CN104610360A - Method for preparing tenofovir disoproxil fumarate - Google Patents

Method for preparing tenofovir disoproxil fumarate Download PDF

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CN104610360A
CN104610360A CN201510076929.7A CN201510076929A CN104610360A CN 104610360 A CN104610360 A CN 104610360A CN 201510076929 A CN201510076929 A CN 201510076929A CN 104610360 A CN104610360 A CN 104610360A
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tynofovir
vitamin
preparation
tenofovir disoproxil
disoproxil fumarate
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张贵民
尹少宏
陈波
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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Abstract

The invention relates to a method for preparing high-purity tenofovir disoproxil fumarate. The method comprises the following steps: preparing (R)-4-methyl-1,3-dioxolan-2-one, synthesizing (R)-9-(2-hydroxypropyl)adenine, synthesizing a tenofovir hydrate, refining by virtue of dehydrating and synthesizing tenofovir disoproxil fumarate. The corresponding product is refined and the target product is detected by dehydrating through tenofovir and using alkali-soluble acid-analysis manners, the reaction, separation and purification processes in the subsequent steps are facilitated and the purity and yield of the product are increased. The technical scheme disclosed by the invention has the advantages of simple operation, relatively inexpensive selected reagents, small side effects, high yield and less three wastes produced in the reaction and the environmental protection is facilitated.

Description

A kind of preparation method of tenofovir disoproxil fumarate
Technical field
The invention belongs to medical art, relate to a kind of synthetic method of the medical material tenofovir disoproxil fumarate for acquired immune deficiency syndrome (AIDS) and treating hepatitis B field.
Background technology:
Tenofovir disoproxil fumarate is a kind of new oral broad-spectrum antiviral drug, a kind of acyclic bunch of efabirenz, nucleotide reverse transcriptase inhibitors (the nucleotide reversetranscriptase inhibitors of Gilead sciences company of U.S. development, NtRTIs), chemistry 5-(((1R)-2 (6-amino-9H-purine-9-base)-1-methyl ethoxy) methyl)-2 by name, 4, 6, 8-tetra-oxygen-5-phospha nonane diacid diisopropyl ester-5-oxide compound fumarate, common name tenofovirdisoproxil fumarate, researched and developed by Gilead Sciences company of the U.S., commodity are called Viread, tenofovir disoproxil fumarate be current first by FDA approval be used for the treatment of HIV-1 infect nucleotide analog, there is better tolerance, resistant rate is low, drug withdrawal rebound rate is low, the features such as renal toxicity is little, its importance is also admitted by the World Health Organization, and be proposed as a line antiviral medication.
In Chinese patent CN101279987A, disclose a kind of production process of tenofovir, (R)-9-(2-hydroxypropyl) VITAMIN B4 obtained, mixing of materials heterogeneity in reaction system, causes raw material (R)-1,2-PD reaction effect poor, affect yield and the purity of product, (R), in the synthesis of-9-(2-hydroxypropyl) VITAMIN B4, directly add solvent after reacting completely and carry out crystallization, cause the yield of this step on the low side.
In Chinese patent CN101574356A; disclose a kind of tenofovir pharmaceutical salts and preparation thereof; it is disclosed that with (R)-ethyl lactate be the route that starting raw material synthesizes tenofovir disoproxil fumarate; this route synthetic reaction condition is gentleer; but this route uses the technique of protection and deprotection; increase the step of synthetic route, reduce the total recovery of final tenofovir disoproxil fumarate.
In Chinese patent CN103880884A, disclose a kind of preparation method of high purity tenofovir disoproxil fumarate, containing partial crystallization water in tenofovir disoproxil, affect the esterification process of subsequent step.
Summary of the invention:
In order to overcome deficiency of the prior art, the invention provides a kind of preparation method of tenofovir disoproxil fumarate, improving purity and the yield of tenofovir disoproxil fumarate, the needs of industrialized production can be met.
Contriver economically sets out, and adopts (the R)-1,2-PD of low in raw material price as starting raw material, and obtains (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone with carbonic ether, catalyst reaction.
Contriver is in order to improve (R)-9-(2-hydroxypropyl) VITAMIN B4 yield and purity, have adjusted (R)-4-methyl isophthalic acid, the ratio of 3-dioxy ring penta-2-ketone and VITAMIN B4, define stable reaction system, ensure the carrying out of sufficient reacting, improve (R)-9-(2-hydroxypropyl) VITAMIN B4 yield and purity.
Further, in the synthesis of tenofovir disoproxil fumarate, after carrying out esterification, the yield of tenofovir disoproxil fumarate is very low, contriver recognizes it may is the carrying out that contained by tynofovir, crystal water is unfavorable for esterification, therefore contriver dewaters to tynofovir, and result tenofovir disoproxil fumarate yield significantly improves, and purity also significantly improves.
Present inventor is by a large amount of experiments, constantly grope, preparation and the purifying of tenofovir disoproxil fumarate is realized by six steps, the technical scheme adopted is: first by (R)-1,2-propylene glycol obtains (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone; Mix with VITAMIN B4, DMF in the basic conditions, refining dry (R)-9-(2-hydroxypropyl); Again (R)-9-(2-hydroxypropyl) and metal alkoxide and DMF are reacted obtained (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4; (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4 of gained and bromotrimethylsilane react and generate tynofovir, and tynofovir is dewatered, adding the final product of Virahol, fumaric acid and methylene dichloride is tenofovir disoproxil fumarate.
Synthetic route is as follows:
Concrete technology step is as follows:
(1) (R)-4-methyl isophthalic acid, the preparation of 3-dioxy ring penta-2-ketone
(R)-1,2-PD, catalyzer, carbonic ether are dissolved in solvent and are stirred, and after tlc detection reaction is complete, steaming desolventizes, and obtains product (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone;
(2) synthesis of (R)-9-(2-hydroxypropyl) VITAMIN B4
By (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone, VITAMIN B4, basic catalyst, be added to N, dinethylformamide, after tlc detection reaction is complete, steaming desolventizes, and obtains (R)-9-(2-hydroxypropyl) VITAMIN B4;
(3) synthesis of (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4
(R)-9-(2-hydroxypropyl) VITAMIN B4 adds in reaction vessel, add metal alkoxide and N, dinethylformamide, drip toluoyl oxygen ylmethyl diethyl phosphoric acid, after tlc detection reaction is complete, regulate pH to 6.0-7.0, steaming desolventizes, then add methylene dichloride, obtain (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4;
(4) synthesis of tynofovir hydrate
(R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4 is dissolved in acetonitrile, add bromotrimethylsilane, after tlc detection reaction is complete, be concentrated into dry doubling to be dissolved in water, lower floor's liquid alkaline reagents regulates pH to 2.8-3.8, filter cake adds appropriate purified water, pH to 5.0-6.0 is regulated again with alkaline reagents, then suction filtration, filtrate regulates pH to 3.0-4.0 with acid reagent, obtain (R)-9-(2-phosphate methoxy propyl group) VITAMIN B4, i.e. tynofovir hydrate crude product;
(5) the refining of tynofovir, dewater
By tynofovir hydrate crude product, appropriate purified water dissolving is heated to entirely molten, drip appropriate organic solvent, tynofovir hydrate sterling is obtained after crystallization drying, gained tynofovir hydrate sterling is added appropriate varsol, adopt the mode of reflux to dewater to tynofovir hydrate sterling, obtain tynofovir fine work;
(6) synthesis of tenofovir disoproxil fumarate
Tynofovir fine work is added DMF, acid binding agent, the reaction of chloromethyl propylene carbonate, suction filtration is dry obtains tynofovir two pyrrole furan ester, then adds Virahol and fumaric acid, obtains tenofovir disoproxil fumarate.
Above-mentioned steps (1) (R)-4-methyl isophthalic acid, in the preparation of 3-dioxy ring penta-2-ketone, solvent used is anhydrous methanol, dehydrated alcohol, is preferably as anhydrous methanol; Catalyzer used is the one in sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, is preferably sodium methylate; Carbonic ether used is the one in methylcarbonate, diethyl carbonate, is preferably as methylcarbonate.
The synthesis of above-mentioned steps (2) (R)-9-(2-hydroxypropyl) VITAMIN B4: basic catalyst used is the one in magnesium hydroxide, salt of wormwood, salt of wormwood, sodium methylate, sodium ethylate, potassium hydroxide, sodium hydroxide; Described VITAMIN B4 and (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone ratio is 3:2.4-3.0.
The synthesis of above-mentioned steps (3) (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4: metal alkoxide used is the alkaline-earth alkoxides compound of C1-C4; Described (R)-9-(2-hydroxypropyl) VITAMIN B4 is 1:0.6-1.5 with the ratio of the molar weight of metal alkoxide, is preferably 1:1.
The synthesis of above-mentioned steps (4) tynofovir hydrate: alkaline reagents used is the one in magnesium hydroxide, salt of wormwood, salt of wormwood, sodium methylate, sodium ethylate, potassium hydroxide, sodium hydroxide, is preferably sodium methylate; Acid reagent used is the one in hydrochloric acid, acetic acid, sulfuric acid, is preferably hydrochloric acid.
The refining of above-mentioned steps (5) tynofovir, to dewater: organic solvent used is pentane, formic acid, acetic acid, ether, acetone, butylacetate, three fourth MEEs, isopropyl acetate, ethyl acetate, ethyl formate, is preferably acetone; Varsol used is the one in benzene, toluene, normal hexane, hexanaphthene, suberane, cyclooctane, is preferably cyclooctane.
The synthesis of above-mentioned steps (6) tenofovir disoproxil fumarate: acid binding agent used is quadrol, triethylamine, the one in 2-picoline, is preferably diethylamine.
The present invention's advantage is compared with prior art:
(1) in the beginning process of the synthesis of (R)-9-(2-hydroxypropyl) VITAMIN B4, VITAMIN B4, N is added, dinethylformamide and basic catalyst, and have adjusted (R)-4-methyl isophthalic acid, the ratio of 3-dioxy ring penta-2-ketone and VITAMIN B4, reaction system can be made homogeneous, sufficient reacting, improves (R)-9-(2-hydroxypropyl) VITAMIN B4 molar yield and purity.
(2) in the building-up process of tynofovir, in the mode of alkali-soluble acid analysis, corresponding product is refined, and target product is detected, improve the purity of product, yield and tolerance range, be beneficial to the reaction and separation processes purge process in subsequent step.
(3) in the building-up process of tenofovir disoproxil fumarate, add tynofovir water removal phase, esterification is reduced by moisture effects, improve yield, substantially increased yield and the purity of tenofovir disoproxil fumarate by above operation, be applicable to suitability for industrialized production.
(4) of the present inventionly select (R)-1,2-PD cheap and easy to get to be raw material, the technical scheme after improvement is simple to operate; selected reagent is all comparatively cheap, and side reaction is few, and productive rate is high; the three wastes that reaction process produces are few, are beneficial to the protection of environment.
Embodiment
Embodiment 1:
(1) (R)-4-methyl isophthalic acid, the preparation of 3-dioxy ring penta-2-ketone
33.0g (R)-1,2-propylene glycol, 0.8g sodium hydroxide, 51.3g diethyl carbonate, 10ml dehydrated alcohol add in 500ml there-necked flask, stir, be heated to 95 DEG C of reactions, whether (developping agent is ethyl acetate (V/ml) to tlc detection reaction: sherwood oil (V/ml)=3:2 completely; The smoked colour developing of iodine), after reacting completely, be heated to 120 DEG C and continue to remove solvent under reduced pressure, obtain pale yellow oil (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone 40.6g, purity 98.0%, molar yield 91.6%.
1HNMR(500MHz,CDCl 3):δ4.87-4.86(m,1H),4.58-4.55(m,J=8.5Hz,1H),4.05-4.02(m,J=8.5Hz,1H),1.50-1.49(d,J=6.5Hz,3H)。
Embodiment 2:
(2) synthesis of (R)-9-(2-hydroxypropyl) VITAMIN B4
The N of 575ml is added in 2000ml there-necked flask, dinethylformamide, 49.5g (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone, 45.0g VITAMIN B4 and 0.85g potassium hydroxide, stir, heat to 145 DEG C, be incubated 22 hours, tlc detects (developping agent is methylene dichloride (V/ml): methyl alcohol (V/ml)=9:1), after determining to react completely, be cooled to the reaction solvent that 90 DEG C start to remove under reduced pressure 4/5, Virahol 672ml is added after steaming removes, after being warming up to 80 DEG C of stirring and dissolving, be cooled to 0 DEG C of stirring and crystallizing to filter after 1 hour, filter cake vacuum-drying obtains white solid 57.7g in 8 hours, be (R)-9-(2-hydroxypropyl) VITAMIN B4, molar yield 85.5%, HPLC purity 98.3%.
1H NMR(500MHz,CDCl 3):δ4.87-4.86(m,1H),4.58-4.55(m,J=8.5Hz,1H),4.05-4.02(m,J=8.5Hz,1H),1.50-1.49(d,J=6.5Hz,3H)。
Embodiment 3:
(2) synthesis of (R)-9-(2-hydroxypropyl) VITAMIN B4
The N of 575ml 1 is added in 2000ml there-necked flask, dinethylformamide, 31.5g (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone, 45.0g VITAMIN B4 and 0.85g potassium hydroxide, stir, heat to 135 DEG C, be incubated 22 hours, tlc detects (developping agent is methylene dichloride (V/ml): methyl alcohol (V/ml)=9:1), after determining to react completely, be cooled to the reaction solvent that 80 DEG C start to remove under reduced pressure 4/5, Virahol 672ml is added after steaming removes, after being warming up to 70 DEG C of stirring and dissolving, be cooled to 5 DEG C of stirring and crystallizing suction filtration after 1 hour again, filter cake vacuum-drying obtains white solid 57.7g, be (R)-9-(2-hydroxypropyl) VITAMIN B4, molar yield 84.7%, HPLC purity 97.9%.
1H NMR(500MHz,CDCl 3):δ4.87-4.86(m,1H),4.58-4.55(m,J=8.5Hz,1H),4.05-4.02(m,J=8.5Hz,1H),1.50-1.49(d,J=6.5Hz,3H)。
Embodiment 4:
(3) synthesis of (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4
By (R)-9-(2-hydroxypropyl) VITAMIN B4 55.0g, tert-butyl alcohol magnesium 87.5, dimethylacetamide base methane amide 460ml adds in 1000ml there-necked flask, stirring is warming up to 55 DEG C, slow dropping p-tosyloxymethyl diethyl phosphonate 130.8g, 55 DEG C of stirring reactions 2 hours, after tlc detection (developping agent is: methylene dichloride (V/ml): methyl alcohol (V/ml)=10:1) reacts completely, cool to 20 DEG C, by acetic acid regulator solution pH value to 6.0, solvent is removed under reduced pressure after stirring 30min, after be cooled to 30 DEG C and add methylene dichloride 660ml, purified water 20ml is added after stirring and dissolving, filter, filtrate was with 30g anhydrous sodium sulfate drying 2 hours, filtrate reduced in volume, to dry, obtains (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4,
(4) synthesis of tynofovir hydrate
460ml acetonitrile is joined in (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4, stirring and dissolving, proceed in there-necked flask, 20 DEG C drip bromotrimethylsilane 173.8g, be warmed up to 50 DEG C of reactions 6 hours, after tlc detection (developping agent is: methylene dichloride (V/ml): methyl alcohol (V/ml)=10:1) reacts completely, concentrating under reduced pressure, add water after dry 200ml stirring and dissolving, collecting lower floor's liquid proceeds in there-necked flask, pH to 3.5 is regulated with sodium hydroxide, 0 DEG C of stirring and crystallizing 3 hours, suction filtration, filter cake proceeds in there-necked flask, add 200ml water, with sodium hydrate regulator solution pH to 5.5, suction filtration, filtrate regulates pH3.5 with 10% hydrochloric acid, 0 DEG C of stirring and crystallizing 2 hours, suction filtration, filter cake vacuum-drying obtains 64.6g tynofovir, molar yield 74.2%,
(5) tynofovir is refined, is dewatered
By tynofovir hydrate crude product 60g, add the purified water of 400mL, dissolve under 85 DEG C of water-baths, slowly drip 300mL acetone, be cooled to 10 DEG C of crystallizatioies 10 hours, suction filtration, obtains tynofovir hydrate sterling after drying, gained sterling is added 600ml hexanaphthene, be heated to backflow dewater, dewater and be completely concentrated into dry, obtain tynofovir, purity 99.3%;
(α) D 25=+22.3(c 0.55,0.1M HCl),Mp:278-281℃,1H NMR(500MHz,D2O):δ8.24(s,2H),4.31-4.14(m,2H),4.10-3.94(m,1H),3.72-3.45(m,2H),1.10-1.07(d,3H)。
Embodiment 5:
(3) by (R)-9-(2-hydroxypropyl) VITAMIN B4 55.0g, tert-butyl alcohol magnesium 55.0g, N, N-N,N-DIMETHYLACETAMIDE 460ml adds in 1000ml there-necked flask, and operation steps is identical with the synthesis step (3) of the tynofovir of embodiment 4;
(4) synthesis of tynofovir hydrate
Slow dropping 300mL cyclooctane, operation steps is identical with the synthesis step (4) of the tynofovir hydrate of embodiment 4, obtains tynofovir 67.6g, molar yield 77.8%;
(5) the refining of tynofovir, dewater
Operation steps is identical with the purification step (5) of the tynofovir hydrate of embodiment 4, obtains tynofovir, purity 99.8%;
(α) D 25=+22.3(c 0.55,0.1M HCl),Mp:278-281℃,1H NMR(500MHz,D2O):δ8.24(s,2H),4.31-4.14(m,2H),4.10-3.94(m,1H),3.72-3.45(m,2H),1.10-1.07(d,3H)。
Embodiment 6:
(3) by (R)-9-(2-hydroxypropyl) VITAMIN B4 55.0g, tert-butyl alcohol magnesium 27.5g, N, N-N,N-DIMETHYLACETAMIDE 400ml adds in 1000ml there-necked flask, and operation steps is identical with the synthesis step (3) of the tynofovir of embodiment 4;
(4) synthesis of tynofovir hydrate
Operation steps is identical with the synthesis step (4) of the tynofovir hydrate of embodiment 4, obtains tynofovir 63.6g, molar yield 73.2%;
(5) the refining of tynofovir, dewater
Slow dropping 300mL cyclooctane, operation steps is identical with the purification step (5) of the tynofovir hydrate of embodiment 4, obtains tynofovir, purity 99.5%;
(α) D 25=+22.3(c 0.55,0.1M HCl),Mp:278-281℃,1H NMR(500MHz,D2O):δ8.24(s,2H),4.31-4.14(m,2H),4.10-3.94(m,1H),3.72-3.45(m,2H),1.10-1.07(d,3H)。
Embodiment 7:
(6) synthesis of tenofovir disoproxil fumarate
By step (5) gained (R)-9-(2-phosphate methoxy propyl group) VITAMIN B4, 240mlN, dinethylformamide, triethylamine 85g joins in 1000ml there-necked flask, stir and add chloromethyl propylene carbonate 100g, 60 DEG C of reaction coolings after 8 hours, add ethyl acetate 240ml to stir, suction filtration, filtrate washs 2 times with 200ml saturated nacl aqueous solution, collect organic phase, use anhydrous sodium sulfate drying again 6 hours, filtrate reduced in volume is to dry, 150ml sherwood oil is added in residuum, 0 DEG C is stirred suction filtration after 8 hours, vacuum-drying obtains tynofovir two pyrrole furan ester, 320ml Virahol is added in 500ml there-necked flask, tynofovir two pyrrole furan ester, fumaric acid 15.7g are added 55 DEG C of reactions and be cooled to 0 DEG C of suction filtration after 5 hours, filter cake 20ml washed with isopropyl alcohol, vacuum-drying obtains the white crystal of 67.1g for 10 hours, be tenofovir disoproxil fumarate two pyrrole furan ester, molar yield is 86.1%, and purity is 99.98%.
Ultimate analysis (C 19h 30n 5o 10c 4h 4o 4) measured value (theoretical value, %): C 43.38 (43.47), H 5.65 (5.39), N 10.89 (11.02); ESI-MS (m/z): 520 [M+H] +; 1H NMR (DMSO, d6): δ: 13.08 (s, 2H, COOH), 8.13 (s, 1H, H-2), 8.02 (s, 1H, H-8), 7.15 (s, 2H, NH 2), 6.61 (s, 2H, CH=CH), 5.55-5.65 (m, 4H, OCH 2o), 4.80-4.83 (m, 2H, CH), 4.17-4.24 (m, 2H, CH 2p), 3.88-3.93 (m, 3H, CHO, CH2N) 3.56-3.62 (m, 2H, CH2O), 1.21 (m, 12H, CH3), 1.05 (d, J=6.3Hz, 3H, CH3); IR (KBr) ν (cm-1): 3223,2987,2940,2534,1759,1682,1623,1508,1470,1421,1378,1274,1186,1160,1102.
Comparative example 1:
(2) synthesis of (R)-9-(2-hydroxypropyl) VITAMIN B4
The N of 575ml 1 is added in 2000ml there-necked flask, dinethylformamide, 55g (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone, 45.0g VITAMIN B4 and 0.85g potassium hydroxide, stir, heat to 135 DEG C, be incubated 22 hours, tlc detects (developping agent is methylene dichloride (V/ml): methyl alcohol (V/ml)=9:1), after determining to react completely, be cooled to the reaction solvent that 80 DEG C start to remove under reduced pressure 4/5, Virahol 672ml is added after steaming removes, after being warming up to 70 DEG C of stirring and dissolving, be cooled to 5 DEG C of stirring and crystallizing suction filtration after 1 hour again, filter cake vacuum-drying obtains white solid 57.7g, be (R)-9-(2-hydroxypropyl) VITAMIN B4, molar yield 77.3%, HPLC purity 86.0%.
1H NMR(500MHz,CDCl 3):δ4.87-4.86(m,1H),4.58-4.55(m,J=8.5Hz,1H),4.05-4.02(m,J=8.5Hz,1H),1.50-1.49(d,J=6.5Hz,3H)。
Comparative example 2:
(2) synthesis of (R)-9-(2-hydroxypropyl) VITAMIN B4
The N of 575ml 1 is added in 2000ml there-necked flask, dinethylformamide, 26g (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone, 45.0g VITAMIN B4 and 0.85g potassium hydroxide, stir, heat to 135 DEG C, be incubated 22 hours, tlc detects (developping agent is methylene dichloride (V/ml): methyl alcohol (V/ml)=9:1), after determining to react completely, be cooled to the reaction solvent that 80 DEG C start to remove under reduced pressure 4/5, Virahol 672ml is added after steaming removes, after being warming up to 70 DEG C of stirring and dissolving, be cooled to 5 DEG C of stirring and crystallizing suction filtration after 1 hour again, filter cake vacuum-drying obtains white solid 57.7g, be (R)-9-(2-hydroxypropyl) VITAMIN B4, molar yield 76.6%, HPLC purity 85.2%.
1H NMR(500MHz,CDCl 3):δ4.87-4.86(m,1H),4.58-4.55(m,J=8.5Hz,1H),4.05-4.02(m,J=8.5Hz,1H),1.50-1.49(d,J=6.5Hz,3H)。
Comparative example 3:
(3) by (R)-9-(2-hydroxypropyl) VITAMIN B4 55.0g, tert-butyl alcohol magnesium 100.0g, N, N-N,N-DIMETHYLACETAMIDE 460ml adds in 1000ml there-necked flask, and operation steps is identical with the synthesis step (3) of the tynofovir of embodiment 4;
(4) synthesis of tynofovir hydrate
Operation steps is identical with the synthesis step (4) of the tynofovir hydrate of embodiment 4, obtains tynofovir 45.2g, molar yield 52.1%;
(5) the refining of tynofovir, dewater
Operation steps is identical with the purification step (5) of the tynofovir hydrate of embodiment 4, obtains tynofovir, purity 99.0%;
(α) D 25=+22.3(c 0.55,0.1M HCl),Mp:278-281℃,1H NMR(500MHz,D2O):δ8.24(s,2H),4.31-4.14(m,2H),4.10-3.94(m,1H),3.72-3.45(m,2H),1.10-1.07(d,3H)。
Comparative example 4:
(3) by (R)-9-(2-hydroxypropyl) VITAMIN B4 55.0g, tert-butyl alcohol magnesium 20.0g, N, N-N,N-DIMETHYLACETAMIDE 460ml adds in 1000ml there-necked flask, and operation steps is identical with the synthesis step (3) of the tynofovir of embodiment 4;
(4) synthesis of tynofovir hydrate
Operation steps is identical with the synthesis step (4) of the tynofovir hydrate of embodiment 4, obtains tynofovir 44.8g, molar yield 51.6%;
(5) the refining of tynofovir, dewater
Operation steps is identical with the purification step (5) of the tynofovir hydrate of embodiment 4, obtains tynofovir, purity 99.1%;
(α) D 25=+22.3(c 0.55,0.1M HCl),Mp:278-281℃,1H NMR(500MHz,D2O):δ8.24(s,2H),4.31-4.14(m,2H),4.10-3.94(m,1H),3.72-3.45(m,2H),1.10-1.07(d,3H)。
Comparative example 5:
(6) synthesis of tenofovir disoproxil fumarate
By 70g tynofovir hydrate, 240mlN, dinethylformamide, triethylamine 85g join in 1000ml there-necked flask, stir and add chloromethyl propylene carbonate 100g, 60 DEG C of reaction coolings after 8 hours, add ethyl acetate 240ml stirring, suction filtration, filtrate washs 2 times with 200ml saturated nacl aqueous solution, collect organic phase, use anhydrous sodium sulfate drying again 6 hours, filtrate reduced in volume is to dry, add 150ml sherwood oil in residuum, 0 DEG C is stirred suction filtration after 8 hours, and vacuum-drying obtains tynofovir two pyrrole furan ester; 320ml Virahol is added in 500ml there-necked flask, tynofovir two pyrrole furan ester, fumaric acid 15.7g are added 55 DEG C of reactions and be cooled to 0 DEG C of suction filtration after 5 hours, filter cake 20ml washed with isopropyl alcohol, vacuum-drying obtains the white crystal of 67.1g for 10 hours, be tenofovir disoproxil fumarate two pyrrole furan ester, molar yield is 56.1%, and purity is 97.01%.
Comparative example 6:
By 100g tenofovir, 215gN, dinethylformamide joins in 2L four-hole boiling flask, then adds chloromethyl butylperoxyisopropyl carbonate 230g, is warming up to 61 DEG C, then drips 85g triethylamine, and control dropping temperature and drop rate, about 2 hours dropwise; After dropwising, insulation reaction 2.5 hours, reaction terminates, and is cooled to 8 DEG C in 30 minutes, drips 450ml water, controls dropping temperature and drop rate, drips process temperature and is no more than 20 DEG C; After dropwising, add 250g methylene dichloride, stir, leave standstill, layering; Water layer continuation 250g methylene dichloride extracts 2 times again, then merges organic layer; Add 450ml water in organic layer, adjust PH=3.0 with 20% dilute sulphuric acid, stir, leave standstill, layering, point water-yielding stratum, continues in organic layer to add 150ml water, adjusts PH=3.0 with 20% dilute sulphuric acid, stirs, and leaves standstill, point water-yielding stratum; Combining water layer, adds 460g methylene dichloride, adjusts PH=7.0 with 20% aqueous sodium hydroxide solution, stirs, and leave standstill, layering, gets organic layer, and water layer 200g methylene dichloride extracts 2 times again; Merge organic layer, add 100g anhydrous sodium sulfate drying 45 minutes; After drying, vacuum filtration, by filtrate below 45 DEG C, 0.07MPa-0.1MPa vacuum concentration obtains pale yellow oil, is poured in 2L there-necked flask by above-mentioned pale yellow oil, adds 1080g Virahol, add 46g fumaric acid again, be heated to clearly molten, be then cooled to 5 DEG C in 4 hours, insulation crystallization 8 hours; After crystallization, filter, filter cake 180ml Virahol drip washing, obtains TDF dry product 121g, pure 99.62%, molar yield 55.9% after drying.
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 (10)

1. a preparation method for tenofovir disoproxil fumarate, comprises the following steps:
The first step, is dissolved in solvent stirs (R)-1,2-PD, catalyzer, carbonic ether, and after tlc detection reaction is complete, steaming desolventizes, and obtains product (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone;
Second step, by (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone, VITAMIN B4, basic catalyst, be added to DMF, after tlc detection reaction is complete, steaming desolventizes, and obtains (R)-9-(2-hydroxypropyl) VITAMIN B4;
3rd step, (R)-9-(2-hydroxypropyl) VITAMIN B4 adds in reaction vessel, add metal alkoxide and N, dinethylformamide, drips toluoyl oxygen ylmethyl diethyl phosphoric acid, after tlc detection reaction is complete, regulate pH to 6.0-7.0, steaming desolventizes, and adds methylene dichloride, obtains (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4;
4th step, (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4 is dissolved in acetonitrile, add bromotrimethylsilane, after tlc detection reaction is complete, be concentrated into dry doubling to be dissolved in water, lower floor's liquid alkaline reagents regulates pH to 2.8-3.8, filter cake adds appropriate purified water, pH to 5.0-6.0 is regulated again with alkaline reagents, then suction filtration, filtrate regulates pH to 3.0-4.0 with acid reagent, obtains (R)-9-(2-phosphate methoxy propyl group) VITAMIN B4, i.e. tynofovir hydrate crude product;
5th step, by tynofovir hydrate crude product, appropriate purified water dissolving is heated to entirely molten, drip appropriate organic solvent, tynofovir hydrate sterling is obtained after crystallization drying, gained tynofovir hydrate sterling is added appropriate varsol, adopts the mode of reflux to dewater to tynofovir hydrate sterling, obtain tynofovir;
6th step, adds DMF, acid binding agent, the reaction of chloromethyl propylene carbonate by tynofovir fine work, suction filtration is dry obtains tynofovir two pyrrole furan ester, then adds Virahol and fumaric acid, obtains tenofovir disoproxil fumarate.
2. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, is characterized in that: the described the first step (R)-4-methyl isophthalic acid, and in the preparation of 3-dioxy ring penta-2-ketone, solvent used is anhydrous methanol, dehydrated alcohol; Catalyzer used is the one in sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide; Carbonic ether used is the one in methylcarbonate, diethyl carbonate.
3. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, is characterized in that: the described the first step (R)-4-methyl isophthalic acid, and in the preparation of 3-dioxy ring penta-2-ketone, solvent used is anhydrous methanol; Catalyzer used is sodium methylate; Carbonic ether used is methylcarbonate.
4. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, it is characterized in that: in the preparation of described second step (R)-9-(2-hydroxypropyl) VITAMIN B4, basic catalyst used is the one in magnesium hydroxide, salt of wormwood, salt of wormwood, sodium methylate, sodium ethylate, potassium hydroxide, sodium hydroxide; VITAMIN B4 used and (R)-4-methyl isophthalic acid, 3-dioxy ring penta-2-ketone ratio is 3:2.4-3.0.
5. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, it is characterized in that: in the preparation of described 3rd step (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4, metal alkoxide used is the alkaline-earth alkoxides compound of C1-C4; Described (R)-9-(2-hydroxypropyl) VITAMIN B4 is 1:0.6-1.5 with the ratio of the molar weight of metal alkoxide.;
6. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, it is characterized in that: in described 3rd step in the preparation of (R)-9-(2-(diethylphosphoryl methoxyl group) propyl group) VITAMIN B4, metal alkoxide used is tert-butyl alcohol magnesium; Described (R)-9-(2-hydroxypropyl) VITAMIN B4 is 1:1 with the ratio of the molar weight of metal alkoxide.
7. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, is characterized in that: in described 4th step tynofovir hydrate crude product synthesis; Alkaline reagents used is the one in magnesium hydroxide, salt of wormwood, salt of wormwood, sodium methylate, sodium ethylate, potassium hydroxide, sodium hydroxide; Acid reagent used is the one in hydrochloric acid, acetic acid, sulfuric acid.
8. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, is characterized in that: the refining of described 5th step tynofovir, dewater; Organic solvent used is pentane, formic acid, acetic acid, ether, acetone, butylacetate, three fourth MEEs, isopropyl acetate, ethyl acetate, ethyl formate; Varsol used is the one in benzene, toluene, normal hexane, hexanaphthene, suberane, cyclooctane.
9. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, is characterized in that: the refining of described 5th step tynofovir, dewater; Organic solvent used is acetone, and varsol used is cyclooctane.
10. the preparation method of tenofovir disoproxil fumarate as claimed in claim 1, is characterized in that: the synthesis of described 6th step tenofovir disoproxil fumarate, acid binding agent used is quadrol, triethylamine, the one in 2-picoline.
CN201510076929.7A 2015-02-13 2015-02-13 Method for preparing tenofovir disoproxil fumarate Pending CN104610360A (en)

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CN105440078A (en) * 2015-12-31 2016-03-30 苏州弘森药业有限公司 Method for synthesizing tenofovir disoproxil fumarate conveniently
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CN108285471A (en) * 2018-03-16 2018-07-17 安徽华昌高科药业有限公司 A kind of preparation method of tenofovir
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CN111961081A (en) * 2020-10-20 2020-11-20 北京鑫开元医药科技有限公司 Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine

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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
CN105440078A (en) * 2015-12-31 2016-03-30 苏州弘森药业有限公司 Method for synthesizing tenofovir disoproxil fumarate conveniently
CN105440077A (en) * 2015-12-31 2016-03-30 苏州弘森药业有限公司 Method for synthesizing tenofovir disoproxil fumarate
CN105481897A (en) * 2015-12-31 2016-04-13 苏州弘森药业有限公司 New method for preparing tenofovir disoproxil fumarate
CN105481898A (en) * 2015-12-31 2016-04-13 苏州弘森药业有限公司 Method for synthesizing tenofovir fumarate by two-step process
CN105566393A (en) * 2015-12-31 2016-05-11 苏州弘森药业有限公司 Synthetic method of tenofovir disoproxil fumarate
CN106008603A (en) * 2016-06-03 2016-10-12 东北制药集团股份有限公司 Preparation methods of tenofovir disoproxil and fumarate thereof
CN107400145A (en) * 2017-08-03 2017-11-28 江苏汉斯通药业有限公司 The synthetic method of high-purity tenofovir disoproxil fumarate
CN108329352A (en) * 2018-02-23 2018-07-27 福安药业集团重庆博圣制药有限公司 The preparation method of tenofovir disoproxil fumarate
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CN109053804A (en) * 2018-08-31 2018-12-21 乐平市赛复乐医药化工有限公司 A kind of synthetic method of tenofovir
CN109053804B (en) * 2018-08-31 2021-03-30 乐平市赛复乐医药化工有限公司 Synthesis method of tenofovir
CN111943982A (en) * 2020-08-14 2020-11-17 山东罗欣药业集团股份有限公司 Synthesis process of antiviral drug
CN111961081A (en) * 2020-10-20 2020-11-20 北京鑫开元医药科技有限公司 Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine
CN111961081B (en) * 2020-10-20 2021-03-09 北京鑫开元医药科技有限公司 Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine

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