CN103374038A - Preparation method of antiviral medicine - Google Patents
Preparation method of antiviral medicine Download PDFInfo
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- CN103374038A CN103374038A CN2012101066647A CN201210106664A CN103374038A CN 103374038 A CN103374038 A CN 103374038A CN 2012101066647 A CN2012101066647 A CN 2012101066647A CN 201210106664 A CN201210106664 A CN 201210106664A CN 103374038 A CN103374038 A CN 103374038A
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Abstract
The invention discloses a preparation method of anantiviral medicine tenofovirdisoproxil fumarate. The preparation method disclosed by the invention comprises the following steps of: performing addition reaction on adenine serving as raw material and (R)-epoxypropane in the presence of alkali; then, performing substitution reaction with (diethyoxyl phosphoracyl) methyl-4-methyl benzenesulfonate; then, hydrolyzing by using a hydrobromic acid solution; crystallizing to obtain tenofovir monohydrate; and reacting the product tenofovir monohydrate with chloromethyl isopropyl carbonate and fumaric acid to obtain tenofovirdisoproxil fumarate. The selected initial raw material is low in cost and easily available, and the synthetic line is simplified and the utilization ratio of the raw material and the total yield are improved. The intermediate obtained in the reaction is purified by the recrystallization method, so that the yield is high, less three-wastes are generated in the reaction process, and the cost is low; therefore, the preparation method is favorable for industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of antiviral tenofovir disoproxil fumarate.
Background technology
The present invention relates to the synthetic of a kind of antiviral tenofovir disoproxil fumarate (VI), structural formula is as follows:
Tenofovir disoproxil fumarate (VI) is nucleotide reverse transcriptase inhibitors (the nucleotide reverse transcriptase inhibitors of U.S. Gilead sciences company development, NtRTIs), U.S. FDA is ratified its listing in calendar year 2001, be used for the treatment of acquired immune deficiency syndrome (AIDS) (HIV infection), ratified again it and be used for the treatment of chronic hepatitis B (HBV infection) in 2008.Tenofovir disoproxil fumarate has the characteristics such as better tolerance, resistant rate is low, drug withdrawal bounce-back rate is low, renal toxicity is little, particularly HIV is merged the HBV infected patient and has preferably potential applicability in clinical practice.Tenofovir disoproxil fumarate is the prodrug of tynofovir, because tynofovir is hardly through gastrointestinal absorption, so carry out esterification, salify is tenofovir disoproxil fumarate, the latter has water-soluble, can be rapidly absorbed and in vivo metabolic degradation become tynofovir, the performance antivirus action.
The synthetic method of the tenofovir disoproxil fumarate (VI) of bibliographical information has following 6 kinds at present:
(1) at the initial stage of development of this medicine, U.S. Gilead sciences conducts in-depth research the synthesis technique of this medicine, the synthetic route of a tenofovir disoproxil fumarate is disclosed in patent US5935946, this route is used catalytic hydrogenation take (S)-Racemic glycidol as starting raw material, the first step, exists unsafe factor in large the production, also use simultaneously the sodium ethylate of moisture-sensitive, working condition is harsh, complex manufacturing, and production cost is very high.
(2) in China Patent Publication No. CN101279987A, the synthetic route of a tynofovir (IV) is disclosed, this route starting raw material relative low price, but in building-up process, use the triphosgene of severe toxicity, exist huge unsafe factor in the production, be unfavorable for suitability for industrialized production.
(3) in China Patent Publication No. CN101574356A; a route that synthesizes tenofovir disoproxil fumarate (VI) take (R)-ethyl lactate as starting raw material is disclosed; this route synthetic reaction condition is relatively gentleer; but this route is used the technique of protection and deprotection; increase the step of synthetic route; reduced total recovery; in building-up process, repeatedly use in addition the silica gel chromatographic column purify intermediates; cause this route production cost very high, be difficult to realize suitability for industrialized production.
(4) at Czech's chemical communication (Collect Czech Chem Commun; 1995; 60:1196-1212); the author openly reported for work one take (R)-isobutyl lactate as starting raw material the route of synthetic tynofovir (IV); this route synthetic reaction condition is also relatively gentleer; but this route is used the technique of protection and deprotection for twice; increase the step of synthetic route; reduced total recovery; this route is used expensive Red-Al (red aluminium) as going back original reagent simultaneously; use the macroporous resin purification intermediate, cause this route production cost very high, be difficult to large-scale application.
(5) in the US Patent No. 6653296 above-mentioned route (4) has been carried out process modification; the similarly route of a synthetic tynofovir (IV) is disclosed; this route has omitted amino protection and deprotection steps; all the other steps are identical; but owing in synthesis step, still have protection, deprotection technique and red aluminium reducing step; production cost is still very high, is difficult to suitability for industrialized production.
(6) China Patent Publication No. CN101648974A has used for reference the method that chiral structure is introduced in route (4) and the route (5), the synthetic route of another synthetic tenofovir disoproxil fumarate (VI) take (R)-methyl lactate as starting raw material is disclosed, this route is relatively short, starting raw material is also cheaper, but introducing, chiral structure needs three-step reaction, production cost is very high, the silica gel chromatography column purification is all wanted in simultaneously a few step reactions of this route, energy consumption is very large, is difficult to realize large production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of tenofovir disoproxil fumarate (VI) overcomes limitation and defective that above-mentioned prior art exists, can satisfy industrialized production.
In order to achieve the above object, the technical solution adopted in the present invention is: the present invention is take VITAMIN B4 as starting raw material, under base catalysis, with (R)-propylene oxide reaction, obtain (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II) through crystallization; (II) in the presence of alkali, obtain (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester reaction; (III) with the hydrobromic acid solution reaction, obtain a hydration tynofovir (IV) through crystallization; (IV) under the phase-transfer catalyst effect with organic bases and chloromethyl sec.-propyl carbonate reaction to (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-pure) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) di-isopropyl carbonic ether (V); (V) with the fumaric acid reaction, obtain tenofovir disoproxil fumarate (VI) through crystallization, reaction formula is as follows:
Technological process is as follows:
The first step: (R)-1-(6-amino-9H-purine-9-yl) propyl group-preparation of 2-alcohol (II)
Under 60～100 ℃ of temperature of reaction, VITAMIN B4 (I) is dissolved in the polar organic solvent, in the presence of alkali with (R)-propylene oxide reaction, obtain (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-pure (II) through crystallization;
Second step: (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) preparation of phosphoric acid ester (III)
Under-10～40 ℃ of temperature of reaction, the first step is reacted products therefrom (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II) to be dissolved in the polar solvent system, in the presence of mineral alkali, obtain (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester reaction;
The 3rd step: the preparation of a hydration tynofovir (IV)
Under 30～100 ℃ of temperature of reaction, second step is reacted products therefrom (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) and hydrobromic acid solution reaction, obtain a hydration tynofovir (IV) through crystallization;
The 4th step: (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen the bases)) preparation of two (methylene radical) di-isopropyl carbonic ether (V)
Under 30～80 ℃ of temperature of reaction, the three-step reaction products therefrom is dissolved in the polar organic solvent, under the phase-transfer catalyst effect with organic bases and chloromethyl sec.-propyl carbonate reaction to (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-pure) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) di-isopropyl carbonic ether (V);
The 5th step: the preparation of tenofovir disoproxil fumarate (VI)
Under 40～80 ℃ of temperature of reaction, with the 4th step products therefrom (V) and fumaric acid reaction, obtain tenofovir disoproxil fumarate (VI) through crystallization.
The above-mentioned the first step: (R)-1-(6-amino-9H-purine-9-yl) propyl group-preparation of 2-alcohol (II) is as starting raw material take VITAMIN B4 (I), in the presence of alkali with (R)-propylene oxide reaction obtains (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-pure (II), wherein alkali is NaOH, KOH, NaHCO
3, KHCO
3, Na
2CO
3, K
2CO
3, Cs
2CO
3One or more combination, preferred Na
2CO
3Polar organic solvent is DMF, DMAC, the combination of one or more of NMP or DMSO, preferred DMF; (R)-and the consumption of propylene oxide is 1～4 times of VITAMIN B4 (I) mole number, preferred 1.5～3 times; Temperature of reaction is 60 ℃～100 ℃, preferred 70～80 ℃; Used recrystallisation solvent is that volume ratio is 10: 1～1: 1 toluene and the mixed solvent of used reaction solvent, and preferred recrystallisation solvent is toluene and the DMF mixing solutions of volume ratio 3: 1～1.5: 1; Tc is-10～20 ℃, preferred 0～10 ℃.
Above-mentioned second step: (R)-preparation of diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) is the first step to be reacted products therefrom (II) obtain (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester reaction in the presence of alkali, wherein alkali is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide or tert-butyl alcohol magnesium, preferred tert-butyl alcohol magnesium; The reaction solvent system is selected from DMF, DMAC, one or more combinations of NMP or DMSO, preferred DMF; Wherein temperature of reaction is-10～40 ℃, preferred 0～25 ℃; Directly drop into next step reaction through the aftertreatment products therefrom.
Above-mentioned the 3rd step: the preparation of a hydration tynofovir (IV) is with intermediate (III) and hydrobromic acid aqueous solution reaction, obtain a hydration tynofovir (IV) through crystallization, wherein hydrobromic consumption is 1～8 times of intermediate (III) mole number, preferred 3～6 times; Temperature of reaction is 30～100 ℃, preferred 70～90 ℃; The solvent of one hydration tynofovir (IV) crystallization purifying is water, and Tc is 0～10 ℃.
The fourth step: (R) - (((((1 - (6 - amino-9H-purin-9 - yl) propyl-2 - ol) oxy) methyl)-phosphoric acid group) bis (oxy)) (methylene) diisopropyl carbonate (V) is prepared by the intermediate (IV) in a polar organic solvent, a phase transfer catalyst with an organic base and chloromethyl isopropyl carbonate reaction to (R) - (((((1 - (6 - amino-9H-purin-9 - yl) propyl-2 - ol) oxy) methyl)-phosphoric acid group) bis (oxy)) bis (methylene)-diisopropyl carbonate (V).Wherein polar organic solvent is DMF, DMAC, one or more combinations among NMP or the DMSO, phase-transfer catalyst is tetrabutylammonium chloride, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride, triethyl benzyl brometo de amonio or triethyl benzyl ammonium iodide, preferred triethyl benzyl brometo de amonio; The consumption of phase-transfer catalyst is 0.5～2 times of mole number of intermediate (IV), preferred 1～1.5 times; Organic bases is one or more combination of triethylamine (TEA), diisopropylethylamine (DIPEA) or pyridine; The consumption of organic bases is 2～6 times of hydration tynofovir (IV) mole number; The consumption of chloromethyl sec.-propyl carbonic ether is 2～6 times of hydration tynofovir (IV) mole number; The solvent that reacts used is one or more combinations among DMF, DMAC, NMP or the DMSO; Temperature of reaction is 30～80 ℃, preferred 50～60 ℃; The aftertreatment products therefrom directly drops into next step reaction.
Above-mentioned the 5th step: the preparation of tenofovir disoproxil fumarate (VI) is that intermediate (V) is dissolved in the polar organic solvent, with fumaric acid reaction through crystallization to tenofovir disoproxil fumarate (VI).Wherein the consumption of fumaric acid is 1～2 times of mole number of intermediate (V), preferred 1～1.2 times; Polar organic solvent is Virahol; Temperature of reaction is 40～80 ℃, preferred 50～60 ℃.
The present invention has that raw material is easy to be easy to get, simple, with low cost, the synthetic overall yield advantages of higher of operational path, and concrete advantage and innovative point that the present invention has are as follows:
1. to select (R)-propylene oxide cheap and easy to get be chiral source in the present invention, at Na
2CO
3Exist lower, obtain (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II) with the VITAMIN B4 reaction, the selected reagent of technique after the improvement is all comparatively cheap, side reaction is few, productive rate is high, high by crystallization gained intermediate (II) purity, the three wastes that reaction process produces are few, are fit to very much suitability for industrialized production.
2. the present invention has improved the preparation method of three-step reaction product (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III), select Hydrogen bromide as hydrolysing agent, can Reaction time shorten, reduce production costs, the technique that simplifies the operation more is conducive to suitability for industrialized production.
3. the present invention has improved the preparation method of four-step reaction product (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) di-isopropyl carbonic ethers (V), adopting triethyl benzyl brometo de amonio is catalyzer, can improve reaction yield, Reaction time shorten, by product is less simultaneously, reaction conditions is gentle, is more suitable for suitability for industrialized production.
Embodiment
The present invention is described by the following specific embodiments, can better understand the present invention by specific embodiment, but scope of the present invention is not subjected to the restriction of these embodiment:
Embodiment 1:
The first step: (R)-1-(6-amino-9H-purine-9-yl) propyl group-preparation of 2-alcohol (II)
In the there-necked flask of drying, add VITAMIN B4 (200.00g), yellow soda ash (7.80g) and DMF (1000ml), stirring at room 20min, slowly add again (R)-propylene oxide (150.50g), afterwards at 95 ℃ of reaction 6h, reaction system is cooled to room temperature, and slowly add toluene (2000ml), stir 15h at 0 ℃ after dripping, filter, filter cake washs with normal hexane, vacuum-drying, obtain (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II) 197.20g, productive rate 69%.
1H?NMR(400MHz，CDCl
3)δ：8.31(s，1H)，7.81(s，1H)，5.58(s，2H)，4.29-4.19(m，2H)，4.11(dd，J＝13.8，7.2Hz，1H)，2.95(s，1H)，1.28(d，J＝6.4Hz，3H).
MS(ESI)：m/z[M+H]
+calcd?forC
8H
11N
5O：193.1；found：194.2.
Embodiment 2:
The first step: (R)-1-(6-amino-9H-purine-9-yl) propyl group-preparation of 2-alcohol (II)
In the there-necked flask of drying, add VITAMIN B4 (80.00g), sodium hydroxide 1.20g (60.70g) and DMF (500ml), stirring at room 20min, slowly add again (R)-propylene oxide (68.80g), afterwards at 80 ℃ of reaction 5h, reaction system is cooled to room temperature, and slowly add toluene (1050ml), stir 16h at 0 ℃ after dripping, filter, filter cake washs with normal hexane, vacuum-drying, obtain (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II) 74.00g, productive rate 65%.
Embodiment 3:
Second step: (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) preparation of phosphoric acid ester (III)
In the there-necked flask of drying, add intermediate (II) (36.00g) and DMF (240ml) stirring and dissolving, add trimethyl carbinol lithium 18.37g at 0 ℃, afterwards at room temperature reaction 2h, slowly add again (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 60.08g, 0 ℃ of reaction 12h is afterwards at synthermal lower adding trimethyl carbinol lithium 9.19g, behind the stirring 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester (30.04g), stir 5h; Add again trimethyl carbinol lithium 4.5g, stir 1h, add again (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 15.02g, equality of temperature stirs 12h, in reaction system, slowly add vinegar acid for adjusting pH to 6～7, the mixture concentrating under reduced pressure obtains faint yellow oily thing, and the crude product productive rate directly drops into next step reaction (embodiment 5) with quantitative Analysis.
Embodiment 4:
Second step: (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) preparation of phosphoric acid ester (III)
In the there-necked flask of drying, add intermediate (II) (18.00g) and NMP (93ml) stirring and dissolving, add tert-butyl alcohol magnesium 19.55g at 0 ℃, afterwards at room temperature reaction 2h, slowly add again (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 30.04g, 0 ℃ of reaction 14h is afterwards at synthermal lower adding tert-butyl alcohol magnesium 9.77g, behind the stirring 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester (15.00g), stir 6h; Add again tert-butyl alcohol magnesium 4.88g, stir 1h, add again (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 7.50g, equality of temperature stirs 14h, in reaction system, slowly add vinegar acid for adjusting pH to 6～7, the mixture concentrating under reduced pressure obtains faint yellow oily thing, and the crude product productive rate directly drops into next step reaction (embodiment 6) with quantitative Analysis.
Embodiment 5:
The 3rd step: the preparation of a hydration tynofovir (IV)
The faint yellow oily thing of embodiment 3 gained is dissolved in 40% hydrobromic acid solution (150.00g), 80 ℃ of reaction 8h, be cooled to room temperature, add ethyl acetate (120ml) washing, water is used ethyl acetate (120ml) washing again behind the separatory, and to reconcile pH with sodium hydroxide solution be 2.5～3.5, be cooled to 2 ℃ of stirring and crystallizing, cross filter solid, washing with acetone, vacuum-drying obtains hydration tynofovir (IV) 18.88g, two-step reaction (embodiment 3 and 5) overall yield 33%.
1H?NMR(400MHz，DMSO-d
6)δ：8.14(s，2H)，7.21(s，2H)，4.90-4.31(bs，2H)，4.30-4.25(m，1H)，4.19-4.14(m，1H)，3.93-3.89(m，1H)，3.58(qd，J＝13.2，9.6Hz，2H)，1.03(d，J＝6.3Hz，3H).
MS(ESI)：m/z[M-H]
-calcd?for?C
9H
14N
5O
4P：287.1；found：286.2.
The preparation of embodiment 6: hydration tynofovir (IV)
The faint yellow oily thing of embodiment 4 gained is dissolved in 40% hydrobromic acid solution (56.55g), 90 ℃ of reaction 5h, be cooled to room temperature and add ethyl acetate (80ml) washing, water is used ethyl acetate (80ml) washing again behind the separatory, and to reconcile pH with sodium hydroxide solution be 2.5～3.5, is cooled to 2 ℃ of stirring and crystallizing, cross filter solid, washing with acetone, vacuum-drying obtain hydration tynofovir (IV) 11.35g, two-step reaction (embodiment 4 and 6) overall yield 40%.
Embodiment 7:(R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) preparation of two (methylene radical) di-isopropyl carbonic ether (V)
In the there-necked flask of drying, add intermediate (IV) (3.67g) and DMF (16ml) stirring and dissolving, add successively triethylamine (7.1ml) and triethyl benzyl brometo de amonio (5.23g) in room temperature, be warming up to afterwards 60 ℃, add again chloromethyl sec.-propyl carbonic ether (8.5ml), equality of temperature reaction 4h, be cooled to room temperature and add entry (16ml) and ethyl acetate (38ml), separatory after fully mixing, water ethyl acetate extraction (2 * 38ml), merge organic phase and wash (2 * 100ml) with water, saturated nacl aqueous solution washing (100ml), Na
2SO
4Drying is filtered, and filtrate is concentrated to obtain solid-state intermediate (V) 5.54g, and crude product productive rate 84% directly drops into next step reaction (embodiment 9).
Embodiment 8:(R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) preparation of two (methylene radical) di-isopropyl carbonic ether (V)
In the there-necked flask of drying, add intermediate (IV) (3.67g) and NMP (16ml) stirring and dissolving, add successively triethylamine (7.1ml) and tetra-n-butyl ammonium bromide (4.12g) in room temperature, be warming up to afterwards 50 ℃, add again chloromethyl sec.-propyl carbonic ether (8.5ml), equality of temperature reaction 6h, be cooled to room temperature and add entry (16ml) and ethyl acetate (38ml), separatory after fully mixing, water ethyl acetate extraction (2 * 38ml), merge organic phase and wash (2 * 100ml) with water, saturated nacl aqueous solution washing (100ml), Na
2SO
4Drying is filtered, and filtrate is concentrated to obtain solid-state intermediate (V) 5.30g, and crude product productive rate 79% directly drops into next step reaction (embodiment 10).
Embodiment 9: the preparation of tenofovir disoproxil fumarate (VI)
Embodiment 7 gained intermediates (V) (5.54g) and fumaric acid (1.43g) be dissolved in the Virahol (34ml), be heated to 60 ℃ of reaction 2.5h, be cooled to 0 ℃ and stir 2h, filter, washed with isopropyl alcohol, vacuum-drying obtains tenofovir disoproxil fumarate (VI) 4.69g, productive rate 69%.
1H?NMR(400MHz，DMSO-d
6)δ：13.05(s，2H)，8.13(s，1H)，8.02(s，1H)，7.12(s，2H)，6.63(s，2H)，5.64-5.46(m，4H)，4.82(dtd，J＝12.5，6.2，1.9Hz，2H)，4.21(ddd，J＝20.5，14.4，5.1Hz，2H)，4.05-3.88(m，3H)，1.24(d，J＝6.2Hz，12H)，1.07(d，J＝6.3Hz，3H).
MS(ESI)：m/z[M-115.0]
+calcd?for?C
19H
30N
5O
10P·C
4H
4O
4：519.2+116.0；found：520.2.
Embodiment 10: the preparation of tenofovir disoproxil fumarate (VI)
Embodiment 8 gained intermediates (V) (5.30g) and fumaric acid (1.18g) be dissolved in the Virahol (30ml), be heated to 50 ℃ of reaction 3h, be cooled to 0 ℃ and stir 3h, filter, washed with isopropyl alcohol, vacuum-drying obtains tenofovir disoproxil fumarate (VI) 3.52g, productive rate 53%.
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification made under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the equivalent replacement mode, be included within protection scope of the present invention.
Claims (6)
1. the preparation method of an antiviral is characterized in that may further comprise the steps:
The first step, under 60～100 ℃ of temperature of reaction, VITAMIN B4 (I) is dissolved in the polar organic solvent, in the presence of alkali with (R)-propylene oxide reaction, obtain (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-pure (II) through crystallization;
Second step, under-10～40 ℃ of temperature of reaction, the first step is reacted products therefrom (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II) to be dissolved in the polar solvent system, in the presence of mineral alkali, obtain (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester reaction;
The 3rd step, under 30～100 ℃ of temperature of reaction, second step is reacted products therefrom (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) and hydrobromic acid solution reaction, obtain a hydration tynofovir (IV) through crystallization;
The 4th step, under 30～80 ℃ of temperature of reaction, the three-step reaction products therefrom is dissolved in the polar organic solvent, under the phase-transfer catalyst effect with organic bases and chloromethyl sec.-propyl carbonate reaction to (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-pure) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) di-isopropyl carbonic ether (V);
In the 5th step, under 40～80 ℃ of temperature of reaction, with the 4th step products therefrom (V) and fumaric acid reaction, obtain tenofovir disoproxil fumarate (VI) through crystallization.
2. the preparation method of a kind of antiviral according to claim 1 is characterized in that used alkali is selected from NaOH, KOH, NaHCO in the preparation of the described the first step (R)-1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol (II)
3, KHCO
3, Na
2CO
3, K
2CO
3, Cs
2CO
3One or more combination; Used polar organic solvent is selected from one or more the combination of DMF, DMAC, NMP or DMSO; The amount of used (R)-propylene oxide is 1～4 times of VITAMIN B4 (I) mole number; Used recrystallisation solvent is that volume ratio is 10: 1～1: 1 toluene and the mixed solvent of used reaction solvent; Tc is-10～20 ℃.
3. the preparation method of a kind of antiviral according to claim 1, it is characterized in that the preparation of described second step (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III), used alkali is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide or tert-butyl alcohol magnesium; The reaction solvent system is selected from one or more the combination of DMF, DMAC, NMP or DMSO.
4. the preparation method of a kind of antiviral according to claim 1 is characterized in that reaction solvent is water in the preparation of described the 3rd step one hydration tynofovir (IV); Used hydrobromic consumption is 1～8 times of (R)-diethyl (((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) mole number; Recrystallisation solvent is water, and Tc is 0～10 ℃.
5. the preparation method of a kind of antiviral according to claim 1, it is characterized in that used phase-transfer catalyst is tetrabutylammonium chloride, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride, triethyl benzyl brometo de amonio or triethyl benzyl ammonium iodide in the preparation of described the 4th step (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) di-isopropyl carbonic ether (V); The consumption of phase-transfer catalyst is 0.5～2 times of hydration tynofovir (IV) mole number; Organic bases is one or more combination of triethylamine (TEA), diisopropylethylamine (DIPEA) or pyridine; The consumption of organic bases is 2～6 times of hydration tynofovir (IV) mole number; The consumption of chloromethyl sec.-propyl carbonic ether is 2～6 times of hydration tynofovir (IV) mole number; The solvent that reacts used is one or more combinations among DMF, DMAC, NMP or the DMSO.
6. the preparation method of a kind of antiviral according to claim 1, it is characterized in that in the preparation of described the 5th step tenofovir disoproxil fumarate (VI) that the consumption of fumaric acid be (R)-(((((1-(6-amino-9H-purine-9-yl) propyl group-2-pure) oxygen) methyl) phosphate) two (oxygen bases)) 1～2 times of the mole number of two (methylene radical) di-isopropyl carbonic ether (V); Used solvent is Virahol.
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| CN105440076A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate |
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| CN106046055A (en) * | 2016-05-27 | 2016-10-26 | 湖北丽益医药科技有限公司 | R-9-(2-phosphonomethoxy propyl)-adenine monohydrate crystals, preparation thereof and preparation of tenofovir disoproxil fumarate |
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