CN109438537A - A kind of preparation method of Suo Feibuwei key intermediate - Google Patents
A kind of preparation method of Suo Feibuwei key intermediate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The present invention relates to one kind such as formulas (I):
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate more particularly to a kind of systems of Suo Feibuwei key intermediate
Preparation Method.
Technical background
Suo Feibuwei (and being translated into rope fluorine cloth Wei, English name Sofosbuvir, trade name Sovaldi) is that lucky Leadd B.V opens
Hair is ratified in 6 Nikkei U.S. Food and Drug Administration (FDA) December in 2013 in beauty in the new drug for the treatment of chronic hepatitis C
State's listing, the approval of 16 Nikkei Europe drug administration (EMEA) January in 2014 are listed in EU countries.Also not in Discussion on Chinese Listed.
The drug is the first drug that certain type hepatitis can be safely and effectively treated without joint interferon.Clinical test confirmation is directed to
The overall continued viral response rate (SVR) of 1 and 4 type hepatitis, the medication combined Peg-IFN alpha-2b and Ribavirin is up to
90%；For 2 type hepatitis, the SVR of the medication combined Ribavirin is 89~95%；For 3 type hepatitis, the medication combined benefit bar
The SVR of Wei Lin is 61~63%.
Compound (I) is the key intermediate for preparing Suo Feibuwei, has the process flow on sale, common to be on the market at present
Red aluminum selectivity of the fluoro- 2 methyl-D-ribos-gamma lactone of compound 3,5- dibenzoyl -2- deoxidation -2- by modified passivation
Reduction generates [the fluoro- 5- hydroxy-4-methyl tetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyl oxygen) -4-] methylbenzene first
Acid esters, [the fluoro- 5- hydroxy-4-methyl tetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyl oxygen) -4-] methyl benzoic acid ester
Product (2'R)-N- benzoyl is prepared by chlorination and compound N-benzoyl-O- (trimethylsilyl) cytimidine condensation
Fluoro- 2'- methylcytidine -3', the 5'- dibenzoate (I) of base -2'- deoxidation -2'-.United States Patent (USP) US2013/0324709A1 is announced
A kind of preparation method of compound (I), the specific steps are as follows:
The patent is modified red aluminum Red-Al and passivator CF when carrying out reduction reaction3CH2OH (trifluoroethanol),
With this condition to the poor selectivity of reactant, it is easy to restore excessive, the production fluoro- 2- methyl-1 of by-product (2R, 3R, 4R) -2-,
3,4,5- penta tetrol -3,5- dibenzoates, specific reaction step are as follows:
The poor selectivity of trifluoroethanol, byproduct of reaction is more, makes troubles for subsequent reactions.
Summary of the invention
In order to solve problem above, the present invention provides a kind of formulas such as (I):
Shown in Suo Feibuwei intermediate preparation method, innovative point is: its preparation route are as follows:
The following steps are included:
(a) cooling in toluene first is added in red aluminum, passivator morphine and toluene is then instilled under -15~-10 DEG C of environment
It mixes, is kept the temperature at -10 DEG C, then heat to the modified red aluminum solution for standby of 25 ± 5 DEG C of preparations；By compound 3,5- dibenzoyl
The fluoro- 2 methyl-D-ribos-gamma lactone (II) of base -2- deoxidation -2- is dissolved in toluene, and it is red that modification is added dropwise after being cooled to -20~-15 DEG C
Aluminum solutions carry out Chemoselective reduction and prepare intermediate product [the fluoro- 5- hydroxyl-of (2R, 3R, 4R) -3- (benzoyl oxygen) -4-
4- methyltetrahydrofuran -2- base] methyl benzoic acid ester (III)；
(b) step (a) after reaction in, catalyst is added in the reaction product of (a) step at -20~-10 DEG C
Tetrabutylammonium bromide and chlorinating agent sulfonic acid chloride, heat preservation carries out chlorination after 15~25 DEG C are warming up to after being added dropwise, and is prepared into
To intermediate product [the chloro- 4- methyltetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyl oxygen) the fluoro- 5- of -4-] methyl benzoic acid
Ester (IV)；
(c) at 20~30 DEG C, N- benzoylcytosine (VI), ammonium sulfate and hexamethyldisilazane are mixed anti-
It answers, temperature rising reflux stirs to clarify concentration, and chlorobenzene dissolution is added, obtains N- benzoyl-O- (trimethylsilyl) cytimidine (V)
Chlorobenzene solution mixes the intermediate product (IV) that step (b) is prepared with the chlorobenzene solution of compound (V), and chlorination is added dropwise
Tin carries out condensation reaction, and the fluoro- 2'- methyl born of the same parents of Suo Feibuwei intermediate (2'R)-N- benzoyl -2'- deoxidation -2'- are prepared
Glycosides -3', 5'- dibenzoate (I).
Further, the mass fraction of red aluminum is 60~70% in step (a) of the invention, red aluminum of the invention and morphine
Mass ratio be 3.5~4:1, cooling temperature of the invention be -20~-10 DEG C, soaking time of the invention be 20~40min.
Further, the molal weight ratio of step (a) compound (II) of the invention and modified red aluminum solution is 1:1.52
~1.58, the Chemoselective reduction time of the invention is 20~26h, the reaction temperature of selective reduction of the invention is 0~
30 DEG C, Chemoselective reduction of the invention carries out in contact plate.
Further, the mass ratio of tetrabutylammonium bromide and sulfonic acid chloride is 0.007~0.009 in step (b) of the invention:
1, chlorination temperature of the invention is 15~25 DEG C, and the chlorination time of the invention is 18~22h.
Further, the mass ratio of compound (VI), ammonium sulfate and hexamethyldisilazane is in step (c) of the invention
0.3~0.5:0.006~0.007:1, warming temperature of the invention are 110~130 DEG C.
Further, the mass ratio of stannic chloride and compound (II) is 0.7~0.8:1, this hair in step (c) of the invention
The mass ratio of bright compound (II) and compound (V) is 1:1.7~1.8, and the reaction time of the invention is 10~80 DEG C, instead
Between seasonable for 16~for 24 hours, the content for the HPLC chloro material that the compound of the present invention (IV) reaction terminates is 0~2%.
The present invention has the advantages that compared with prior art, the present invention the present invention is the passivator of red aluminum with morphine, relatively
Good in the selectivity of trifluoroethanol, morphine, cheap, the present invention is using the morphine passivator that alternatively property restores, one
Determine to reduce the fluoro- 2- methyl-1 of by-product (2R, 3R, 4R) -2- in degree, the generation of 3,4,5- penta tetrol -3,5- dibenzoates,
Be conducive to continuing for subsequent reactions, it is economic and environment-friendly, and industrial production cost is greatly saved, there is huge industry
Prospect of production.
Specific embodiment
The following examples can make professional and technical personnel that the present invention be more fully understood, therefore will not be of the invention
It is limited among scope of embodiments of the invention.
Embodiment 1
A kind of preparation method of Suo Feibuwei intermediate (I), the specific steps are as follows:
Step 1, the preparation of compound (III): in dry three-necked flask, weighing 70% red aluminum 61g (0.21mol),
Then toluene 15g is mixed object and is cooled to -15 DEG C, morpholine 16.5g (0.19mol) and toluene are then instilled into three-necked flask
The mixed liquor of 10g, at -10 DEG C, drop finishes temperature control system in the process, keeps the temperature 30min, is slowly increased to 25 ± 5 DEG C, is added dropwise to heating
Terminate, obtains modified red aluminum solution for standby.
Compound (II) 49.4g (0.133mol) and toluene 150g is thrown in dry three-necked flask, is cooled to -15 DEG C,
The above-mentioned modification red aluminum solution prepared is added dropwise, drop, which finishes to be warming up at 15 DEG C, to be kept the temperature, and is disappeared, is obtained to point board raw material after reaction for 24 hours
Compound (III).
Step 2, the preparation of compound (IV): on the basis of step 1, in -15 DEG C of addition catalyst tetrabutyl phosphonium bromides
Then chlorinating agent sulfonic acid chloride 61.8g (0.458mol) is added dropwise in ammonium 0.5g, drop Bi Ziran rises to 20 DEG C, and heat preservation 20h is reacted,
Then 10 DEG C or less progress reactants separates instill reaction solution in 495g30% sodium citrate aqueous solution, and reaction solution is in paging
Layering, mucus are gradually sunk in funnel, there is heat release, and 8 DEG C rise to 15 DEG C, are dripped and are finished solution as pH3~4,42% hydrogen-oxygen of 32g is added dropwise
Change sodium solution and adjust pH=5, be warming up to 30~35 DEG C, separates organic layer and water layer, 30~35 DEG C of temperature control, organic layer 217g
23% sodium citrate solution washs 1h, then separates organic layer and water layer, and organic layer 150g water washing is primary, and organic layer is pale yellow, water
Layer is colourless, and organic layer, which is concentrated under reduced pressure, to be done, and obtains light yellow oil object, the chlorobenzene dissolved clarification that 500g is added is stand-by, obtains intermediate product (IV).
The preparation of compound (I): step 3 at 25 DEG C, weighs N- benzoylcytosine 25.8g (0.12mol) first
With ammonium sulfate 0.4g in dry three-necked flask, hexamethyldisilazane 60g dispersion is then added dropwise, is warming up to 120 DEG C, reflux
It is stirred to react to clarification, concentration hexamethyldisilazane adds 200g chlorobenzene to dissolve, obtain compound to no flow after system clarification
(V) chlorobenzene solution is spare.
Under normal temperature and pressure, the chlorobenzene solution of the compound (IV) that step 2 is prepared is prepared with above-mentioned react
The chlorobenzene solution of compound (V) mixes, and 38.2g tin tetrachloride is then added dropwise in three-necked flask, is warming up to 75 DEG C of reactions, 20h
Afterwards to compound (IV) (chloro thing) HPLC content less than 2%.Concentration is evaporated chlorobenzene, adds methylene chloride 400 grams, and 100 grams of water, ice
It 200 grams of acetic acid, is dispersed with stirring, crosses and filter out pink salt and excessive N- benzoylcytosine.Filtrate separates organic layer, then uses quality
Score is that 50% glacial acetic acid solution is washed twice, and 100g washing is primary, adds methanol 500g, and normal pressure is steamed to 55g, cooling, and product is precipitated
Fluoro- 2'- methylcytidine -3', 5'- the hexichol first of Suo Feibuwei intermediate (2'R)-N- benzoyl -2'- deoxidation -2'- is prepared
Acid esters (I) 45.2g.
Embodiment 2
A kind of preparation method of Suo Feibuwei intermediate (I), the specific steps are as follows:
The preparation of compound (III): step 1 in dry three-necked flask, weighs 60% red aluminum 70.7g
Then (0.21mol), toluene 15g are mixed object and are cooled to -20 DEG C, morpholine 21.4g is then instilled into three-necked flask
The mixed liquor of (0.25mol) and toluene 10g, at -15 DEG C, drop finishes temperature control system in the process, keeps the temperature 20min, is slowly increased to 25
± 5 DEG C, being added dropwise to heating terminates, and obtains modified red aluminum solution for standby.
Compound (II) 52.4g (0.141mol) and toluene 150g is thrown in dry three-necked flask, is cooled to -15 DEG C,
The above-mentioned modification red aluminum solution prepared is added dropwise, drop, which finishes to be warming up at 15 DEG C, to be kept the temperature, and is disappeared, is obtained to point board raw material after reacting 20h
Compound (III).
Step 2, the preparation of compound (IV): on the basis of step 1, in -15 DEG C of addition catalyst tetrabutyl phosphonium bromides
Then chlorinating agent sulfonic acid chloride 63.5g (0.47mol) is added dropwise in ammonium 0.57g, drop Bi Ziran rises to 25 DEG C, and heat preservation 18h is reacted,
Then 10 DEG C or less progress reactants separates instill reaction solution in 495g30% sodium citrate aqueous solution, and reaction solution is in paging
Layering, mucus are gradually sunk in funnel, there is heat release, and 8 DEG C rise to 15 DEG C, are dripped and are finished solution as pH3~4,42% hydrogen-oxygen of 32g is added dropwise
Change sodium solution and adjust pH=5, is warming up to 30~35 DEG C, separating has several layers of and water layer, and 30~35 DEG C of temperature control, organic layer 217g
23% sodium citrate solution washs 1h, then has separated several layers of and water layer, and organic layer 150g water washing is primary, and organic layer is pale yellow, water
Layer is colourless, and organic layer, which is concentrated under reduced pressure, to be done, and obtains light yellow oil object, the chlorobenzene dissolved clarification that 500g is added is stand-by, obtains intermediate product (IV).
Step 3, the preparation of compound (I): at 25 DEG C, weigh first N- benzoylcytosine 33g (0.15mol) and
Then hexamethyldisilazane 66g dispersion is added dropwise in dry three-necked flask in ammonium sulfate 0.46g, be warming up to 130 DEG C, reflux
It is stirred to react to clarification, concentration hexamethyldisilazane adds 200g chlorobenzene to dissolve, obtain compound to no flow after solution clarification
(V) chlorobenzene solution is spare.
Under normal temperature and pressure, the chlorobenzene solution of the compound (IV) that step 2 is prepared is prepared with above-mentioned react
The chlorobenzene solution of compound (V) mixes, and 30.8g tin tetrachloride is then added dropwise in three-necked flask, is warming up to 80 DEG C of reactions, 16h
Afterwards to compound (IV) (chloro material) HPLC content less than 2%.Concentration is evaporated chlorobenzene, adds methylene chloride 400 grams, and 100 grams of water, ice
It 200 grams of acetic acid, is dispersed with stirring, crosses and filter out pink salt and excessive N- benzoylcytosine.Filtrate separates organic layer, then uses quality
Score is that 50% glacial acetic acid solution is washed twice, and 100g washing is primary, adds methanol 500g, and normal pressure is steamed to 55g, cooling, and product is precipitated
Fluoro- 2'- methylcytidine -3', 5'- the hexichol first of Suo Feibuwei intermediate (2'R)-N- benzoyl -2'- deoxidation -2'- is prepared
Acid esters (I) 48.7g.
Embodiment 3
A kind of preparation method of Suo Feibuwei intermediate (I), the specific steps are as follows:
The preparation of compound (III): step 1 in dry three-necked flask, weighs 65% red aluminum 68.9g
Then (0.22mol), toluene 15g are mixed object and are cooled to -15 DEG C, morpholine 14g is then instilled into three-necked flask
The mixed liquor of (0.16mol) and toluene 10g, at -20 DEG C, drop finishes temperature control system in the process, and heat preservation 40 is slowly increased to 25 ± 5
DEG C, being added dropwise to heating terminates, and obtains modified red aluminum solution for standby.
In the compound that feeds intake in contact plate (II) 53.8g (0.145mol) and toluene 150g, it is cooled to -15 DEG C, in dropwise addition
The modification red aluminum solution prepared is stated, drop, which finishes to be warming up at 25 DEG C, to be kept the temperature, and is disappeared after reacting 26h to point board raw material, is obtained compound
(Ⅲ)。
Step 2, the preparation of compound (IV): on the basis of step 1, in -15 DEG C of addition catalyst tetrabutyl phosphonium bromides
Then chlorinating agent sulfonic acid chloride 57.4g (0.425mol) is added dropwise in ammonium 0.4g, drop Bi Ziran rises to 25 DEG C, and heat preservation 22h is reacted,
Then 10 DEG C or less progress reactants separates instill reaction solution in 495g30% sodium citrate aqueous solution, and reaction solution is in paging
Layering, mucus are gradually sunk in funnel, there is heat release, and 8 DEG C rise to 15 DEG C, are dripped and are finished solution as pH3~4,42% hydrogen-oxygen of 32g is added dropwise
Change sodium solution and adjust pH=5, is warming up to 30~35 DEG C, separating has several layers of and water layer, and 30~35 DEG C of temperature control, organic layer 217g
23% sodium citrate solution washs 1h, then has separated several layers of and water layer, and organic layer 150g water washing is primary, and organic layer is pale yellow, water
Layer is colourless, and organic layer, which is concentrated under reduced pressure, to be done, and obtains light yellow oil object, the chlorobenzene dissolved clarification that 500g is added is stand-by, obtains intermediate product (IV).
The preparation of compound (I): step 3 at 25 DEG C, weighs N- benzoylcytosine 26.5g (0.123mol) first
With ammonium sulfate 0.37g in dry three-necked flask, hexamethyldisilazane 53g dispersion is then added dropwise, is warming up to 130 DEG C, returns
Stream is stirred to react to clarification, and hexamethyldisilazane is concentrated after reaction to no flow, adds 200g chlorobenzene to dissolve, obtains compound
(V) chlorobenzene solution is spare.
Under normal temperature and pressure, the chlorobenzene solution of the compound (IV) that step 2 is prepared is prepared with above-mentioned react
The chlorobenzene solution of compound (V) mixes, and 37.66g tin tetrachloride is then added dropwise in three-necked flask, is warming up to 70 DEG C of reactions,
To compound (IV) HPLC (chloro material) content less than 2% after for 24 hours.Concentration is evaporated chlorobenzene, adds methylene chloride 400 grams, water 100
Gram, it 200 grams of glacial acetic acid, is dispersed with stirring, crosses and filter out pink salt and excessive N- benzoylcytosine.Filtrate separates organic layer, then
It is that 50% glacial acetic acid solution is washed twice with mass fraction, 100g washing is primary, adds methanol 500g, and normal pressure is steamed to 55g, cooling, analysis
Suo Feibuwei intermediate (2'R)-N- benzoyl -2'- deoxidation -2'- fluoro- 2'- methylcytidine -3', 5'- is prepared in product out
Dibenzoate (I) 47.6g.
The fluoro- 2'- first of Suo Feibuwei intermediate (2'R)-N- benzoyl -2'- deoxidation -2'- is prepared in Examples 1 to 3
Base cytidine -3', 5'- dibenzoate (I), total recovery are that 57.6~60.5%, HLPC purity is 99.4~99.6% left sides
The right side, diastereoisomer: 0.14~0.16% or so.Fusing point: 234.1~240.5 DEG C, hydrogen spectrum (1H-NMR)(CDCl3,
500MHz): δ 1.48 (d, 3H), 4.62 (dd, 1H), 4.72 (d, 1H), 4.88 (d, 1H), 5.56 (br dd, 1H), 6.51 (br
d,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), elemental analysis (C31H26FN3O7, %) and (measured value/calculated value): C 65.14/65.02, H
4.59/4.66 N7.35/7.22.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.Any label in claim should not be construed as limiting the claims involved.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (6)
1. a kind of formula such as (I):
Shown in Suo Feibuwei intermediate preparation method, it is characterised in that: its preparation route are as follows:
The following steps are included:
(a) cooling in toluene first is added in red aluminum, passivator morphine is then instilled under -15~-10 DEG C of environment and toluene is mixed
It closes, is kept the temperature at -10 DEG C, then heat to the modified red aluminum solution for standby of 25 ± 5 DEG C of preparations；By compound 3,5- dibenzoyl-
The fluoro- 2 methyl-D-ribos-gamma lactone (II) of 2- deoxidation -2- is dissolved in toluene, and it is molten that modified red aluminum is added dropwise after being cooled to -20~-15 DEG C
Liquid carries out Chemoselective reduction and prepares intermediate product [the fluoro- 5- hydroxyl -4- first of (2R, 3R, 4R) -3- (benzoyl oxygen) -4-
Base tetrahydrofuran -2- base] methyl benzoic acid ester (III)；
(b) step (a) after reaction in, at -20~-10 DEG C in the reaction product of (a) step be added four fourth of catalyst
Base ammonium bromide and chlorinating agent sulfonic acid chloride, heat preservation carries out chlorination after 15~25 DEG C are warming up to after being added dropwise, and is prepared
Between product [the chloro- 4- methyltetrahydrofuran -2- base of (2R, 3R, 4R) -3- (benzoyl oxygen) the fluoro- 5- of -4-] methyl benzoic acid ester
(Ⅳ)；
(c) at 20~30 DEG C, N- benzoylcytosine (VI), ammonium sulfate and hexamethyldisilazane hybrid reaction rise
Chlorobenzene dissolution is added to concentration is clarified in warm return stirring, and the chlorobenzene for obtaining N- benzoyl-O- (trimethylsilyl) cytimidine (V) is molten
Liquid mixes the intermediate product (IV) that step (b) is prepared with the chlorobenzene solution of compound (V), and stannic chloride is added dropwise and carries out
Suo Feibuwei intermediate (2'R)-N- benzoyl -2'- deoxidation fluoro- 2'- methylcytidine -3' of -2'- is prepared in condensation reaction,
5'- dibenzoate (I).
2. a kind of preparation method of Suo Feibuwei intermediate according to claim 1, it is characterised in that: the step (a)
The mass fraction of middle red aluminum is 60~70%, and the mass ratio of the red aluminum and morphine is 3.5~4:1, and the cooling temperature is -20
~-10 DEG C, the soaking time is 20~40min.
3. a kind of preparation method of Suo Feibuwei intermediate according to claim 1, it is characterised in that: the step (a)
The molal weight ratio of compound (II) and modified red aluminum solution is 1:1.52~1.58, the Chemoselective reduction time is 20
~26h, the reaction temperature of the selective reduction are 0~30 DEG C, and the Chemoselective reduction carries out in contact plate.
4. a kind of preparation method of Suo Feibuwei intermediate according to claim 1, it is characterised in that: the step (b)
The mass ratio of middle tetrabutylammonium bromide and sulfonic acid chloride is 0.007~0.009:1, and the chlorination temperature is 15~25 DEG C, institute
Stating the chlorination time is 18~22h.
5. a kind of preparation method of Suo Feibuwei intermediate according to claim 1, it is characterised in that: the step (c)
The mass ratio of middle compound (VI), ammonium sulfate and hexamethyldisilazane is 0.3~0.5:0.006~0.007:1, the heating
Temperature is 110~130 DEG C.
6. a kind of preparation method of Suo Feibuwei intermediate according to claim 1, it is characterised in that: the step (c)
The mass ratio of middle stannic chloride and compound (II) is 0.7~0.8:1, and the compound (II) and the mass ratio of compound (V) are
1:1.7~1.8, the reaction time are 10~80 DEG C, the reaction time is 16~for 24 hours, the compound (IV) reaction terminates
The content of HPLC chloro material is 0~2%.
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| CN110981863A (en) * | 2019-12-24 | 2020-04-10 | 南京正大天晴制药有限公司 | Preparation method of β -glucoside compound with high stereoselectivity |
| 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 |
| CN113861249A (en) * | 2021-10-27 | 2021-12-31 | 江苏福瑞康泰药业有限公司 | Synthetic method of sofosbuvir intermediate |
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