CN101134765A - Method for synthesizing adefovir dipivoxil ester - Google Patents
Method for synthesizing adefovir dipivoxil ester Download PDFInfo
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Abstract
The present invention relates to medicine synthesis technology, and is especially Adefovir dipivoxil synthesizing process, which includes the following steps: 1. methylation reaction of 2-chlorethanol, paraformaldehyde and anhydrous hydrogen chloride to produce 1-chloro-2-chloromethoxyl ethane; 2. reaction of 1-chloro-2-chloromethoxyl ethane and trimorpholinyl phosphate to obtain 2-dimorpholinyl chloroethoxyl methyl phosphonate; 3. condensation of 2-dimorpholinyl chloroethoxyl methyl phosphonate and adenine in DMF in the presence of anhydrous K2CO3 catalyst to obtain 9-(2-dimorpholinylphsphonomethoxylethyl) adenine; 4. hydrochloric acid hydrolysis of 9-(2-dimorpholinylphsphonomethoxylethyl) adenine in DMF aqua to obtain 9-(2-phsphonomethoxylethyl) adenine; and 5. reaction of 9-(2-phsphonomethoxylethyl) adenine and chloromethyl pivalate in DMF under the catalysis of triethylamine to obtain Adefovir dipivoxil.
Description
Technical field:
The present invention relates to a kind of medicine synthetic method, particularly a kind of synthetic method of anti-hbv drug adefovir ester.
Background technology:
Adefovir ester is a kind of new oral broad-spectrum antiviral drug, by suppressing viral dna polymerase and cryotron transcriptase, suppress transcribing and duplicating of virus, hepatitis B virus and hiv virus etc. there is stronger restraining effect, lamivudine and the drug-fast hepatitis B virus of Famciclovir also there is stronger restraining effect, be the open loop efabirenz, it is the prodrug of Adefovir (PMEA), bioavailability is big than Adefovir, adefovir ester is developed by U.S. Gilead Sciences company, Nikkei drugs approved by FDA Initial Public Offering in September 20 in 2002, English name Adefovir Dipivoxil, trade(brand)name Hepsera, two (pivaloyloxymethoxy) phosphono methoxyl groups of chemical name: 9-{2-[] ethyl } VITAMIN B4, structural formula is as follows:
Its molecular formula: C
20H
32N
5O
8P; Molecular weight: 501.48.Be used for the treatment of adult's chronic hepatitis B, determined curative effect, untoward reaction is few and slight.
The synthetic Adefovir of bibliographical information " 9-(2-phosphono methoxy ethyl) VITAMIN B4 " operational path (PMEA) has following several:
Synthetic method 1
With Acetyl Chloride 98Min. (III) is raw material, under zinc chloride catalysis with 1,3-dioxolane (IV) react 2-acetoxyl group-1-chlorine methoxyl group thing (V), V and triethyl-phosphite through Arbuzov react (2-acetoxyethoxy) methyl-phosphorous acid diethyl ester (VI), VI gets (2-hydroxy ethoxy) methyl-phosphorous acid diethyl ester VII, VII and Tosyl chloride/Et through acidic hydrolysis, column chromatography for separation
3N or CBr
4/ Ph
3P, CCl
4/ Ph
3The P reaction gets (2-tolysulfonyl oxygen base oxethyl) methyl-phosphorous acid diethyl ester (VIII), (2-bromine oxethyl) methyl-phosphorous acid diethyl ester (IX), (2-chloroethoxy) methyl-phosphorous acid diethyl ester (4) respectively, VIII and IX get PMEA-diethyl ester (6) with VITAMIN B4 (5) condensation under NaH catalysis, get PMEA (7) through the TMSBr hydrolysis again, 4 press synthetic method 1 gets (7).
This method is by Acetyl Chloride 98Min. (III) and 1; 3-dioxolane (IV) react 2-acetoxyl group-1-chlorine methoxyl group thing (V); again through 4 steps of Arbuzov reaction, acidic hydrolysis, bromo (or chloro, tosylation) react side chain (IX), (4) and (VIII); get PMEA (7) with VITAMIN B4 (5) condensation under alkaline part, TMSBr hydrolysis again; synthetic route is long, yield is low; and acidic hydrolysis product and halo (or sulfonylation) reaction product all needs column chromatographic isolation and purification; complex process, complex operation.
Synthetic method 2
2-acetoxyl group-1-chloromethyl thing (V) and triisopropyl phosphite through Arbuzov react (2-acetoxyethoxy) diisopropylmethylpho-sphonate(DIMP) (X), X also can be by acetyl bromide (XI) and 1,3-dioxolane (IV) react 2-acetoxyl group-1-brooethyl thing (XII), make through Arbuzov reaction with triisopropyl phosphite again.X gets (2-mesyloxy oxyethyl group) diisopropylmethylpho-sphonate(DIMP) (XIV) through acidic hydrolysis, methylsulfonylization, XIV in DMF through Cs
2CO
3Catalysis and VITAMIN B4 (5) condensation gets PMEA-diisopropyl ester (II), and II gets (7) through hydrolysis.This method synthetic route is longer, (XIV) with VITAMIN B4 (5) condensation, uses a large amount of expensive Cs
2CO
3Make catalyzer, and the metal caesium is difficult for removing fully in the product.
Synthetic method 3
With acetyl bromide (XI) is raw material, with Paraformaldehyde 96 (2) react bromomethyl acetate (XV), XV in benzene through NaH catalysis and HP (O) (OEt)
2React acetoxy-methyl diethyl phosphonate (XVI), XVI gets hydroxymethyl phosphonic acid diethyl ester (XVII) through sodium ethylate hydrolysis, acidifying, XVII and Tosyl chloride in ether, react tolysulfonyl oxygen ylmethyl diethyl phosphonate (XVIII).VITAMIN B4 (5) in DMF through sodium hydroxide catalysis and ethylene carbonate (XIX) react N
9-fast the cry of certain animals of (2-hydroxyethyl) gland (XX), XVIII and XX get PMEA-diethyl ester (6) through NaH or NaOt-Bu catalyzing and condensing in DMF, and hydrolysis gets PMEA (7) again.This method bromomethyl acetate (XV) with
Condensation gets acetoxy-methyl diethyl phosphonate (XVI) and needs with NaH and a kind solvent benzene, severe reaction conditions, and toxicity is bigger.
Synthetic method 4
Bromomethyl acetate (XV) in benzene through NaH catalysis and HP (O) (OCH
3)
2React acetoxy-methyl dimethyl phosphonate (XXI), XXI also can be by XV and P (OCH
3)
3Reaction makes.XXI gets hydroxymethyl phosphonic acid dimethyl ester (XXII) through sodium methylate hydrolysis, acidifying, XXII and Tosyl chloride react tolysulfonyl oxygen ylmethyl dimethyl phosphonate (XXIII).N
9-(2-hydroxyethyl) VITAMIN B4 (XX) gets N with the Benzoyl chloride acidylate under TMSCI catalysis
6-benzoyl-N
9-(2-hydroxyethyl) VITAMIN B4 (XXIV), XXIII and XXIV condensation reaction get N
6-benzoyl-PMEA-methyl esters (XXV), XXV go protection and portion water to solve the PMEA-mono-methyl through NaOH, and (XXVD, XXVI gets (7) at-50 ℃ through the TMSI hydrolysis.This method 9-(2-hydroxyethyl) VITAMIN B4 (XX) is through N
6The protection of-benzoyl is again with side chain
(XXIII) condensation, go the protection and portion water solve (XXVI), get PMEA (7) with TMSI at-50 ℃ of following methyl ester removals again, synthesis technique is loaded down with trivial details, severe reaction conditions, yield is lower, is difficult to suitability for industrialized production.
Synthetic method 5
VITAMIN B4 (5) and (2-hydroxy ethoxy) methyl-phosphorous acid diethyl ester (VII) get PMEA-ethyl ester (6) through Mitsunobu reaction, column chromatography for separation under diethyl azodiformate (DEAD), triphenylphosphine catalysis, get PMEA (7) through the TMSBr hydrolysis again.This method VITAMIN B4 (5) and side chain (VII) through Mitsunobu react (6), need with a large amount of DEAD and Ph
3P, and need column chromatographic isolation and purification.
The method by the synthetic adefovir ester of Adefovir (PMEA) of bibliographical information mainly contains:
Synthetic method 1
PMEA through DCM catalysis and chloromethyl pivalate reaction, gets adefovir ester through column chromatography for separation in DMF.
Synthetic method 2
PMEA in N-Methyl pyrrolidone (NMP), through triethylamine catalysis and chloromethyl pivalate react adefovir ester.
Synthetic method 3
PMEA (7) with single to methoxyl group triphenylmethyl chloride (XXVII) react N
6-mMTr thing (XXVIII), XXVIII react with trimethylacetic acid iodine methyl esters in pyridine, go protecting group to get (8) through acid again.
Above method reactions steps is long, complex process, and yield is low.
The present invention carries out process modification on the prior art basis, overcome the defective of prior art.
Summary of the invention:
The invention provides a kind of synthetic method of new adefovir ester (8 formula compound), its chemical equation is as follows:
The operation steps of this method is as follows:
Step 1, ethylene chlorhydrin and Paraformaldehyde 96, anhydrous hydrogen chloride get 1-chloro-2-chlorine methyl ethyl ether through chloromethylation;
Step 2,1-chloro-2-chlorine methyl ethyl ether and tricresyl phosphite morphine quinoline ester react 2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters;
Step 3,2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters; In DMF through anhydrous K
2CO
3Catalysis and VITAMIN B4 condensation get 9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4;
Step 4,9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4 get 9-(2-phosphono methoxyethyl) VITAMIN B4 through hydrochloric acid hydrolysis in DMF, water;
Step 5,9-(2-phosphono methoxyethyl) VITAMIN B4 through triethylamine catalysis and chloromethyl pivalate reaction, get adefovir ester in DMF.
Also can be described as:
Ethylene chlorhydrin (1) gets 1-chloro-2-chlorine methyl ethyl ether (3) with Paraformaldehyde 96, anhydrous hydrogen chloride through chloromethylation, (3) with tricresyl phosphite morphine quinoline ester react 2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters (4), (4) in DMF, get 9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4 (6) through anhydrous K 2CO3 catalysis and VITAMIN B4 (5) condensation, (6) in DMF, water, get 9-(2-phosphono methoxyethyl) VITAMIN B4 (7 through hydrochloric acid hydrolysis, PMEA), (7) in DMF through the reaction of triethylamine catalysis and chloromethyl pivalate, refining adefovir ester (8).
Technology total recovery about 16.0% of the present invention, through groping repeatedly, this operational path maturation, raw material is easy to get, and meets the suitability for industrialized production requirement.
More than raw materials used can having bought from the market of reaction also can be synthesized according to document, belongs to the prior art category.
Synthetic method of the present invention has the following advantages:
(1) this project triethyl-phosphite (or three isopropyl esters) of replacing bibliographical information with tricresyl phosphite morphine quinoline ester and (3) react 2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters (4), (4) with VITAMIN B4 (5) condensation, again through hydrochloric acid hydrolysis get 9-(2-phosphono methoxyethyl) VITAMIN B4 (7, PMEA).
(2) the starting point raw material is easy to get, and document employing l-chloro-2-chlorine methyl ethyl ether etc. are as the starting point raw material; And the employing of this project is ethylene chlorhydrin.
(3) condensation catalyst difference, document adopts NaH, Cs
2CO
3, DBU etc., cost an arm and a leg; This project anhydrous K
2CO
3
(4) the condensed products document adopts column chromatographic isolation and purification; This project recrystallization method.
(5) the PMEA-ethyl ester of bibliographical information is hydrolyzed with bromotrimethylsilane, and bromotrimethylsilane costs an arm and a leg, and consumption is big; This project obtains 9-(2-phosphono methoxyethyl) VITAMIN B4 with hydrochloric acid hydrolysis 9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4.
(6) this project synthesis technique total recovery reaches about 16%, the total recovery height.
Method of the present invention, the synthetic route step is short, and raw material is easy to get, the reaction conditions gentleness, no particular requirement, easy to operate, the recovery rate height.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
1.1-chloro-2-chlorine methyl ethyl ether (3) is synthetic
Charging capacity:
Operation steps:
Paraformaldehyde 96 (2) 30.0g is suspended among ethylene chlorhydrin (1) 80.5g, stirring at room, fed anhydrous hydrogen chloride gas 22 hours, the solid dissolving, branch vibration layer. organic layer adds Calcium Chloride Powder Anhydrous 20.0g drying, feeds nitrogen 4h, filters. underpressure distillation, collect the little yellow transparent liquid of bp62-66 ℃/29Mg (3) 90.6g, yield 70.2%.Quality controlling means: bp62-66 ℃/29mmHg.
Attached: the preparation of anhydrous hydrogen chloride gas: concentrated hydrochloric acid, sodium-chlor mix, and slowly drip the vitriol oil, and the hydrogen chloride gas of generation is drying to obtain through the vitriol oil.
2.2-chloroethene oxygen methyl acid diethyl ester (4)
Feed ratio
(3) 82.3g is heated with stirring to 90' ℃, drips tricresyl phosphite morphine quinoline ester 122.9g, drip off, and oil bath 120-125 ℃ of reaction 4.5h, underpressure distillation is collected bp150-153 ℃/2mHg colourless transparent liquid (4) 122.1g, yield 83.0%.Quality controlling means: bp150-153 ℃/2mmHg.
(3.9-2-morphine quinoline base phosphono methoxyethyl) VITAMIN B4 (6)
Feed ratio
N
2Under the protection, VITAMIN B4 (5) 58.6g, DMF600.0ml, anhydrous K
2CO
2118.8g, stir, in 100 ℃ of reactions 8 hours, cooling, suction filtration, filtrate decompression reclaims solvent, gets light yellow sticking shape solid, get off-white color crystallization (6) 74.4g, yield 52.1%, mp133-136 ℃ of quality controlling means: silica gel G F with ethyl acetate-methyl alcohol (4: 1) recrystallization secondary
25-1, developping agent: methylene dichloride: methyl alcohol=4: 1 fluoroscopic examination impure points are less than 2%, mp133-136 ℃.
(4.9-2-phosphono methoxyethyl) VITAMIN B4 (7)
Feed ratio
N
2Under the protection, acetonitrile 70.2gml, (6) 70.2g; bromotrimethylsilane 175.0ml, stirring at room reaction 24 hours gets light yellow liquid; concentrating under reduced pressure adds entry 280.0ml in the residue, acetone 800.0ml; stir 4h, cooling, suction filtration; the small amount of acetone washing; dry white solid (7) 52.0g, yield 89.3%, mp〉270 ℃.Quality controlling means: silica gel G F
254, developping agent: methylene dichloride: methyl alcohol=4: 1, fluoroscopic examination impure point is less than 2%, mp〉and 270 ℃.5.9-(two (pivaloyloxymethoxy) phosphono methoxyl groups of 2-[] ethyl) VITAMIN B4 (8, adefovir ester)
Feed ratio
N
2Protection down; DMF310.0ml; (7) 46.8g; triethylamine 160.0ml, chloromethyl pivalate 140.0ml, 40 ℃ of stirring reaction 30h; add ethyl acetate 460.0ml; stirring at room 1h, suction filtration, filtrate water; saturated nacl aqueous solution is respectively given a baby a bath on the third day after its birth inferior; anhydrous sodium sulfate drying; filter concentrating under reduced pressure, residue 800g silica gel H column chromatography for separation (eluent: methyl alcohol: the dichloromethane gradient wash-out) get little yellow oil 40.5g; add methylene dichloride 160.0ml; heating for dissolving. add 5.0 activated carbon decolorizing 30min, filtered while hot, filtrate decompression is concentrated into dried; sherwood oil (60-90 ℃) washing; Vanadium Pentoxide in FLAKES vacuum-drying gets off-white powder shape solid adefovir ester (8) 36.8g, yield 42.8%, mp93-94 ℃.
Claims (8)
1. the synthetic method of an adefovir ester is characterized in that, may further comprise the steps:
Step 1, ethylene chlorhydrin and Paraformaldehyde 96, anhydrous hydrogen chloride get 1-chloro-2-chlorine methyl ethyl ether through chloromethylation;
Step 2,1-chloro-2-chlorine methyl ethyl ether and tricresyl phosphite morphine quinoline ester react 2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters;
Step 3,2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters; In DMF through anhydrous K
2CO
3Catalysis and VITAMIN B4 condensation get 9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4;
Step 4,9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4 get 9-(2-phosphono methoxyethyl) VITAMIN B4 through hydrochloric acid hydrolysis in DMF, water;
Step 5,9-(2-phosphono methoxyethyl) VITAMIN B4 through triethylamine catalysis and chloromethyl pivalate reaction, get adefovir ester in DMF.
2. the synthetic method of claim 1 is characterized in that,
Step 1 adopts following method, and Paraformaldehyde 96 is suspended in the ethylene chlorhydrin, and stirring at room fed anhydrous hydrogen chloride gas 22 hours, the solid dissolving, branch vibration layer, organic layer adds the Calcium Chloride Powder Anhydrous drying, feeds nitrogen 4h, filter, little yellow transparent liquid is collected in underpressure distillation.
3. the synthetic method of claim 1 is characterized in that, step 2 adopts following method,
1-chloro-2-chlorine methyl ethyl ether is heated with stirring to 90 ℃, drips tricresyl phosphite morphine quinoline ester, drip off, and oil bath 120-125 ℃ of reaction 4.5h, colourless transparent liquid is collected in underpressure distillation.
4. the synthetic method of claim 1 is characterized in that, step 3 adopts following method,
At N
2Protection mixes 2-chloroethene oxygen methyl-phosphorous acid two morphine quinoline esters, VITAMIN B4, DMF, anhydrous K down
2CO
3, stir, 100 ℃ of reactions 8 hours, cooling, suction filtration, filtrate decompression reclaims solvent, light yellow sticking shape solid, use ethyl acetate: methyl alcohol=4: 1 gets the off-white color crystallization for the solvent recrystallization secondary.
5. the synthetic method of claim 1 is characterized in that, step 4 adopts following method,
At N
2Protection mixes 9-(2-two morphine quinoline base phosphono methoxyethyls) VITAMIN B4 down, acetonitrile, bromotrimethylsilane, stirring at room reaction 24 hours; get light yellow liquid, concentrating under reduced pressure adds entry in the residue, and acetone stirs 4h; cooling, suction filtration, small amount of acetone washing, the dry white solid that gets.
6. the synthetic method of claim 1 is characterized in that, step 5 adopts following method,
N
2Protection mixes 9-(2-phosphono methoxyethyl) VITAMIN B4, DMF down; triethylamine; chloromethyl pivalate, 40 ℃ of stirring reaction 30h add ethyl acetate; stirring at room 1h; suction filtration, filtrate water, saturated nacl aqueous solution are respectively given a baby a bath on the third day after its birth inferior, anhydrous sodium sulfate drying; filter; concentrating under reduced pressure, residue gets little yellow oil with 800g silica gel H column chromatography for separation, adds methylene dichloride; heating for dissolving; add activated carbon decolorizing 30min, filtered while hot, filtrate decompression is concentrated into dried; petroleum ether, Vanadium Pentoxide in FLAKES vacuum-drying get off-white powder shape solid adefovir ester.
7. the synthetic method of claim 6 is characterized in that,
In the step 5, the described silica gel H column chromatography for separation of using, its used eluent is: methyl alcohol: the dichloromethane gradient wash-out.
8. the synthetic method of claim 6 is characterized in that,
In the step 5, described petroleum ether temperature is at 60-90 ℃.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101812089A (en) * | 2010-04-07 | 2010-08-25 | 陶灵刚 | Adefovir dipivoxil compound and novel preparation method thereof |
| CN101830932A (en) * | 2009-02-26 | 2010-09-15 | 湖南欧亚生物有限公司 | Synthesis process of adefovir dipivoxil raw medicine |
| CN101891767A (en) * | 2010-07-21 | 2010-11-24 | 浙江贝得药业有限公司 | Preparation method of adefovir dipivoxil |
| CN102516100A (en) * | 2011-12-14 | 2012-06-27 | 华宝食用香精香料（上海）有限公司 | N-[2-(methoxymethoxy)-2-propenyl]-4,4-diethoxy butylamine compound and preparation method and application thereof |
| CN101607971B (en) * | 2008-06-18 | 2012-09-19 | 天津天士力集团有限公司 | Method for synthesizing 9-[2-(diethylphosphono methoxyl)ethyl]adenine |
-
2006
- 2006-08-30 CN CNB2006101120627A patent/CN100554274C/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607971B (en) * | 2008-06-18 | 2012-09-19 | 天津天士力集团有限公司 | Method for synthesizing 9-[2-(diethylphosphono methoxyl)ethyl]adenine |
| CN101830932A (en) * | 2009-02-26 | 2010-09-15 | 湖南欧亚生物有限公司 | Synthesis process of adefovir dipivoxil raw medicine |
| CN101812089A (en) * | 2010-04-07 | 2010-08-25 | 陶灵刚 | Adefovir dipivoxil compound and novel preparation method thereof |
| CN101812089B (en) * | 2010-04-07 | 2012-05-09 | 陶灵刚 | Adefovir dipivoxil compound and novel preparation method thereof |
| CN101891767A (en) * | 2010-07-21 | 2010-11-24 | 浙江贝得药业有限公司 | Preparation method of adefovir dipivoxil |
| CN102516100A (en) * | 2011-12-14 | 2012-06-27 | 华宝食用香精香料（上海）有限公司 | N-[2-(methoxymethoxy)-2-propenyl]-4,4-diethoxy butylamine compound and preparation method and application thereof |
| CN102516100B (en) * | 2011-12-14 | 2013-12-18 | 华宝食用香精香料（上海）有限公司 | N-[2-(methoxymethoxy)-2-propenyl]-4,4-diethoxy butylamine compound and preparation method and application thereof |
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|---|---|
| CN100554274C (en) | 2009-10-28 |
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