CN105061535A - Synthetic method of sofosbuvir intermediate - Google Patents
Synthetic method of sofosbuvir intermediate Download PDFInfo
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Abstract
The invention relates to a synthetic method of sofosbuvir intermediate-(2'R)-N- benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine-3',5'-dibenzoate represented by a formula (I) (shown in the specification). The synthetic method comprises the steps of generating a reduction product compound IV of a compound III from the compound III in the presence of modified red aluminum, generating a chlorinated compound V from the compound IV through sulfoxide chloride chlorination under the catalysis of N,N-dimethylformamide, after separating organic materials and aluminum salt from the compound V, directly condensing the compound V with a compound VI N-benzoyl-O-(trimethylsilyl)cytosine, and carrying out hydrolysis by virtue of an acetic acid solution, so as to obtain (2'R)-N- benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine-3',5'-dibenzoate represented by the formula (I). The synthetic method has the advantages of high yield, convenience in operation and suitability in industrial production.
Description
Technical field
The present invention relates to the fluoro-2'-methylcytidine of one (2'R)-N-benzoyl-2'-deoxidation-2'--3', the synthetic method of 5'-dibenzoate.
Background technology
Suo Feibuwei (Compound II per), have another name called: rope fluorine cloth Wei, English name: Sofosbuvir, the exploitation of Shi Ji Leadd B.V is used for the treatment of the new drug of chronic hepatitis C, in approval in Nikkei U.S. food Drug Administration December 6 in 2013 (FDA) in U.S.'s listing, Nikkei Europe drug administration January 16 in 2014 (EMEA), approval was gone on the market in EU countries.This medicine is first without the need to combining the medicine of Interferon, rabbit with regard to some type third liver of the safe and effective treatment of energy, and market capacity is huge.In Suo Feibuwei synthesis technique, the industrial following (reference: [1] J.Org.Chem., 2009,74,6819-6824 of conventional route; [2] US2010056770 (2010); [3] US2103324709 (2013)):
The fluoro-2'-methylcytidine of Suo Feibuwei key intermediate (2'R)-N-benzoyl-2'-deoxidation-2'--3', 5'-dibenzoate (Compound I) is general with 3, 5-dibenzoyl-2-deoxidation-2-fluoro-2 methyl-D-ribo-gamma lactone (compound III) is raw material, through modification red aluminium reducing, generate [(2R, 3R, 4R)-3-(benzoyl oxygen)-4-fluoro-5-hydroxy-4-methyl tetrahydrofuran (THF)-2-base] methyl benzoic acid ester (compound IV), compound IV generates [(2R through chloro, 3R, 4R) the chloro-4-methyltetrahydrofuran of-3-(benzoyl oxygen) the fluoro-5-of-4--2-base] methyl benzoic acid ester (compound V), compound V under stannic chloride catalysis with through and N-benzoyl-O-(trimethylsilyl) cytosine(Cyt) (compound VI) condensation, after acetum hydrolysis treatment:
Wherein, have through SULPHURYL CHLORIDE/four butyl bromation amine (reference: [1] J.Org.Chem., 2009,74,6819-6824 by compound VI synthetic compound V bibliographical information; [2] US2010056770 (2010); [3] US2103324709 (2013)) and triphenyl phosphorus/NCS chloro and obtain (reference: [4] 2009152095 (2009); [5] WO2010075549 (2010)) chloro and obtaining:
In aforesaid method, be in the technique of chlorinating agent with triphenyl phosphorus/NCS, agents useful for same triphenyl phosphorus and NCS price more expensive, and (reference: [4] 2009152095 (2009) in finding bibliographical information; [5] WO2010075549 (2010)) all obtain chloro thing (compound V) with the method for column chromatography, the method cannot be applied to industrial production.Therefore in actual production, comparatively conventional with SULPHURYL CHLORIDE/Tetrabutyl amonium bromide technique.In the technique of SULPHURYL CHLORIDE/Tetrabutyl amonium bromide, due to the chlorsulfonic acid boiling point higher (151 DEG C) of SULPHURYL CHLORIDE chloro time institute by-product, after chlorination, remove cumbersome, document is usually after its reaction, with a large amount of sodium citrate aqueous solution hydrolysis (about 4.4 equivalent), then wash and be separated and obtain chloro thing (compound V).By the buffering of Trisodium Citrate system to pH, the hydrolysis of chloro thing can be reduced, but thus this process produces larger waste water.
Summary of the invention
The object of this invention is to provide high, the easy to operate and fluoro-2'-methylcytidine of (the 2'R)-N-benzoyl-2'-deoxidation-2'--3' of applicable suitability for industrialized production of a kind of yield, the synthetic method of 5'-dibenzoate.
For realizing goal of the invention of the present invention, adopt following technical scheme:
The fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' shown in a kind of formula (I), the synthetic method of 5'-dibenzoate, comprising:
Compound III that is 3, 5-dibenzoyl-2-deoxidation-2-fluoro-2-methyl-D-ribo-gamma lactone is under the effect of the red aluminium of modification (red aluminium and equimolar trifluoroethanol react and obtain), generate reduzate the compound IV i.e. [(2R of compound III, 3R, 4R)-3-(benzoyl oxygen)-4-fluoro-5-hydroxy-4-methyl tetrahydrofuran (THF)-2-base] methyl benzoic acid ester, compound IV is at N, under the katalysis of dinethylformamide (DMF), chloro compounds V i.e. [(2R is generated through sulfur oxychloride chloro, 3R, 4R) the chloro-4-methyltetrahydrofuran of-3-(benzoyl oxygen) the fluoro-5-of-4--2-base] methyl benzoic acid ester, compound V is after being separated organic materials with aluminium salt, direct warp and compound VI and the condensation of N-benzoyl-O-(trimethylsilyl) cytosine(Cyt), acetum hydrolysis treatment obtains the fluoro-2'-methylcytidine of (the 2'R)-N-benzoyl-2'-deoxidation-2'--3' shown in formula (I), 5'-dibenzoate, reaction formula is as follows:
Further, described synthetic method specifically operates in accordance with the following steps:
Compound III with the red aluminium of modification for reductive agent, the reduzate compound IV of reacting generating compound III in toluene, gained compound IV does not need through further process, add N, dinethylformamide is catalyzer, the sulfur oxychloride of control temperature needed for-30 ~ 5 DEG C of dropwise reactions, dropwising rear control temperature makes compound IV chloro generate chloro-product compound V at 10 ~ 35 DEG C, react intensification and drive the hydrogenchloride and sulfurous gas that produce in process away, evaporated under reduced pressure toluene, add toluene again, organism is extracted, obtain the toluene solution of compound V, the toluene solution of compound V is concentrated into dry, add methylene chloride and dissolve to obtain the dichloromethane solution of compound V, the dichloromethane solution of compound V mixes with compound VI, drip tin tetrachloride and carry out condensation reaction, after condensation, the dichloromethane solution of target product Compound I is obtained through acetum hydrolysis treatment, gained solution obtains target product Compound I through the refining isomer that removes.
In the present invention, compound III reacting generating compound IV, compound V and compound VI condensation and acetum is subsequently hydrolyzed, the refining of Compound I all can operate according to the report of existing document under the effect of modification red aluminium.
Further, the molar ratio of compound III and sulfur oxychloride is 1:2.75 ~ 4.0, is preferably 1:3.5.
Further, the molar ratio of compound III and DMF is 1:0.18 ~ 0.4, is preferably 1:0.2.
Further, the temperature that adds of sulfur oxychloride controls at-30 ~ 5 DEG C, is preferably-20 ~-15 DEG C
Further, after reinforced, control chlorination temperature at 10 ~ 35 DEG C, be preferably 20 ~ 25 DEG C.
The present invention has following beneficial outcomes:
1. in the chloro stage, with sulfur oxychloride/DMF (SOCl
2/ DMF) substitute SULPHURYL CHLORIDE/Tetrabutyl amonium bromide be chlorinating agent, by the by product of generation and excessive chloro sulfoxide are removed through the mode of distillation, avoid using water in its last handling process, reduce the loss of dissolving in the hydrolysis risk of chloro-product and water, improve the yield of product.
2. because the aftertreatment of chloro stage decreases hydrolysing step, wastewater flow rate is reduced, process Environmental Safety, and industrial operation is easier.
Below in conjunction with embodiment, the invention will be further described:
Embodiment
Following type reaction is used for illustrating the present invention.All belong within the technical scheme that the present invention protects inventing the simple replacement done or improvement etc. those skilled in that art.
The fluoro-2'-methylcytidine of embodiment 1 (2'R)-N-benzoyl-2'-deoxidation-2'--3', the preparation of 5'-dibenzoate
-25 ~-15 DEG C of temperature, under nitrogen protection, the red aluminium (70% content) of 100 grams, instills the mixed liquid of 35 grams of toluene and 35 grams of trifluoroethanols, drips off to be warming up to room temperature and to stir 1 hour again, stand-by.
-20 ~-15 DEG C of temperature; under nitrogen protection; 74.4 grams of (0.2mol) 3; 5-dibenzoyl-2-deoxidation-2-fluoro-2 methyl-D-ribo-gamma lactone (compound III), 150 grams of toluene add in reaction flask, the red aluminum solutions 148 grams of slowly instillation upper step modification; within about 3 hours, drip off; drip off rear insulation 30 minutes, TLC traces into raw material point and disappears, and obtains the toluene solution of compound IV.
Upper step reaction solution, at-20 ~-15 DEG C of temperature, add N, dinethylformamide (DMF) 2.9 grams (0.04mol), slowly drips sulfur oxychloride 83.3 grams (0.7mol), drips off, naturally be warming up to 20 ~ 25 DEG C and carry out chlorination, TLC traces into compound IV point and disappears, and decompression pulls away produced sulfurous gas and hydrogenchloride, then less than 50 DEG C evaporated under reduced pressure toluene.Clout adds toluene 250 grams, and dispersed with stirring, separates organic layer.Organic layer evaporated under reduced pressure obtains chloro thing.Add methylene chloride 300 grams and dissolve, obtain chloro thing (compound V) solution.
In autoclave; N-benzoyl-O-(trimethylsilyl) cytosine(Cyt) (compound V) of 86.1 grams is dissolved in the methylene dichloride of 200 grams; add above-mentioned chloro thing dichloromethane solution; afterwards; add tin tetrachloride 104 grams (0.4mol), 75 ~ 80 DEG C of reactions disappear to chloro thing for about 20 hours substantially.Reaction solution is as cold as room temperature, pending.
In reaction flask, add 160 grams of acetic acid+12 grams of water, temperature control 20-25 DEG C, upper step condensation gob is entered in sour water, stir 1 hour, filter.
Filtrate adds in the solution of 400 grams of acetic acid+380 grams of water, 30 DEG C, stirs 30 minutes, layering, then wash 3 times with the solution of 120 grams of acetic acid+135 grams of water, wash 2 times, activated carbon decolorizing, filter, filtrate adds methyl alcohol 800 grams, reclaims methylene dichloride to interior temperature 52 DEG C, be as cold as 20 DEG C to stir 3 hours, spend the night, obtain product 68.5 grams, yield: 60.0%.HPLC purity: 99.2%, diastereomer: 0.11%.Fusing point: 239.5 ~ 240.6 DEG C, hydrogen spectrum (
1h-NMR) (CDCl
3, 500MHz): δ 1.48 (d, 3H), 4.62 (dd, 1H), 4.72 (d, 1H), 4.88 (d, 1H), 5.56 (brdd, 1H), 6.51 (brd, 1H), 7.46-7.56 (m, 7H), 7.61-7.70 (m, 3H), 7.88 (m, 2H), 8.06-8.10 (m, 5H), 8.70 (s, 1H), mass spectrum (ESI-MS): 572 (M+1), ultimate analysis (C
31h
26fN
3o
7, %) and (measured value/calculated value): C65.14/65.02, H4.59/4.66, N7.35/7.22.
Embodiment 2 ~ 12
With reference to embodiment 1, different SOCl
2, DMF consumption, sulfur oxychloride dropping temperature is different, the asynchronous reaction yield of chloro temperature (outside dechlorination foundry skill, feed intake and other processing mode identical with embodiment 1), reaction conditions and result as shown in table 1 below:
Table 1
Claims (10)
1. the fluoro-2'-methylcytidine of (the 2'R)-N-benzoyl-2'-deoxidation-2'--3' shown in a formula (I), the synthetic method of 5'-dibenzoate, comprising:
Compound III that is 3, 5-dibenzoyl-2-deoxidation-2-fluoro-2-methyl-D-ribo-gamma lactone is under the effect of the red aluminium of modification, generate reduzate the compound IV i.e. [(2R of compound III, 3R, 4R)-3-(benzoyl oxygen)-4-fluoro-5-hydroxy-4-methyl tetrahydrofuran (THF)-2-base] methyl benzoic acid ester, compound IV is at N, under the katalysis of dinethylformamide, chloro compounds V i.e. [(2R is generated through sulfur oxychloride chloro, 3R, 4R) the chloro-4-methyltetrahydrofuran of-3-(benzoyl oxygen) the fluoro-5-of-4--2-base] methyl benzoic acid ester, compound V is after being separated organic materials with aluminium salt, direct warp and compound VI and the condensation of N-benzoyl-O-(trimethylsilyl) cytosine(Cyt), acetum hydrolysis treatment obtains the fluoro-2'-methylcytidine of (the 2'R)-N-benzoyl-2'-deoxidation-2'--3' shown in formula (I), 5'-dibenzoate, reaction formula is as follows:
2. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 1, the synthetic method of 5'-dibenzoate, is characterized in that: described synthetic method specifically operates in accordance with the following steps:
Compound III with the red aluminium of modification for reductive agent, the reduzate compound IV of reacting generating compound III in toluene, gained compound IV does not need through further process, add N, dinethylformamide is catalyzer, the sulfur oxychloride of control temperature needed for-30 ~ 5 DEG C of dropwise reactions, dropwising rear control temperature makes compound IV chloro generate chloro-product compound V at 10 ~ 35 DEG C, react intensification and drive the hydrogenchloride and sulfurous gas that produce in process away, evaporated under reduced pressure toluene, add toluene again, organism is extracted, obtain the toluene solution of compound V, the toluene solution of compound V is concentrated into dry, add methylene chloride and dissolve to obtain the dichloromethane solution of compound V, the dichloromethane solution of compound V mixes with compound VI, drip tin tetrachloride and carry out condensation reaction, after condensation, the dichloromethane solution of target product Compound I is obtained through acetum hydrolysis treatment, gained solution obtains target product Compound I through the refining isomer that removes.
3. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 1, the synthetic method of 5'-dibenzoate, is characterized in that: the molar ratio of compound III and sulfur oxychloride is 1:2.75 ~ 4.0.
4. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 2, the synthetic method of 5'-dibenzoate, is characterized in that: the molar ratio of compound III and sulfur oxychloride is 1:2.75 ~ 4.0.
5. the fluoro-2'-methylcytidine of (the 2'R)-N-benzoyl-2'-deoxidation-2'--3' as described in one of Claims 1 to 4, the synthetic method of 5'-dibenzoate, is characterized in that: the molar ratio of compound III and sulfur oxychloride is 1:3.5.
6. the fluoro-2'-methylcytidine of (the 2'R)-N-benzoyl-2'-deoxidation-2'--3' as described in one of Claims 1 to 4, the synthetic method of 5'-dibenzoate, is characterized in that: the molar ratio of compound III and DMF is 1:0.18 ~ 0.4.
7. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 6, the synthetic method of 5'-dibenzoate, is characterized in that: the molar ratio of compound III and DMF is 1:0.2.
8. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 1 or 2, the synthetic method of 5'-dibenzoate, is characterized in that: the temperature that adds of sulfur oxychloride controls at-20 ~-15 DEG C.
9. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 1 or 2, the synthetic method of 5'-dibenzoate, is characterized in that: control chlorination temperature at 20 ~ 25 DEG C after reinforced.
10. the fluoro-2'-methylcytidine of (2'R)-N-benzoyl-2'-deoxidation-2'--3' as claimed in claim 8, the synthetic method of 5'-dibenzoate, is characterized in that: control chlorination temperature at 20 ~ 25 DEG C after reinforced.
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Cited By (6)
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| CN106810515A (en) * | 2017-02-06 | 2017-06-09 | 抚州市星辰药业有限公司 | The midbody compound and its synthetic method of a kind of synthesis Suo Feibuwei |
| CN107522763A (en) * | 2016-06-22 | 2017-12-29 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of the MU glycosides of 2 ' fluorine of (2 ' R) 2 ' deoxidation 2 ' |
| CN107540640A (en) * | 2016-06-27 | 2018-01-05 | 江苏福瑞生物医药有限公司 | A kind of reductive modification agent and its preparation method and application |
| CN107629099A (en) * | 2017-07-26 | 2018-01-26 | 杭州科本药业有限公司 | A kind of preparation technology of Suo Feibuwei intermediates |
| CN109422781A (en) * | 2017-08-25 | 2019-03-05 | 江苏瑞科医药科技有限公司 | The preparation method of one kind fluoro- 2- metil-D-ribofuranose base chloride of (2R) -2- deoxidation -2- |
| CN113354700A (en) * | 2021-05-06 | 2021-09-07 | 江苏阿尔法药业股份有限公司 | Preparation method of sofosbuvir intermediate |
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| CN107522763B (en) * | 2016-06-22 | 2020-10-02 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine |
| CN107540640A (en) * | 2016-06-27 | 2018-01-05 | 江苏福瑞生物医药有限公司 | A kind of reductive modification agent and its preparation method and application |
| CN106810515A (en) * | 2017-02-06 | 2017-06-09 | 抚州市星辰药业有限公司 | The midbody compound and its synthetic method of a kind of synthesis Suo Feibuwei |
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| CN107629099B (en) * | 2017-07-26 | 2020-05-26 | 江苏科本药业有限公司 | Preparation process of sofosbuvir intermediate |
| CN109422781A (en) * | 2017-08-25 | 2019-03-05 | 江苏瑞科医药科技有限公司 | The preparation method of one kind fluoro- 2- metil-D-ribofuranose base chloride of (2R) -2- deoxidation -2- |
| CN113354700A (en) * | 2021-05-06 | 2021-09-07 | 江苏阿尔法药业股份有限公司 | Preparation method of sofosbuvir intermediate |
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