CN109574961A - The method for preparing Suo Feibuwei intermediate - Google Patents
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention provides a kind of methods for preparing Suo Feibuwei intermediate.The described method comprises the following steps: 2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester cyclic sulfate and 4- phenyl -2- oxazolidone condensation reaction obtain the first compound；First compound and fluorization agent carry out fluorination reaction, and acid is then added and carries out deprotection reaction, obtains second compound；The second compound and sodium ethoxide reaction, obtain third compound；After the third compound carries out rearrangement reaction, rearrangement product reacts to obtain the Suo Feibuwei intermediate with chlorobenzoyl chloride.The method provided by the present application for preparing Suo Feibuwei intermediate provides new approaches for synthesis Suo Feibuwei intermediate.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, in particular to a kind of method for preparing Suo Feibuwei intermediate.
Background technique
Suo Feibuwei (English name Sofosbuvir, trade name Sovaldi) is slow for treating by the exploitation of lucky Leadd B.V
The drug of property hepatitis, is a kind of Hepatitis C Virus (HCV) nucleotide analog NS5B polymerase inhibitors.It is suitable as joining
Close composition treatment chronic hepatitis C (CHC) infection in antiviral therapy scheme.In December, 2013 through U.S.'s food and medicine
Surveillance Authority (FDA) approval lists in the U.S., and in January, 2014 is ratified in EU countries through European drug administration (EMEA)
City.2017 in Discussion on Chinese Listed.The drug global marketing total value reaches 9,000,000,000 U.S. dollars within 2017, have huge social value and
Commercial value.
During synthesizing Suo Feibuwei, the fluoro- 2- methyl D of 2R-2- deoxidation -2--erythro form pentonic acid-gamma lactone -3,
5- dibenzoate is the key intermediate of Suo Feibuwei.Wang et al. is using R- glyceraldehyde acetonide as raw material, with ethoxycarbonyl
Wittig reaction occurs for methylene triphenylphosphine, then cis- vicinal diol compound is obtained through potassium permanganate oxidation, with dichloro
Sulfoxide reaction cyclization, then through hypochlorite oxidation under tetramethyl piperidine nitrogen oxides (TEMPO) effect, it is then anti-through fluoro
It answers, then carries out cyclization under hydrochloric acid effect, finally carry out hydroxyl protection with chlorobenzoyl chloride (BzCl) and react to obtain the key
Intermediate.Mayers et al. first passes through esterification, is re-introduced into fluorine atom, then in acid item using hexa-atomic lactonic ring as raw material
Part reacts to obtain 5-membered ring compounds by cyclic condensation, then carries out hydroxyl protection with chlorobenzoyl chloride and react to obtain among the key
Body.Existing synthetic method there is a problem of more than at high cost, side reaction.
In view of this, the present invention is specifically proposed.
Summary of the invention
The purpose of the present invention is to provide a kind of method for preparing Suo Feibuwei intermediate, the method is at low cost, secondary
It reacts less, high income.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A method of Suo Feibuwei intermediate is prepared, the described method comprises the following steps:
A.2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester cyclic sulfate and 4- phenyl -2- are disliked
Oxazolidone condensation reaction obtains the first compound；
B. first compound and fluorization agent carry out fluorination reaction, and acid is then added and carries out deprotection reaction, obtain the
Two compounds；
C. the second compound and sodium ethoxide reaction, obtain third compound；
D. after the third compound carries out rearrangement reaction, rearrangement product reacts to obtain the Suo Feibuwei with chlorobenzoyl chloride
Intermediate；The structural formula of the Suo Feibuwei intermediate are as follows:
Using the reaction method, by ester amine exchange, selective fluorination, deprotection, transesterification, rearrangement and esterification,
Reaction impurities are few, stereoselectivity is good, the side reactions such as elimination reaction, high income do not occur.
Preferably, in the step A, 2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester
The molar ratio of cyclic sulfate and the 4- phenyl -2- oxazolidone is 1:1.5-2.0, and reaction dissolvent is toluene, catalyst 4-
Dimethylamino naphthyridine；Preferably, reaction temperature is 60-80 DEG C, and the reaction time is 8-12 hours.
It selects toluene as solvent, addition 4-dimethylaminopyridine as catalyst, helps to promote reaction efficiency, improve
Yield.Further preferred temperature and reaction time, it can be further improved yield.
It is further preferred that further including the first post-processing step in the step A:
System is cooled to 20-30 DEG C after reaction, with saturated common salt water washing, merges organic phase, is concentrated to get described
First compound.
System is isolated and purified after post treatment, the yield of the first compound can achieve 90-95%.
Preferably, in the fluorination reaction, the molar ratio of first compound and the fluorization agent is 1:1.8-2.0；
Preferably, solvent is anhydrous Isosorbide-5-Nitrae-dioxane, and the fluorization agent is tetraethyl ammonium fluoride, and reaction temperature is 105-115 DEG C, instead
It is 16-18 hours between seasonable.
It is further preferred that obtaining mixed liquor after the fluorination reaction, the mixed liquor, which is cooled to room temperature, adds 2,
2- dimethoxy propane and the acid are reacted；Preferably, the additive amount of the 2,2-dimethoxypropane is the mixing
10-15 times of liquid product, the acid are concentrated hydrochloric acid, and additive amount is the 1.0-1.5eq of first compound.
It participates in reacting using chiral auxiliary, efficiently solves fluorination reaction poor selectivity, the low problem of yield.
Preferably, further include the second post-processing step in the step B:
It after the deprotection reaction terminates, is extracted, is then sequentially washed with the first cleaning solution and the second cleaning solution
Desiccant dryness is added in the organic phase being obtained by extraction, and filtrate obtains the second compound through vacuum distillation after suction filtration；It is preferred that
Ground, the solvent used that extracts is ethyl acetate, and first cleaning solution is cold saturated sodium bicarbonate solution, and described second washes
Washing liquid is saturated salt solution, and the desiccant is anhydrous sodium sulfate.
By post-processing, the yield of second compound can achieve 80-85%.
Preferably, in the step C, reaction condition are as follows: heating reflux reaction 1-2 hours, ethyl acetate after fully reacting
The third compound is obtained by extraction；Preferably, the second compound and the molar ratio of the sodium ethoxide are 1:1.2-1.5,
The solvent of reaction system is dehydrated alcohol.
By the selection to reaction condition and reagent, the yield of third compound can achieve 90-95%.
Preferably, the rearrangement reaction are as follows: acid, stirring are added in the mixture of Xiang Suoshu third compound and dehydrated alcohol
Organic solvent azeotropic is added after fully reacting in mixed system and removes moisture, then vacuum distillation obtains the rearrangement product；
Preferably, the molar ratio of the third compound, the acid and the chlorobenzoyl chloride is 1:0.5:6.5-7, and the acid is hydrochloric acid,
Adding manner is to be added dropwise, and reaction temperature is room temperature, and the reaction time is 22-26 hours, and the organic solvent is toluene, the toluene
Additive amount be 2-4 times of the mixed system volume.
Preferably, the rearrangement product and the chlorobenzoyl chloride react are as follows:
The first solvent, the second solvent is added in the rearrangement product and obtains reaction mixture, by institute under the conditions of the first temperature
It states chlorobenzoyl chloride and the reaction mixture is added, carry out first segment reaction, rise to second temperature, continue second segment reaction, through the
Three post-processings obtain the Suo Feibuwei intermediate；Preferably, first solvent is acetonitrile, second solvent is pyridine,
First temperature is -2 to 0 DEG C, and the second temperature is 10-30 DEG C, and the time of the first segment reaction is 10-20min, institute
The time for stating second segment reaction is 40-60min.
It is further preferred that third post-processing are as follows: then second segment regulation system pH after reaction is extracted
To organic phase, washing, suction filtration obtain the Suo Feibuwei intermediate；Preferably, the pH is 6-7, and extractant is acetic acid second
Ester, cleaning solution are the saturated sodium bicarbonate solution and saturated salt solution sequentially used.
By rearrangement and esterification, Suo Feibuwei intermediate is obtained.Selection and rear place to reaction condition and reagent
Reason, the yield of Suo Feibuwei intermediate reach 75-80%.
Compared with prior art, the invention has the benefit that
(1) a kind of new approaches for synthesizing Suo Feibuwei intermediate are provided；
(2) side reaction is few, at low cost, processing is simple.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is the H spectrogram for the third compound that embodiment obtains；
Fig. 2 is the H spectrogram for the Suo Feibuwei intermediate that comparative example obtains；
Fig. 3 is the high-efficient liquid phase chromatogram for the Suo Feibuwei intermediate that embodiment obtains.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Embodiment 1
2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester epithio acid is taken according to molar ratio 1:1.5
Toluene reaction is added in salt, 4- phenyl -2- oxazolidone, and reaction temperature is 60 DEG C, and the reaction time is 12 hours.After reaction,
20 DEG C are cooled to, with saturated common salt water washing 2 times, merges organic phase, is concentrated to get yellow oil (the first compound), yield
It is 90%, is directly used in the next step.Reaction equation is as follows:
The first compound, tetraethyl ammonium fluoride, anhydrous Isosorbide-5-Nitrae-dioxane, the first compound and four are added in reaction flask
The molar ratio of ethyl ammonium fluoride is 1:2.0, and gained reaction mixture is heated to 105 DEG C, and solvent refluxing is stirred to react 16 hours.
After TLC (thin-layered chromatography) monitoring raw material reacts completely, reaction mixture is cooled to room temperature, 2,2-dimethoxypropane is added
(10 times of reaction mixture volumes), concentrated hydrochloric acid (1.0eq of the first compound), is stirred at room temperature 3 hours, thin-layered chromatography (TLC)
Monitoring raw material reacts completely.Ethyl acetate is added and extracts 3 times (10 times of volumes), collects organic phase, it is molten with cold saturated sodium bicarbonate
Liquid, saturated salt solution wash organic phase 2 times respectively, and anhydrous sodium sulfate drying is added, filters, filtrate obtains light through evaporating solvent under reduced pressure
Yellow oil (second compound), yield 85%, product purifies without isolation, is used for the next step.The following institute of reaction equation
Show:
Second compound, dehydrated alcohol, sodium ethoxide are added in reaction flask, the molar ratio of second compound and sodium ethoxide is
1:1.5 is heated to reflux 1 hour, after TLC (thin-layered chromatography) monitoring raw material reacts completely, is extracted with ethyl acetate 3 times, is merged
Ethyl acetate phase is concentrated to get yellow oil (third compound), yield 90%, and fusing point is 142-144 DEG C.Reaction equation is such as
Shown in lower:
Third compound, dehydrated alcohol are added in round-bottomed flask, hydrochloric acid is added dropwise to reaction mixture, it is small to be stirred at room temperature 22
When, thin-layered chromatography (TLC) monitoring raw material reacts completely.Toluene (2 times of volumes) is added and is azeotroped off moisture, evaporating solvent under reduced pressure
Obtain brown solid.Brown solid is dissolved in second eyeball (5 times of volumes), is added pyridine (1 times of volume), is stirred and cool down
To 0 DEG C, benzene first phthalein chlorine is added dropwise into reaction mixture, the molar ratio of third compound, hydrochloric acid and chlorobenzoyl chloride is 1:
0.5:6.5 stirs 10 minutes at 0 DEG C, is gradually increased to 30 DEG C, continues stirring 60 minutes.Dilute hydrochloric acid is added and adjusts pH=6, acetic acid
Ethyl ester extraction, collects organic phase, is washed respectively with saturated sodium bicarbonate solution, saturated salt solution, filters, filtrate is through rotary evaporation
Instrument obtains White crystal compound (Suo Feibuwei intermediate) after steaming solvent, yield 95%, and fusing point is 136-138 DEG C.Reaction
Formula is as follows:
Embodiment 2
2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester epithio acid is taken according to molar ratio 1:2.0
Toluene reaction is added in salt, 4- phenyl -2- oxazolidone, and reaction temperature is 80 DEG C, and the reaction time is 8 hours.After reaction,
30 DEG C are cooled to, with saturated common salt water washing 2 times, merges organic phase, is concentrated to get yellow oil (the first compound), yield
It is 95%, is directly used in the next step.
The first compound, tetraethyl ammonium fluoride, anhydrous Isosorbide-5-Nitrae-dioxane, the first compound and four are added in reaction flask
The molar ratio of ethyl ammonium fluoride is 1:2.0, and gained reaction mixture is heated to 115 DEG C, and solvent refluxing is stirred to react 18 hours.
After TLC (thin-layered chromatography) monitoring raw material reacts completely, reaction mixture is cooled to room temperature, 2,2-dimethoxypropane is added
(15 reaction mixture times volume), concentrated hydrochloric acid (1.5eq of the first compound), is stirred at room temperature 3 hours, thin-layered chromatography (TLC)
Monitoring raw material reacts completely.Ethyl acetate is added and extracts 3 times (10 times of volumes), collects organic phase, it is molten with cold saturated sodium bicarbonate
Liquid, saturated salt solution wash organic phase 2 times respectively, and anhydrous sodium sulfate drying is added, filters, filtrate obtains light through evaporating solvent under reduced pressure
Yellow oil (second compound), yield 80%, product purifies without isolation, is used for the next step.
Second compound, dehydrated alcohol, sodium ethoxide are added in reaction flask, the molar ratio of second compound and sodium ethoxide is
1:1.2 is heated to reflux 2 hours, after TLC (thin-layered chromatography) monitoring raw material reacts completely, is extracted with ethyl acetate 3 times, is merged
Ethyl acetate phase is concentrated to get yellow oil (third compound), yield 95%, and fusing point is 142-144 DEG C.
Third compound, dehydrated alcohol are added in round-bottomed flask, hydrochloric acid is added dropwise to reaction mixture, it is small to be stirred at room temperature 26
When, thin-layered chromatography (TLC) monitoring raw material reacts completely.Toluene (4 times of volumes) is added and is azeotroped off moisture, evaporating solvent under reduced pressure
Obtain brown solid.Brown solid is dissolved in second eyeball (5 times of volumes), is added pyridine (1.5 times of volumes), is stirred and drop
Benzene first phthalein chlorine is added dropwise into reaction mixture to -2 DEG C in temperature, and the molar ratio of third compound, hydrochloric acid and chlorobenzoyl chloride is 1:
0.5:7 stirs 20 minutes at -2 DEG C, is gradually increased to 10 DEG C, continues stirring 40 minutes.Dilute hydrochloric acid is added and adjusts pH=7, acetic acid second
Ester extraction, collects organic phase, is washed respectively with saturated sodium bicarbonate solution, saturated salt solution, filters, filtrate is through Rotary Evaporators
White crystal compound (Suo Feibuwei intermediate) is obtained after steaming solvent, yield 90%, fusing point is 136-138 DEG C.
Embodiment 3
2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester epithio acid is taken according to molar ratio 1:1.8
Toluene reaction is added in salt, 4- phenyl -2- oxazolidone, and reaction temperature is 70 DEG C, and the reaction time is 10 hours.After reaction,
25 DEG C are cooled to, with saturated common salt water washing 2 times, merges organic phase, is concentrated to get yellow oil (the first compound), yield
It is 92%, is directly used in the next step.
The first compound, tetraethyl ammonium fluoride, anhydrous Isosorbide-5-Nitrae-dioxane, the first compound and four are added in reaction flask
The molar ratio of ethyl ammonium fluoride is 1:1.9, and gained reaction mixture is heated to 110 DEG C, and solvent refluxing is stirred to react 17 hours.
After TLC (thin-layered chromatography) monitoring raw material reacts completely, reaction mixture is cooled to room temperature, 2,2-dimethoxypropane is added
(12 times of reaction mixture volumes), concentrated hydrochloric acid (1.2eq of the first compound), is stirred at room temperature 3 hours, thin-layered chromatography (TLC)
Monitoring raw material reacts completely.Ethyl acetate is added and extracts 3 times (10 times of volumes), collects organic phase, it is molten with cold saturated sodium bicarbonate
Liquid, saturated salt solution wash organic phase 2 times respectively, and anhydrous sodium sulfate drying is added, filters, filtrate obtains light through evaporating solvent under reduced pressure
Yellow oil (second compound), yield 81%, product purifies without isolation, is used for the next step.
Second compound, dehydrated alcohol, sodium ethoxide are added in reaction flask, the molar ratio of second compound and sodium ethoxide is
1:1.4 is heated to reflux 1.5 hours, after TLC (thin-layered chromatography) monitoring raw material reacts completely, is extracted with ethyl acetate 3 times, is closed
And ethyl acetate phase, it is concentrated to get yellow oil (third compound), yield 92%.
Third compound, dehydrated alcohol are added in round-bottomed flask, hydrochloric acid is added dropwise to reaction mixture, it is small to be stirred at room temperature 24
When, thin-layered chromatography (TLC) monitoring raw material reacts completely.Toluene (3 times of volumes) is added and is azeotroped off moisture, evaporating solvent under reduced pressure
Obtain brown solid.Brown solid is dissolved in second eyeball (5 times of volumes), is added pyridine (2 times of volumes), is stirred and cool down
To 0 DEG C, benzene first phthalein chlorine is added dropwise into reaction mixture, the molar ratio of third compound, hydrochloric acid and chlorobenzoyl chloride is 1:
0.5:6.5-7 stirs 15 minutes at 0 DEG C, is gradually increased to 20 DEG C, continues stirring 45 minutes.Dilute hydrochloric acid is added and adjusts pH=6.5,
Ethyl acetate extraction, collects organic phase, is washed respectively with saturated sodium bicarbonate solution, saturated salt solution, filters, filtrate is through rotating
Evaporimeter obtains White crystal compound (Suo Feibuwei intermediate) after steaming solvent, yield 93%, and fusing point is 136-138 DEG C.
Third compound (fluoro- 2- methyl -4,5- (the 1- methyl of the red valeric acid -2- deoxidation -2- of D- that embodiment is obtained respectively
Ethylidene)-ethyl ester) and Suo Feibuwei intermediate sterling progress Structural Identification, as depicted in figs. 1 and 2.
The parsing of Fig. 1 data are as follows:1H NMR (500MHz, CDCl3): 1.55 (d, 3H, J=22.4Hz), 2.24 (1H, br),
3.15 (1H, br), 3.70 (dd, 1H, J1=13.3Hz, J2=3.3Hz), 3.95 (dd, 1H, J1=13.3Hz, J2=
1.5Hz), 4.56 (1H, m), 4.12 (dd, 1H, J1=7.2Hz, J2=21.5Hz).
Fig. 2 data parsing are as follows: 1H NMR (500MHz, DMSO-d6): 1.68 (d, 3H, J=24.2Hz), 4.62-4.74
(m, 2H), 5.11-5.15 (m, 1H), 5.76 (dd, 1H, J1=7.0, J2=18.4Hz), 7.46 (m, 2H), 7.55 (m, 2H),
7.62(m,1H),7.70(m,1H),7.93(m,2H),8.06(m,2H),8.08(m,2H)。13C NMR(125MHz,DMSO-
d6):18.7,63.9,72.5,78.3,92.3,128.9,129.4,129.5,129.6,130.0,133.3,134.3,134.8,
165.4,165.9,170.2。
Suo Feibuwei intermediate 2R-2- deoxidation -2- fluoro- 2- methyl D-erythro form pentonic acid-gamma lactone -3,5- dibenzoic acid
The high-efficient liquid phase chromatogram of ester sterling is as shown in Figure 3.
Comparative example 1
Reaction obtains the Suo Feibuwei intermediate according to the following formula, and highest total recovery is 24.9%.
Comparative example 2
Reaction obtains the Suo Feibuwei intermediate according to the following formula, and highest total recovery is 16.4%.
The method that the application prepares Suo Feibuwei intermediate, fluorination reaction is selectively good, and post-processing is not needed by chirality
The means such as chromatography post separation；Chiral auxiliary is cheap and easy to get, easily sloughs, and reduces process costs；High-purity 2R-2- can effectively be obtained
The fluoro- 2- methyl D of deoxidation -2--erythro form pentonic acid-gamma lactone -3,5- dibenzoate, optical purity > 98；It is suitble to business metaplasia
It produces；Method provided by the invention is averaged total recovery as 59-70%.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of method for preparing Suo Feibuwei intermediate, which is characterized in that the described method comprises the following steps:
A.2-C- methyl -4, S-O- (1- methyl ethylidene)-D-arabinose acetoacetic ester cyclic sulfate and 4- phenyl -2- oxazolidine
Ketone condensation reaction obtains the first compound；
B. first compound and fluorization agent carry out fluorination reaction, and acid is then added and carries out deprotection reaction, obtains the second change
Close object；
C. the second compound and sodium ethoxide reaction, obtain third compound；
D. after the third compound carries out rearrangement reaction, rearrangement product and chlorobenzoyl chloride react to obtain among the Suo Feibuwei
Body；The structural formula of the Suo Feibuwei intermediate are as follows:
2. the method according to claim 1, wherein in the step A, 2-C- methyl -4, S-O- (1- first
Base ethylidene) molar ratio of-D-arabinose acetoacetic ester cyclic sulfate and the 4- phenyl -2- oxazolidone is 1:1.5-2.0,
Reaction dissolvent is toluene, and catalyst is 4-dimethylaminopyridine；Preferably, reaction temperature is 60-80 DEG C, reaction time 8-12
Hour.
3. according to the method described in claim 2, it is characterized in that, further including the first post-processing step in the step A:
System is cooled to 20-30 DEG C after reaction, with saturated common salt water washing, merges organic phase, is concentrated to get described first
Compound.
4. the method according to claim 1, wherein in the fluorination reaction, first compound and described
The molar ratio of fluorization agent is 1:1.8-2.0；Preferably, solvent is anhydrous Isosorbide-5-Nitrae-dioxane, and the fluorization agent is tetraethyl fluorine
Change ammonium, reaction temperature is 105-115 DEG C, and the reaction time is 16-18 hours.
5. described mixed according to the method described in claim 4, it is characterized in that, obtain mixed liquor after the fluorination reaction
It closes liquid and is cooled to room temperature and add 2,2- dimethoxy propane and the acid is reacted；Preferably, 2, the 2- dimethoxy
The additive amount of propane is 10-15 times of the mixeding liquid volume, and the acid is concentrated hydrochloric acid, and additive amount is first compound
1.0-1.5eq。
6. the method according to claim 1, wherein further including the second post-processing step in the step B:
It after the deprotection reaction terminates, is extracted, then sequentially washs extraction with the first cleaning solution and the second cleaning solution
Desiccant dryness is added in obtained organic phase, and filtrate obtains the second compound through vacuum distillation after suction filtration；Preferably, institute
Stating the solvent that extraction uses is ethyl acetate, and first cleaning solution is cold saturated sodium bicarbonate solution, second cleaning solution
For saturated salt solution, the desiccant is anhydrous sodium sulfate.
7. the method according to claim 1, wherein in the step C, reaction condition are as follows: heating reflux reaction
1-2 hours, the third compound was obtained by extraction in ethyl acetate after fully reacting；Preferably, the second compound with it is described
The molar ratio of sodium ethoxide is 1:1.2-1.5, and the solvent of reaction system is dehydrated alcohol.
8. the method according to claim 1, wherein the rearrangement reaction are as follows: Xiang Suoshu third compound and nothing
Acid is added in the mixture of water-ethanol, organic solvent azeotropic is added after being stirred to react completely in mixed system and removes moisture, so
Vacuum distillation obtains the rearrangement product afterwards；Preferably, the molar ratio of the third compound, the acid and the chlorobenzoyl chloride
For 1:0.5:6.5-7, the acid is hydrochloric acid, and adding manner is to be added dropwise, and reaction temperature is room temperature, and the reaction time is 22-26 hours,
The organic solvent is toluene, and the additive amount of the toluene is 2-4 times of the mixed system volume.
9. according to the method described in claim 8, it is characterized in that, the rearrangement product and the chlorobenzoyl chloride react are as follows:
The first solvent, the second solvent is added in the rearrangement product and obtains reaction mixture, by the benzene under the conditions of the first temperature
The reaction mixture is added in formyl chloride, carries out first segment reaction, rises to second temperature, continues second segment reaction, after third
Processing obtains the Suo Feibuwei intermediate；Preferably, first solvent is acetonitrile, second solvent is pyridine, described
First temperature is -2 to 0 DEG C, and the second temperature is 10-30 DEG C, and the time of first segment reaction is 10-20min, described the
The time of second-stage reaction is 40-60min.
10. according to the method described in claim 8, it is characterized in that, the third post-processes are as follows: the second segment reaction terminates
Regulation system pH afterwards, is then obtained by extraction organic phase, and washing, suction filtration obtain the Suo Feibuwei intermediate；Preferably, the pH
For 6-7, extractant is ethyl acetate, and cleaning solution is the saturated sodium bicarbonate solution and saturated salt solution sequentially used.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111848554A (en) * | 2020-08-03 | 2020-10-30 | 苏州开元民生科技股份有限公司 | Synthetic method of sofosbuvir intermediate impurity |
| CN114292154A (en) * | 2021-12-01 | 2022-04-08 | 上海泰坦科技股份有限公司 | Diphenylmethane compound and preparation method thereof |
| CN115925754A (en) * | 2022-10-24 | 2023-04-07 | 江苏阿尔法药业股份有限公司 | Catalytic synthesis process of sofosbuvir |
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| CN111848554B (en) * | 2020-08-03 | 2022-05-03 | 苏州开元民生科技股份有限公司 | Synthetic method of sofosbuvir intermediate impurity |
| CN114292154A (en) * | 2021-12-01 | 2022-04-08 | 上海泰坦科技股份有限公司 | Diphenylmethane compound and preparation method thereof |
| CN115925754A (en) * | 2022-10-24 | 2023-04-07 | 江苏阿尔法药业股份有限公司 | Catalytic synthesis process of sofosbuvir |
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