CN108675984A - The preparation method of Suo Feibuwei intermediates - Google Patents
The preparation method of Suo Feibuwei intermediates Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000000543 intermediate Substances 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- -1 sulfurous acid diesters Chemical class 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 239000002994 raw material Substances 0.000 claims description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 claims description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 150000004756 silanes Chemical group 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 claims 2
- 239000000654 additive Substances 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 229940092714 benzenesulfonic acid Drugs 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 claims 1
- 229960001826 dimethylphthalate Drugs 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000012805 post-processing Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 230000006837 decompression Effects 0.000 description 7
- BDUPRNVPXOHWIL-UHFFFAOYSA-N dimethyl sulfite Chemical compound COS(=O)OC BDUPRNVPXOHWIL-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000003963 dichloro group Chemical group Cl* 0.000 description 5
- 208000006154 Chronic hepatitis C Diseases 0.000 description 4
- 208000005176 Hepatitis C Diseases 0.000 description 4
- 208000010710 hepatitis C virus infection Diseases 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- 229940076563 sovaldi Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation methods of Suo Feibuwei intermediates, the method for preparing intermediate is reacted with sulfurous acid diesters using substrate, the apparent chloride impurity generated in production procedure among subsequent reactions can not only effectively be avoided, and it is used reagent environmental protection, safety, preparation method economy, simplicity, post-processing is simple, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation methods of Suo Feibuwei intermediates, belong to field of medicine and chemical technology.
Background technology
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 in the new drug for the treatment of chronic hepatitis C, in 6 Nikkei U.S. Food and Drug Administration (FDA) approval December in 2013 in U.S.
State lists, and January in 2014, the approval of 16 Nikkei Europe drug administration (EMEA) was listed in EU countries.
Suo Feibuwei is a kind of Hepatitis C Virus (HCV) nucleotide analog NS5B polymerase inhibitors, while Suo Fei
Bu Wei is also currently the only using NS5B polymerases as the marketed drug of target spot.It is used to treat chronic hepatitis C, especially
The composition treatment chronic hepatitis C (CHC) being suitable as in combination antiviral therapy scheme infects.Suo Feibuwei is through experiment
Confirm therapeutic gene 1,2,3 or 4 type hepatitis subjects to include effectively the liver cell for meeting Milan standard and waiting for liver transfer operation
Cancer subject and HCV/HIV-1 concurrent infection subjects.
There is extremely important market value in view of Suo Feibuwei, therefore, research and development the grinding as this field of Suo Feibuwei
Study carefully hot spot.Currently, having there is the report of some patents or non-patent literature for the preparation method of Suo Feibuwei.For example, exist
WO 2008045419, JOC, 2,011 76 (20), 8311-8319, J Med Chem, 2010,53 (19): 7202 -
7218 etc. report the synthesis technology of Suo Feibuwei, and synthetic route can be simply expressed as：
。
Wherein formula B is the important intermediate substance of Suo Feibuwei synthesis.At present for the synthesis major way of formula B compounds
Including acylated method, oxidizing process etc..
During acylated method synthesis formula B compounds, inevitably it is intended at present using chlorine such as thionyl chloride, sulfonic acid chlorides
Change reagent.These chlorination reagents not only pollute greatly, but also not environmentally.Simultaneously as the chlorination reagents such as thionyl chloride and sulfonic acid chloride
After addition, chloride impurity SF-Cl is easy tod produce, structure is as follows：
；
Therefore, how effectively to avoid generating chloride impurity in subsequent preparation process, and this preparation method is economic, letter
Just, it is suitable for the mode of industrialized production, and the reaction reagent that it is used should also be as being environmental protection, safety.This just becomes
Those skilled in the art's technical issues that need to address in Suo Feibuwei preparation processes research and development at present.
Invention content
The technical problem to be solved by the present invention is to, it avoids introducing chlorination reagent in the building-up process of compound B, and
Chloride impurity is generated in the subsequent synthesis of Suo Feibuwei.Meanwhile a kind of suitable synthesis path is found, it avoids sub- using dichloro
Sulfone, sulfonic acid chloride etc. not environmentally, unfriendly reagent.
In order to solve the above-mentioned technical problem, the invention discloses a kind of preparation method of Suo Feibuwei intermediates, the preparations
Method and process route is as follows：
,
Wherein, R1, R2For silanes protecting group, benzyl class protecting group, or one kind in the acetals protecting group that is collectively formed；
R3, R4For alkyl, aryl, aralkyl.
Specifically include following steps：
1）It using compound II as raw material, is dissolved in the first solvent, and sulfurous acid diesters is added into the system（Compound
Ⅲ）, the first catalyst；Then it at a temperature of 70-80 DEG C, is heated to that there is no alcohol to steam, adjusts pH to 7-8, contained
The reaction mixture of compounds Ⅳ；
2）Acetonitrile solvent is added into the reaction mixture obtained in step 1, and TEMPO is added under conditions of 0 ± 0.2 DEG C
（Tetramethyl piperidine）And sodium bicarbonate, it is then slowly added into NaClO solution, stirring at normal temperature 1 hour obtains chemical compounds I.
As a preferred technical solution, after being steamed there is no alcohol in step 1, continues stirring to the reaction was complete, be cooled to
Room temperature, and reaction mixture is poured slowly into water, then adjust pH to 7-8.
And further preferred scheme is the purification step for further including chemical compounds I, specially that chemical compounds I product is molten
Liquid concentrates, and dichloromethane is used in combination to extract, water washing, and anhydrous sodium sulfate drying is concentrated under reduced pressure to give pale yellowish oil compounds
Ⅰ。
Wherein, the first solvent is preferably toluene.
Meanwhile further preferably the first catalyst is p-methyl benzenesulfonic acid or methanesulfonic acid or p-methyl benzenesulfonic acid in the present invention
With the mixture of methanesulfonic acid.
It is further preferred that in step 1, pH to 7-8. is adjusted using sodium carbonate or triethylamine
Further preferred embodiment is that sulfurous acid diesters are dimethyl sulfite.
Meanwhile we are further disclosed in the present invention as a preferred technical solution, compound II：Sulfurous acid two
Ester：The molar ratio of first catalyst is 1：（1~3）：（0.01~0.1）.
It is further preferred that compound II：Sulfurous acid diesters：The molar ratio of first catalyst is 1：（1.05~1.15）：
（0.01~0.05）.
In addition, as other optimal technical scheme, we are also disclosed in the present invention, MCompound ii（g）：MTEMPO（mg）:
VNaClO（mL）=1：（1~10）：（1~20）Further preferably, MCompound ii（g）：MTEMPO（mg）: MNaClO（mL）=1：（5.5~
10）：（10~11）, and the molar ratio of compound ii and sodium bicarbonate is 1：（1~10）, particularly preferred compound ii and carbon
The molar ratio of sour hydrogen sodium is 1：2.
It should be understood that since step 1 and step 2 are reacted by one-step method.That is in the first step
After rapid, purification procedures are not present, therefore in the adding procedure of follow-up raw material, using MCompound iiTo measure.
As a kind of perferred technical scheme, a concentration of 10%-13% of NaClO solution.
Room temperature refers to 25 ± 5 DEG C in the present invention.
The present invention provides a kind of preparation method of Suo Feibuwei intermediates, change sulfonic acid chloride that previous tradition uses,
The method that thionyl chloride prepares intermediate reacts the method for preparing intermediate using substrate with sulfurous acid diesters, can not only be effective
The apparent chloride impurity generated in production procedure among subsequent reactions is avoided, and is used reagent environmental protection, safety, system
Preparation Method economy, simplicity, post-processing is simple, is suitable for industrialized production.
Specific implementation mode
In order to better understand the present invention, below we the present invention will be further elaborated in conjunction with specific embodiments.
Embodiment 1
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, dimethyl sulfite（37.55g 0.341 mol）, toluene 800mL, p-methyl benzenesulfonic acid（2.58g 0.015mol）,
70-80 DEG C is stirred to react, and then has methanol to distillate, and after eliminating methanol, is stirred for having reacted to raw material for a period of time, be cooled to
Room temperature is poured into water, and PH to 7-8 is adjusted with sodium carbonate, and after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloro is added
Methane, cold water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, then add
Enter TEMPO catalyst 455mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
820mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（87.42g 94%）.
Embodiment 2
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, sulfurous acid diisopropyl ester（56.69g 0.341 mol）, toluene 800mL, methanesulfonic acid（1.44g 0.015mol）, 70-
80 DEG C are stirred to react, and then have methanol to distillate, and after eliminating methanol, are stirred for having reacted to raw material for a period of time, are cooled to room
Temperature is poured into water, and PH to 7-8 is adjusted with sodium carbonate, and after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloromethane is added
Alkane, cold water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, adds
TEMPO catalyst 455mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
820mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（86.96g 93.5%）.
Embodiment 3
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, dimethyl sulfite（37.55g 0.341 mol）, toluene 800mL, methanesulfonic acid（1.44g 0.015mol）, 70-80
It DEG C is stirred to react, then there is methanol to distillate, after eliminating methanol, be stirred for a period of time has reacted to raw material, is cooled to room temperature,
It is poured into water, PH to 7-8 is adjusted with sodium carbonate, after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloromethane is added,
Cold water washs, and anhydrous sodium sulfate drying is concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, adds
TEMPO catalyst 455mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
820mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（85.6g 92%）.
Embodiment 4
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, dimethyl sulfite（37.55g 0.341 mol）, toluene 800mL, p-methyl benzenesulfonic acid（2.58g 0.015mol）,
70-80 DEG C is stirred to react, and then has methanol to distillate, and after eliminating methanol, is stirred for having reacted to raw material for a period of time, be cooled to
Room temperature is poured into water, and PH to 7-8 is adjusted with sodium carbonate, and after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloro is added
Methane, cold water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, then add
Enter TEMPO catalyst 745mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
745mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（82.77g 89%）.
Embodiment 5
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, dimethyl sulfite（34.69g 0.315 mol）, toluene 800mL, p-methyl benzenesulfonic acid（0.516g, 0.003mol）,
70-80 DEG C is stirred to react, and then has methanol to distillate, and after eliminating methanol, is stirred for having reacted to raw material for a period of time, be cooled to
Room temperature is poured into water, and PH to 7-8 is adjusted with sodium carbonate, and after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloro is added
Methane, cold water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, then add
Enter TEMPO catalyst 455mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
820mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（74.4g 80%）.
Embodiment 6
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, dimethyl sulfite（37.55g 0.341 mol）, toluene 800mL, p-methyl benzenesulfonic acid（2.58g 0.015mol）,
70-80 DEG C is stirred to react, and then has methanol to distillate, and after eliminating methanol, is stirred for having reacted to raw material for a period of time, be cooled to
Room temperature is poured into water, and PH to 7-8 is adjusted with sodium carbonate, and after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloro is added
Methane, cold water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, then add
Enter TEMPO catalyst 745mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
745mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（85.6g 92%）.
Embodiment 7
Chemical compounds I synthesis detailed process be：In the reaction bulb equipped with vacuum distillation apparatus, compound ii is added（74.5g,
0.3mol）, dimethyl sulfite（34.7g, 0.315 mol）, toluene 800mL, p-methyl benzenesulfonic acid（0.52g, 0.003mol）,
70-80 DEG C is stirred to react, and then has methanol to distillate, and after eliminating methanol, is stirred for having reacted to raw material for a period of time, be cooled to
Room temperature is poured into water, and PH to 7-8 is adjusted with sodium carbonate, and after removing p-methyl benzenesulfonic acid, toluene is recovered under reduced pressure in liquid separation, and dichloro is added
Methane, cold water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure to give yellow oil.At 0 DEG C, anhydrous acetonitrile is added, then add
Enter TEMPO catalyst 455mg and sodium bicarbonate（50.4g 0.6mol）.NaClO solution is slowly added at 0 DEG C（10-13%,
820mL）, stirring at normal temperature reaction 1h.Concentration organic phase is simultaneously extracted, water washing with dichloromethane, anhydrous sodium sulfate drying, and decompression is dense
Contracting obtains light yellow oil chemical compounds I（83.7g 90%）.
The above is the specific implementation mode of the present invention.It should be pointed out that for those skilled in the art
For, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also considered as
Protection scope of the present invention.
Claims (10)
1. the preparation method of Suo Feibuwei intermediates, which is characterized in that the preparation method process route is as follows：
,
Wherein, R1, R2For silanes protecting group, benzyl class protecting group, or one kind in the acetals protecting group that is collectively formed；R3,
R4For alkyl, aryl, aralkyl.
2. the preparation method of Suo Feibuwei intermediates according to claim 1, which is characterized in that specifically include following step
Suddenly：
1）It using compound II as raw material, is dissolved in the first solvent, and sulfurous acid diesters is added into the system（Compound
Ⅲ）, the first catalyst；Then it at a temperature of 70-80 DEG C, is heated to that there is no alcohol to steam, adjusts pH to 7-8, obtain containing change
Close the reaction mixture of object IV；
2）Acetonitrile solvent is added into the reaction mixture obtained in step 1, and TEMPO is added under conditions of 0 ± 0.2 DEG C
（Tetramethyl piperidine）And sodium bicarbonate, it is then slowly added into NaClO solution, stirring at normal temperature 1 hour obtains chemical compounds I.
3. the preparation method of Suo Feibuwei intermediates according to claim 2, it is characterised in that：When in step 1 there is no
After alcohol steams, continues stirring to the reaction was complete, be cooled to room temperature, and reaction mixture is poured slowly into water, then adjust
Save pH to 7-8.
4. the preparation method of Suo Feibuwei intermediates according to claim 2, it is characterised in that：It further include chemical compounds I
Chemical compounds I reaction mixture is specially concentrated, dichloromethane is used in combination to extract by separating step, water washing, anhydrous sodium sulfate drying,
It is concentrated under reduced pressure to give light yellow oil chemical compounds I.
5. the preparation method of Suo Feibuwei intermediates according to claim 2, it is characterised in that：First solvent is preferably first
Benzene.
6. the preparation method of Suo Feibuwei intermediates according to claim 2, it is characterised in that：First catalyst is to first
The mixture of benzene sulfonic acid or methanesulfonic acid or p-methyl benzenesulfonic acid and methanesulfonic acid.
7. the preparation method of Suo Feibuwei intermediates according to claim 2, it is characterised in that：Carbonic acid is utilized in step 1
Sodium or triethylamine adjust pH to 7-8.
8. the preparation method of Suo Feibuwei intermediates according to claim 2, it is characterised in that：Sulfurous acid diesters are sulfurous
Dimethyl phthalate.
9. the preparation method of Suo Feibuwei intermediates according to claim 2, which is characterized in that the additive amount of each substance selects
From following any mixed proportion：
A. compound II：Sulfurous acid diesters：The molar ratio of first catalyst is 1：（1~3）：（0.01~0.1）；
B. compound II：Sulfurous acid diesters：The molar ratio of first catalyst is 1：（1.05~1.15）：（0.01~0.05）；
C.MCompound ii（g）：MTEMPO（mg）: VNaClO（mL）=1：（1~10）：（1~20）；
D.MCompound ii（g）：MTEMPO（mg）: MNaClO（mL）=1：（5.5~10）：（10~11）；
E. the molar ratio of compound ii and sodium bicarbonate is 1：（1~10）；
F. the molar ratio of compound ii and sodium bicarbonate is 1：2.
10. the preparation method of Suo Feibuwei intermediates according to claim 2, which is characterized in that the concentration of NaClO solution
For 10%-13%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159388A (en) * | 2020-09-30 | 2021-01-01 | 湖南阿斯达新材料有限公司 | Preparation method of vinyl sulfate derivative |
| CN115322170A (en) * | 2022-08-29 | 2022-11-11 | 苏州华一新能源科技股份有限公司 | A kind of preparation method of vinyl sulfate |
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| CN1803767A (en) * | 2005-01-12 | 2006-07-19 | 中国科学院福建物质结构研究所 | Method for preparing glycol sulfite |
| CN101600725A (en) * | 2006-10-10 | 2009-12-09 | 法莫赛特股份有限公司 | Preparation of ribofuranosyl pyrimidine nucleosides |
| US20140364446A1 (en) * | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
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| CN1803767A (en) * | 2005-01-12 | 2006-07-19 | 中国科学院福建物质结构研究所 | Method for preparing glycol sulfite |
| CN101600725A (en) * | 2006-10-10 | 2009-12-09 | 法莫赛特股份有限公司 | Preparation of ribofuranosyl pyrimidine nucleosides |
| US20140364446A1 (en) * | 2013-06-05 | 2014-12-11 | Idenix Pharmaceuticals, Inc. | 1',4'-thio nucleosides for the treatment of hcv |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112159388A (en) * | 2020-09-30 | 2021-01-01 | 湖南阿斯达新材料有限公司 | Preparation method of vinyl sulfate derivative |
| CN112159388B (en) * | 2020-09-30 | 2022-10-11 | 湖南阿斯达新材料有限公司 | Preparation method of vinyl sulfate derivative |
| CN115322170A (en) * | 2022-08-29 | 2022-11-11 | 苏州华一新能源科技股份有限公司 | A kind of preparation method of vinyl sulfate |
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