CN103374038B - A kind of preparation method of antiviral - Google Patents
A kind of preparation method of antiviral Download PDFInfo
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Abstract
The invention discloses a kind of method preparing antiviral tenofovir disoproxil fumarate.The present invention take VITAMIN B4 as raw material, in the presence of a base with (R)-propylene oxide generation addition reaction, again with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester generation substitution reaction, be hydrolyzed with hydrobromic acid solution again, crystallization obtains a hydration tynofovir, and products therefrom is obtained by reacting tenofovir disoproxil fumarate with chloromethyl butylperoxyisopropyl carbonate, fumaric acid again.Starting raw material selected by the present invention is cheap and easy to get, and simplifies synthetic route, improves raw material availability and overall yield.Reaction gained intermediate recrystallization method is purified, and productive rate is high, and the three wastes that reaction process produces are few, with low cost, be conducive to industrial production.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method of antiviral tenofovir disoproxil fumarate.
Background technology
The present invention relates to a kind of synthesis of antiviral tenofovir disoproxil fumarate (VI), structural formula is as follows:
Tenofovir disoproxil fumarate (VI) is the nucleotide reverse transcriptase inhibitors (nucleotidereversetranscriptaseinhibitors of Gileadsciences company of U.S. development, NtRTIs), U.S. FDA ratifies its listing in calendar year 2001, be used for the treatment of acquired immune deficiency syndrome (AIDS) (HIV), within 2008, ratify again it and be used for the treatment of chronic hepatitis B (HBV infection).Tenofovir disoproxil fumarate has the features such as better tolerance, resistant rate is low, drug withdrawal rebound rate is low, renal toxicity is little, particularly merges HBV infection patient to HIV and has good potential applicability in clinical practice.Tenofovir disoproxil fumarate is the prodrug of tynofovir, because tynofovir is hardly through gastrointestinal absorption, so esterification will be carried out, salify is tenofovir disoproxil fumarate, the latter has water-soluble, can to be rapidly absorbed and metabolic degradation becomes tynofovir in vivo, to play antivirus action.
The synthetic method of the tenofovir disoproxil fumarate (VI) of current bibliographical information has following 6 kinds:
(1) at the initial stage of development of this medicine, the synthesis technique of U.S. Gileadsciences to this medicine conducts in-depth research, the synthetic route of a tenofovir disoproxil fumarate is disclosed in patent US5935946, this route is with (S)-Racemic glycidol for starting raw material, and the first step uses catalytic hydrogenation, there is unsafe factor in large production, also use the sodium ethylate of moisture-sensitive simultaneously, working condition is harsh, and complex manufacturing, production cost is very high.
(2) in China Patent Publication No. CN101279987A, disclose the synthetic route of a tynofovir (IV), this route starting raw material relative low price, but in building-up process, use the triphosgene of severe toxicity, there is huge unsafe factor in production, be unfavorable for suitability for industrialized production.
(3) in China Patent Publication No. CN101574356A; disclosing one with (R)-ethyl lactate is the route that starting raw material synthesizes tenofovir disoproxil fumarate (VI); this route synthetic reaction condition is gentleer; but this route uses the technique of protection and deprotection; increase the step of synthetic route; reduce total recovery; silica gel chromatographic column purify intermediates is repeatedly used in addition in building-up process; cause this route production cost very high, be difficult to realize suitability for industrialized production.
(4) at Czech chemical communication (CollectCzechChemCommun, 1995, 60:1196-1212), author openly reported for work one with (R)-isobutyl lactate be starting raw material synthesis tynofovir (IV) route, this route synthetic reaction condition is also gentleer, but this route uses the technique of protection and deprotection for twice, increase the step of synthetic route, reduce total recovery, this route uses expensive Red-Al (red aluminium) as going back original reagent simultaneously, use macroporous resin purification intermediate, cause this route production cost very high, be difficult to large-scale application.
(5) in US Patent No. 6653296, process modification has been carried out to above-mentioned route (4); disclose the route of synthesis tynofovir (IV) similarly; this route eliminates amino protection and deprotection steps; all the other steps are identical; but owing to still there is protection, deprotection technique and red aluminium reducing step in synthesis 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 in route (4) and route (5), chiral structure is introduced, disclose the synthetic route that another take (R)-methyl lactate as starting raw material synthesis tenofovir disoproxil fumarate (VI), this route is relatively short, starting raw material is also cheaper, but chiral structure is introduced needs three-step reaction, production cost is very high, silica gel chromatography column purification is all wanted in a few step reaction of this route simultaneously, energy consumption is very large, and large production is difficult to realize.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of tenofovir disoproxil fumarate (VI), overcome limitation and the defect of the existence of above-mentioned prior art, can industrialized production be met.
In order to achieve the above object, the technical solution adopted in the present invention is: the present invention take VITAMIN B4 as starting raw material, under base catalysis, with (R)-propylene oxide reaction, obtain (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) through crystallization; (II) (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) in the presence of a base, is obtained by reacting with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester; (III) react with hydrobromic acid solution, obtain a hydration tynofovir (IV) through crystallization; (IV) that reacts with organic bases and chloromethyl butylperoxyisopropyl carbonate under phase-transfer catalyst effect arrives (R)-(((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V); (V) react with fumaric acid, obtain tenofovir disoproxil fumarate (VI) through crystallization, reaction formula is as follows:
Technological process is as follows:
The first step: the preparation of (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II)
Under 60 ~ 100 DEG C of temperature of reaction, VITAMIN B4 (I) is dissolved in polar organic solvent, in the presence of a base with (R)-propylene oxide reaction, obtain (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) through crystallization;
Second step: the preparation of (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III)
Under-10 ~ 40 DEG C of temperature of reaction, the first step being reacted products therefrom (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) is dissolved in polar solvent system, in the presence of an inorganic base, (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) is obtained by reacting with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester;
3rd step: the preparation of a hydration tynofovir (IV)
Under 30 ~ 100 DEG C of temperature of reaction, second step is reacted products therefrom (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) to react with hydrobromic acid solution, obtain a hydration tynofovir (IV) through crystallization;
4th step: the preparation of (R)-(((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V)
Under 30 ~ 80 DEG C of temperature of reaction, be dissolved in polar organic solvent by three-step reaction products therefrom, that reacts with organic bases and chloromethyl butylperoxyisopropyl carbonate under phase-transfer catalyst effect arrives (R)-(((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V);
5th step: the preparation of tenofovir disoproxil fumarate (VI)
Under 40 ~ 80 DEG C of temperature of reaction, the 4th step products therefrom (V) and fumaric acid are reacted, obtains tenofovir disoproxil fumarate (VI) through crystallization.
The above-mentioned the first step: the preparation of (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) is for starting raw material with VITAMIN B4 (I), obtain (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) in the presence of a base with (R)-propylene oxide reaction, wherein alkali is NaOH, KOH, NaHCO
3, KHCO
3, Na
2cO
3, K
2cO
3, Cs
2cO
3one or more combination, preferred Na
2cO
3; Polar organic solvent is one or more the combination of DMF, DMAC, NMP or DMSO, preferred DMF; (R) consumption of-propylene oxide is 1 ~ 4 times of VITAMIN B4 (I) mole number, preferably 1.5 ~ 3 times; Temperature of reaction is 60 DEG C ~ 100 DEG C, preferably 70 ~ 80 DEG C; Recrystallisation solvent used is volume ratio is the toluene of 10: 1 ~ 1: 1 and the mixed solvent of reaction solvent used, and preferred recrystallisation solvent is toluene and the DMF mixing solutions of volume ratio 3: 1 ~ 1.5: 1; Tc is-10 ~ 20 DEG C, preferably 0 ~ 10 DEG C.
Above-mentioned second step: the preparation of (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) the first step is reacted products therefrom (II) to be obtained by reacting (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III) in the presence of a base with (diethoxy phosphono) methyl-4-toluene sulfonic acide ester, wherein alkali is trimethyl carbinol lithium, sodium tert-butoxide, potassium tert.-butoxide or tert-butyl alcohol magnesium, preferred tert-butyl alcohol magnesium; 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 DEG C, preferably 0 ~ 25 DEG C; Next step reaction is directly dropped into through aftertreatment products therefrom.
Above-mentioned 3rd step: the preparation of a hydration tynofovir (IV) is reacted at intermediate (III) and hydrobromic acid aqueous solution, a hydration tynofovir (IV) is obtained through crystallization, wherein hydrobromic consumption is 1 ~ 8 times of intermediate (III) mole number, preferably 3 ~ 6 times; Temperature of reaction is 30 ~ 100 DEG C, preferably 70 ~ 90 DEG C; The solvent of one hydration tynofovir (IV) crystallization purifying is water, and Tc is 0 ~ 10 DEG C.
Above-mentioned 4th step: the preparation of (R)-(((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V) is dissolved in polar organic solvent by intermediate (IV), that reacts with organic bases and chloromethyl butylperoxyisopropyl carbonate under phase-transfer catalyst effect arrives (R)-(((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V).Wherein polar organic solvent is DMF, DMAC, one or more combinations in NMP or DMSO, phase-transfer catalyst is tetrabutylammonium chloride, tetra-n-butyl ammonium bromide, tetrabutylammonium iodide, triethyl benzyl ammonia chloride, triethylbenzyl brometo de amonio or triethylbenzyl ammonium iodide, preferred triethylbenzyl brometo de amonio; The consumption of phase-transfer catalyst is 0.5 ~ 2 times of the mole number of intermediate (IV), preferably 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 butylperoxyisopropyl carbonate is 2 ~ 6 times of hydration tynofovir (IV) mole number; The solvent reacting used is one or more combinations in DMF, DMAC, NMP or DMSO; Temperature of reaction is 30 ~ 80 DEG C, preferably 50 ~ 60 DEG C; Aftertreatment products therefrom directly drops into next step reaction.
Above-mentioned 5th step: the preparation of tenofovir disoproxil fumarate (VI) is dissolved in polar organic solvent by intermediate (V), with fumaric acid react through crystallization to tenofovir disoproxil fumarate (VI).Wherein the consumption of fumaric acid is 1 ~ 2 times of the mole number of intermediate (V), preferably 1 ~ 1.2 times; Polar organic solvent is Virahol; Temperature of reaction is 40 ~ 80 DEG C, preferably 50 ~ 60 DEG C.
The present invention has that raw material is easy to be easy to get, and operational path is simple, with low cost, synthesis overall yield advantages of higher, the concrete advantage that the present invention has and innovative point as follows:
1. the present invention selects (R)-propylene oxide cheap and easy to get to be chiral source, at Na
2cO
3under existence, (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) is obtained by reacting with VITAMIN B4, reagent selected by technique after 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 very applicable to suitability for industrialized production.
2. present invention improves over the preparation method of three-step reaction product (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III), select Hydrogen bromide as hydrolysing agent, can Reaction time shorten, reduce production cost, simplify the operation technique, is more conducive to suitability for industrialized production.
3. present invention improves over the preparation method of four-step reaction product (R)-(((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V), triethylbenzyl brometo de amonio is adopted to be catalyzer, reaction yield can be improved, 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, be can better understand the present invention by specific embodiment, but scope of the present invention is not by the restriction of these embodiments:
Embodiment 1:
The first step: the preparation of (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II)
VITAMIN B4 (200.00g) is added in the there-necked flask of drying, sodium carbonate (7.80g) and DMF (1000ml), stirring at room temperature 20min, slowly add (R)-propylene oxide (150.50g) again, afterwards at 95 DEG C of reaction 6h, reaction system is cooled to room temperature, and slowly add toluene (2000ml), 15h is stirred at 0 DEG C after dripping, filter, filter cake n-hexane, vacuum-drying, obtain (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) 197.20g, productive rate 69%.
1HNMR(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]
+calcdforC
8H
11N
5O：193.1；found：194.2.
Embodiment 2:
The first step: the preparation of (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II)
VITAMIN B4 (80.00g) is added in the there-necked flask of drying, sodium hydroxide 1.20g (60.70g) and DMF (500ml), stirring at room temperature 20min, slowly add (R)-propylene oxide (68.80g) again, afterwards at 80 DEG C of reaction 5h, reaction system is cooled to room temperature, and slowly add toluene (1050ml), 16h is stirred at 0 DEG C after dripping, filter, filter cake n-hexane, vacuum-drying, obtain (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II) 74.00g, productive rate 65%.
Embodiment 3:
Second step: the preparation of (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III)
Intermediate (II) (36.00g) and DMF (240ml) stirring and dissolving is added in the there-necked flask of drying, trimethyl carbinol lithium 18.37g is added at 0 DEG C, afterwards at room temperature reaction 2h, slowly add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 60.08g again, 0 DEG C of reaction 12h, trimethyl carbinol lithium 9.19g is added afterwards under synthermal, after stirring 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester (30.04g), stir 5h; Add trimethyl carbinol lithium 4.5g again, stir 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 15.02g again, equality of temperature stirs 12h, vinegar acid for adjusting pH to 6 ~ 7 are slowly added in reaction system, mixture concentrating under reduced pressure obtains pale yellow oil, and crude yield, with quantitative Analysis, directly drops into next step reaction (embodiment 5).
Embodiment 4:
Second step: the preparation of (R)-diethyl (((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphoric acid ester (III)
Intermediate (II) (18.00g) and NMP (93ml) stirring and dissolving is added in the there-necked flask of drying, tert-butyl alcohol magnesium 19.55g is added at 0 DEG C, afterwards at room temperature reaction 2h, slowly add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 30.04g again, 0 DEG C of reaction 14h, tert-butyl alcohol magnesium 9.77g is added afterwards under synthermal, after stirring 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester (15.00g), stir 6h; Add tert-butyl alcohol magnesium 4.88g again, stir 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 7.50g again, equality of temperature stirs 14h, vinegar acid for adjusting pH to 6 ~ 7 are slowly added in reaction system, mixture concentrating under reduced pressure obtains pale yellow oil, and crude yield, with quantitative Analysis, directly drops into next step reaction (embodiment 6).
Embodiment 5:
3rd step: the preparation of a hydration tynofovir (IV)
Embodiment 3 gained pale yellow oil is dissolved in the hydrobromic acid solution (150.00g) of 40%, 80 DEG C of reaction 8h, be cooled to room temperature, add ethyl acetate (120ml) washing, after separatory, aqueous phase uses ethyl acetate (120ml) to wash again, and be 2.5 ~ 3.5 with sodium hydroxide solution conciliation pH, be cooled to 2 DEG C of stirring and crystallizing, filtering solids, washing with acetone, vacuum-drying obtains hydration tynofovir (IV) 18.88g, two-step reaction (embodiment 3 and 5) overall yield 33%.
1HNMR(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]
-calcdforC
9H
14N
5O
4P：287.1；found：286.2.
The preparation of embodiment 6: hydration tynofovir (IV)
Embodiment 4 gained pale yellow oil is dissolved in the hydrobromic acid solution (56.55g) of 40%, 90 DEG C of reaction 5h, be cooled to room temperature and add ethyl acetate (80ml) washing, after separatory, aqueous phase uses ethyl acetate (80ml) to wash again, and be 2.5 ~ 3.5 with sodium hydroxide solution conciliation pH, be cooled to 2 DEG C of stirring and crystallizing, filtering solids, washing with acetone, vacuum-drying obtains hydration tynofovir (IV) 11.35g, two-step reaction (embodiment 4 and 6) overall yield 40%.
Embodiment 7:(R)-the preparation of (((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V)
Intermediate (IV) (3.67g) and DMF (16ml) stirring and dissolving is added in the there-necked flask of drying, triethylamine (7.1ml) and triethylbenzyl brometo de amonio (5.23g) is added successively in room temperature, be warming up to 60 DEG C afterwards, add chloromethyl butylperoxyisopropyl carbonate (8.5ml) again, equality of temperature reaction 4h, be cooled to room temperature and add water (16ml) and ethyl acetate (38ml), separatory after abundant mixing, aqueous phase is extracted with ethyl acetate (2 × 38ml), merge organic phase washed with water (2 × 100ml), saturated nacl aqueous solution washing (100ml), Na
2sO
4drying, filters, and filtrate is concentrated obtains solid intermediate (V) 5.54g, crude yield 84%, directly drops into next step reaction (embodiment 9).
Embodiment 8:(R)-the preparation of (((((1-(6-amino-9H-purine-9-base) propyl group-2-alcohol) oxygen) methyl) phosphate) two (oxygen bases)) two (methylene radical) diisopropyl carbonate (V)
Intermediate (IV) (3.67g) and NMP (16ml) stirring and dissolving is added in the there-necked flask of drying, triethylamine (7.1ml) and tetra-n-butyl ammonium bromide (4.12g) is added successively in room temperature, be warming up to 50 DEG C afterwards, add chloromethyl butylperoxyisopropyl carbonate (8.5ml) again, equality of temperature reaction 6h, be cooled to room temperature and add water (16ml) and ethyl acetate (38ml), separatory after abundant mixing, aqueous phase is extracted with ethyl acetate (2 × 38ml), merge organic phase washed with water (2 × 100ml), saturated nacl aqueous solution washing (100ml), Na
2sO
4drying, filters, and filtrate is concentrated obtains solid intermediate (V) 5.30g, crude yield 79%, directly drops into next step reaction (embodiment 10).
Embodiment 9: the preparation of tenofovir disoproxil fumarate (VI)
Embodiment 7 gained intermediate (V) (5.54g) and fumaric acid (1.43g) are dissolved in Virahol (34ml), be heated to 60 DEG C of reaction 2.5h, be cooled to 0 DEG C and stir 2h, filter, washed with isopropyl alcohol, vacuum-drying obtains tenofovir disoproxil fumarate (VI) 4.69g, productive rate 69%.
1HNMR(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]
+calcdforC
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 intermediate (V) (5.30g) and fumaric acid (1.18g) are dissolved in Virahol (30ml), be heated to 50 DEG C of reaction 3h, be cooled to 0 DEG C 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 present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification made under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be equivalent replacement mode, be included within protection scope of the present invention.
Claims (1)
1. a preparation method for antiviral, is characterized in that comprising the following steps:
The first step, adds VITAMIN B4 200.00g in the there-necked flask of drying, sodium carbonate 7.80g and DMF1000ml, stirring at room temperature 20min, slowly add (R)-propylene oxide 150.50g again, afterwards at 95 DEG C of reaction 6h, reaction system is cooled to room temperature, and slowly add toluene 2000ml, stir 15h at 0 DEG C after dripping, filter, filter cake n-hexane, vacuum-drying, obtains (R)-1-(6-amino-9H-purine-9-base) propyl group-2-alcohol (II);
Second step, intermediate (II) 18.00g and NMP93ml stirring and dissolving is added in the there-necked flask of drying, tert-butyl alcohol magnesium 19.55g is added at 0 DEG C, afterwards at room temperature reaction 2h, more slowly add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 30.04g, 0 DEG C of reaction 14h, tert-butyl alcohol magnesium 9.77g is added afterwards under synthermal, after stirring 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 15.00g, stir 6h; Add tert-butyl alcohol magnesium 4.88g again, stir 1h, add (diethoxy phosphono) methyl-4-toluene sulfonic acide ester 7.50g again, equality of temperature stirs 14h, vinegar acid for adjusting pH to 6 ~ 7 are slowly added in reaction system, mixture concentrating under reduced pressure obtains pale yellow oil, and crude yield, with quantitative Analysis, directly drops into next step reaction;
3rd step, previous step gained pale yellow oil is dissolved in the hydrobromic acid solution 56.55g of 40%, 90 DEG C of reaction 5h, be cooled to room temperature and add ethyl acetate 80ml washing, after separatory, aqueous phase is again with ethyl acetate 80ml washing, and is 2.5 ~ 3.5 with sodium hydroxide solution conciliation pH, be cooled to 2 DEG C of stirring and crystallizing, filtering solids, washing with acetone, vacuum-drying obtains a hydration tynofovir (IV);
4th step, intermediate (IV) 3.67g and DMF16ml stirring and dissolving is added in the there-necked flask of drying, triethylamine 7.1ml and triethylbenzyl brometo de amonio 5.23g is added successively in room temperature, be warming up to 60 DEG C afterwards, add chloromethyl butylperoxyisopropyl carbonate 8.5ml again, equality of temperature reaction 4h, be cooled to room temperature and add water 16ml and ethyl acetate 38ml, separatory after abundant mixing, aqueous phase is extracted with ethyl acetate 2 × 38ml, merge organic phase washed with water 2 × 100ml, saturated nacl aqueous solution washing 100ml, Na
2sO
4drying, filters, and filtrate is concentrated obtains solid intermediate (V);
5th step, previous step gained intermediate (V) 5.54g and fumaric acid 1.43g is dissolved in Virahol 34ml, is heated to 60 DEG C of reaction 2.5h, be cooled to 0 DEG C and stir 2h, filter, washed with isopropyl alcohol, vacuum-drying obtains tenofovir disoproxil fumarate (VI).
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| CN103641858B (en) * | 2013-12-31 | 2016-01-20 | 湖南千金湘江药业股份有限公司 | A kind of tenofovir disoproxil fumarate and preparation method thereof |
| TWI660965B (en) * | 2014-01-15 | 2019-06-01 | 美商基利科學股份有限公司 | Solid forms of tenofovir |
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