetic acid methyl esters (II) for raw material, drip at a slow speed oxalyl chloride under catalyzer existence condition and carry out chloro, then esterification is carried out, temperature of reaction with ethanol: room temperature after first cryosel bath; Solvent for use is selected from acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, pyridine, N-methylpyrrole piperazine ketone.
6. carry out chlorination under catalyzer existence condition according to claim 5, it is characterized in that used catalyst is selected from DMF, DMA and pyridine, preferred DMF; Chlorinating agent used is sulfur oxychloride and oxalyl chloride, preferred oxalyl chloride.
7. the preparation method of adefovir ester ethyl ester impurity (IV) according to claim 5, it is characterized in that Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.0 ~ 1.5 with the mol ratio of oxalyl chloride, Adefovir list trimethylacetic acid methyl esters (II) is 1: 1.5 ~ 2.5 with the mol ratio of methyl alcohol, and Adefovir list trimethylacetic acid methyl esters (II) is 1: 15 ~ 25 with the mass volume ratio of solvent.
8. the preparation of [[2-(6-pivalyl amino-9H-purine-9-base)-oxyethyl group] methyl] phosphonic acids two (oxy acid methyl neopentyl) ester (V) according to claim 1, it is characterized in that adefovir ester amide impurities (V) with adefovir ester (I) for raw material, drip pivaloyl chloride under acid binding agent existence condition to carry out amidation and obtain, amidate action temperature: room temperature after the bath of first cryosel; Solvent for use is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, Pyrrolidine, N-Methyl pyrrolidone, DMF.
9. generate adefovir ester amide impurities (V) under acid binding agent existence condition according to claim 8, it is characterized in that acid binding agent used is triethylamine, adefovir ester (I) is 1: 1.2 ~ 1.8 with the mol ratio of triethylamine.
10. the preparation method of adefovir ester amide impurities (V) according to claim 8, it is characterized in that the refining employing silica gel column chromatography method of adefovir ester amide impurities (VI), eluent adopts methanol/ethyl acetate system, particular methanol: ethyl acetate=1: 40 ~ 50.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5663159A (en) * | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN101812089A (en) * | 2010-04-07 | 2010-08-25 | 陶灵刚 | Adefovir dipivoxil compound and novel preparation method thereof |
| CN101812090A (en) * | 2010-05-10 | 2010-08-25 | 浙江车头制药有限公司 | Preparation method of adefovir monoester |
| CN102143967A (en) * | 2008-09-11 | 2011-08-03 | Cj第一制糖株式会社 | Purification method for adefovir dipivoxil |
-
2015
- 2015-11-13 CN CN201510788399.9A patent/CN105294762A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5663159A (en) * | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN102143967A (en) * | 2008-09-11 | 2011-08-03 | Cj第一制糖株式会社 | Purification method for adefovir dipivoxil |
| CN101812089A (en) * | 2010-04-07 | 2010-08-25 | 陶灵刚 | Adefovir dipivoxil compound and novel preparation method thereof |
| CN101812090A (en) * | 2010-05-10 | 2010-08-25 | 浙江车头制药有限公司 | Preparation method of adefovir monoester |
Non-Patent Citations (1)
| Title |
|---|
| YUTAKA K. ET AL: ""Phenylsulfanylation of 3′,4′-Unsaturated Adenosine Employing Thiophenol-N-Iodosuccinimide Leads to 4′- Phenylsulfanylcordycepin: Synthesis of 4′-Substituted Cordycepins on the Basis of Substitution of the Phenylsulfanyl Leaving Group"", 《J. ORG. CHEM》 * |
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Application publication date: 20160203 |