CN106810541A - A kind of method that one-step method prepares Suo Feibuwei intermediates - Google Patents
A kind of method that one-step method prepares Suo Feibuwei intermediates Download PDFInfo
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- CN106810541A CN106810541A CN201611253859.9A CN201611253859A CN106810541A CN 106810541 A CN106810541 A CN 106810541A CN 201611253859 A CN201611253859 A CN 201611253859A CN 106810541 A CN106810541 A CN 106810541A
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- Prior art keywords
- suo feibuwei
- methyl
- intermediates
- step method
- feibuwei intermediates
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- 238000000034 method Methods 0.000 title claims abstract description 57
- 239000000543 intermediate Substances 0.000 title claims abstract description 31
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 12
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- 238000009413 insulation Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- -1 1- methyl Vinyl Chemical group 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229910006024 SO2Cl2 Inorganic materials 0.000 abstract description 4
- 230000003247 decreasing effect Effects 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 abstract description 2
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 abstract 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 abstract 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 4
- 239000012159 carrier gas Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of method that one-step method prepares Suo Feibuwei intermediates, chlorosulfuric acid is used by 2 C methyl 4,5 O (1 methyl ethylene) D arabinose acetoacetic esters（SO2Cl2）It is esterified.The method that one-step method of the present invention prepares Suo Feibuwei intermediates, the synthetic route is short, synthesis target product Suo Feibuwei intermediates are completed by a step, so as to by reducing reactions steps, simultaneously because eliminating oxidation step of the prior art, therefore raw materials consumption is greatly decreased with to reduce the generation of high-salt wastewater.
Description
Technical field
The invention belongs to organic compound synthesis technical field, in particular it relates in a kind of one-step method preparation Suo Feibuwei
The method of mesosome.
Background technology
Suo Feibuwei is Gilid Science Co. of the U.S.（GileadSciences, Inc. hereinafter referred to as " lucky moral "）Newly grind
The anti-hepatitis patent drug of hair, the product obtains FDA (Food and Drug Adminstration) in December, 2013（FDA）Approval, in 2014
January in year obtains European Union's approval, is the first granted medicine that can be used for the full oral treatment regimes of hepatitis C.The synthesis of prior art
Route, as shown in figure 1, from initiation material 2-C- methyl -4,5-O- (1- methyl ethylenes)-D-R acetoacetic ester（1）With
Sub- sulphur sulphonic acid ester (2) of thionyl chloride synthesis, then obtain sulphonic acid ester (3) through hypochlorite oxidation.It is long to there is synthetic route in the technique, and
And need complicated last handling process, because the technique is using a large amount of excessive sodium hypochlorite, during post processing must using it is substantial amounts of also
Former agent sodium sulfite is neutralized, and is returned this and is produced a large amount of brine wastes, and the technique uses stronger oxidizing agent sodium hypochlorite, wherein containing
Free chlorine, cause a large amount of side reactions to produce, therefore the yield is low, it is of poor quality.Additionally, the intermediate of synthetic route preparation
Total recovery is relatively low, and only 60% or so, it is unfavorable for industrial applications.
Therefore, above mentioned problem is urgently to be resolved hurrily.
The content of the invention
Goal of the invention：For the deficiencies in the prior art, Suo Feibuwei is prepared the invention provides a kind of one-step method
The method of intermediate, process route is long in solving prior art processes, and yield is low, poor product quality, and quantity of three wastes is big and is difficult place
The shortcomings of reason, it is more suitable for industrialization production requirements.
Technical scheme：The invention provides a kind of method that one-step method prepares Suo Feibuwei intermediates, by 2-C- methyl -4,
5-O- (1- methyl ethylenes)-D-R acetoacetic ester uses chlorosulfuric acid（SO2Cl2）It is esterified.It is of the present invention
The method that one-step method prepares Suo Feibuwei intermediates, the synthetic route is short, and synthesis target product Suo Feibuwei is completed by a step
Intermediate, so that by reducing reactions steps, while because eliminating oxidation step of the prior art, therefore former material is greatly decreased
Expect consumption with to reduce the generation of high-salt wastewater.Additionally, the method high income for preparing Suo Feibuwei intermediates of the present invention,
Total recovery brings up to more than 90% by the 60% of original technique.And good product quality is prepared, original process purity 90-95% is brown
Color liquid, the present invention can be stably obtained content up to more than 98% weak yellow liquid.
Further, the method that above-mentioned one-step method prepares Suo Feibuwei intermediates, is additionally added tiing up with catalytic performance
Sour agent is reacted.Acid binding agent with catalytic performance, can strengthen SO2Cl2Activity, reaches and not only improve yield purpose but also improve
The quality of target product.
It is preferred that the method that above-mentioned one-step method prepares Suo Feibuwei intermediates, it is characterised in that：The 2-C- methyl-
4,5-O- (1- methyl ethylenes)-D-R acetoacetic esters add solvent and acid binding agent, and 5- is reacted at 10-30 DEG C with chlorosulfuric acid
10 hours, reaction was finished, and through washing, anhydrous magnesium sulfate dries, dichloromethane is evaporated off and obtains.
It is preferred that the method that above-mentioned one-step method prepares Suo Feibuwei intermediates, 2-C- methyl -4,5-O- (1- first
Base vinyl)-D-R acetoacetic ester adds solvent and acid binding agent, and it is cooled under less than 15 DEG C, stirring condition and keeps 10-20
DEG C and be slowly added dropwise chlorosulfuric acid；After chlorosulfuric acid completion of dropwise addition, 10-30 DEG C is to slowly warm up to, and insulation 5-10 is small at this temperature
When；Insulation terminates to add water washing to separate organic phase, and organic phase is concentrated to dryness after being dried through anhydrous magnesium sulfate and obtains.
Further, the method that above-mentioned one-step method prepares Suo Feibuwei intermediates, 2-C- methyl -4,5-O- (1-
Methyl ethylene) mol ratio of-D-R acetoacetic ester and chlorosulfuric acid is 1：1.05-1.2.
Further, the method that above-mentioned one-step method prepares Suo Feibuwei intermediates, the acid binding agent is α-methylpyridine.
The special acid binding agent α-methylpyridine with catalytic performance is used simultaneously, enhances SO2Cl2Activity, reaches and both improve yield mesh
Improve the quality of target product again.
Further, the method that above-mentioned one-step method prepares Suo Feibuwei intermediates, the solvent is dichloromethane.
Beneficial effect：Compared with prior art, the present invention has advantages below：One-step method of the present invention prepares Suo Fei
The method of cloth Wei intermediate, advantage of the present invention is that former technological process is short, and high income, quality is good, moreover it is possible to raw material are greatly decreased and disappear
Consume with to reduce the generation of high-salt wastewater.Simultaneous reactions high income, steady quality is easy to industrialized production.
Brief description of the drawings
Fig. 1 is the synthetic route chart of the Suo Feibuwei intermediates of prior art of the present invention；
The synthetic route chart of Fig. 2 Suo Feibuwei intermediates of the present invention.
Specific embodiment
Below will be by several specific embodiments, the present invention is furture elucidated, these embodiments simply to illustrate that problem,
It is not a kind of limitation.
Embodiment 1
The synthetic route of Suo Feibuwei intermediates as shown in Figure 2, will be added in the reaction bulb of 1000ml 300g dichloromethane,
α-methylpyridine 70g, raw material 2-C- methyl -4,5-O- (1- methyl ethylenes)-D-R acetoacetic ester（1）150g
(0.57mol), is cooled to less than 15 DEG C, and being kept for 10-20 DEG C under stirring condition is slowly added dropwise chlorosulfuric acid 81g (0.60mol), sulphur
Acyl chlorides completion of dropwise addition, is to slowly warm up to 20-25 DEG C, and is incubated 8 hours at this temperature, and insulation terminates to add 300ml water washings
Organic phase is separated, organic phase is concentrated to dryness to obtain target product (3), 171.2g (0.53mol), yield after being dried through anhydrous magnesium sulfate
92.98%, GC purity 99.16%.(GC analysis condition detectors：Hydrogen flameionization（FID）Detector；Chromatogram column type number：DM-
5,30m0.25mmID0.25 μm；Carrier gas/flow：Nitrogen/0.1Mpa；Hydrogen：0.1Mpa；Column temperature：150℃；Perfusor temperature：
180℃；Detector temperature：190℃；Sample size：0.5µl)
Embodiment 2
The synthetic route of Suo Feibuwei intermediates as shown in Figure 2, will be added in the reaction bulb of 500ml 100g dichloromethane,
α-methylpyridine 25g, raw material 2-C- methyl -4,5-O- (1- methyl ethylenes)-D-R acetoacetic ester（1）50g
(0.19mol), is cooled to less than 15 DEG C, and being kept for 10-20 DEG C under stirring condition is slowly added dropwise chlorosulfuric acid 31.0g
(0.23mol), chlorosulfuric acid completion of dropwise addition is to slowly warm up to 25-30 DEG C, and is incubated 5 hours at this temperature, and insulation terminates to add
100ml water washings separate organic phase, and organic phase dries the product that obtain through anhydrous magnesium sulfate, and 50.4g (0.18mol) is received
Rate 94.74%, GC purity 99.04%.(GC analysis condition detectors：Hydrogen flameionization（FID）Detector；Chromatogram column type number：
DM-5,30m0.25mmID0.25 μm；Carrier gas/flow：Nitrogen/0.1Mpa；Hydrogen：0.1Mpa；Column temperature：150℃；Perfusor temperature
Degree：180℃；Detector temperature：190℃；Sample size：0.5µl)
Embodiment 3
The synthetic route of Suo Feibuwei intermediates as shown in Figure 2, will be added in the reaction bulb of 500ml 250g dichloromethane,
α-methylpyridine 60g, raw material 2-C- methyl -4,5-O- (1- methyl ethylenes)-D-R acetoacetic ester（1）100g
(0.38mol), is cooled to less than 15 DEG C, and being kept for 10-20 DEG C under stirring condition is slowly added dropwise chlorosulfuric acid 59.4g (0.44mol),
Chlorosulfuric acid completion of dropwise addition, is to slowly warm up to 15-20 DEG C, and is incubated 10 hours at this temperature, and insulation terminates to add 200ml washings
Wash and separate organic phase, organic phase dries the product that obtain through anhydrous magnesium sulfate, 113.5g (0.35mol), yield 92.10%,
GC purity 99.31%.(GC analysis condition detectors：Hydrogen flameionization（FID）Detector；Chromatogram column type number：DM-5,
30m0.25mmID0.25µm；Carrier gas/flow：Nitrogen/0.1Mpa；Hydrogen：0.1Mpa；Column temperature：150℃；Perfusor temperature：180
℃；Detector temperature：190℃；Sample size：0.5µl)
From embodiment 1-3, the synthetic method of Suo Feibuwei intermediates of the present invention, total recovery is by original technique
60% brings up to more than 90%.And quality is good, original process purity 90-95%, brown liquid, what the present invention can stablize
To content up to more than 98% weak yellow liquid.
The above is only several implementation methods of invention, it is noted that for those skilled in the art
For, on the premise of inventive principle is not departed from, some improvement can also be made, these improvement also should be regarded as protection of the invention
Scope.
Claims (7)
1. a kind of method that one-step method prepares Suo Feibuwei intermediates, it is characterised in that：By 2-C- methyl -4,5-O- (1- methyl
Vinyl)-D-R acetoacetic ester is esterified using chlorosulfuric acid.
2. the method that one-step method according to claim 1 prepares Suo Feibuwei intermediates, it is characterised in that：Being additionally added has
The acid binding agent of catalytic performance is reacted.
3. the method that one-step method according to claim 2 prepares Suo Feibuwei intermediates, it is characterised in that：The 2-C- first
Base -4,5-O- (1- methyl ethylenes)-D-R acetoacetic ester adds solvent and acid binding agent, anti-at 10-30 DEG C with chlorosulfuric acid
Answer 5-10 hours, reaction is finished, through washing, anhydrous magnesium sulfate dries, dichloromethane is evaporated off and obtains.
4. the method that one-step method according to claim 3 prepares Suo Feibuwei intermediates, it is characterised in that：The 2-C- first
Base -4,5-O- (1- methyl ethylenes)-D-R acetoacetic ester adds solvent and acid binding agent, is cooled to less than 15 DEG C, stirring
Under the conditions of kept for 10-20 DEG C and be slowly added dropwise chlorosulfuric acid；After chlorosulfuric acid completion of dropwise addition, 10-30 DEG C, and temperature herein are to slowly warm up to
Degree lower insulation 5-10 hours；Insulation terminates to add water washing to separate organic phase, and organic phase is concentrated into after being dried through anhydrous magnesium sulfate
It is dry to obtain.
5. the method that the one-step method according to claim any one of 1-4 prepares Suo Feibuwei intermediates, it is characterised in that：Institute
State 2-C- methyl -4, the mol ratio of 5-O- (1- methyl ethylenes)-D-R acetoacetic ester and chlorosulfuric acid is 1：1.05-1.2.
6. the method that the one-step method according to claim any one of 2-4 prepares Suo Feibuwei intermediates, it is characterised in that：Institute
Acid binding agent is stated for α-methylpyridine.
7. the method that the one-step method according to claim 3 or 4 prepares Suo Feibuwei intermediates, it is characterised in that：It is described molten
Agent is dichloromethane.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450148A (en) * | 2012-06-04 | 2013-12-18 | 浙江九洲药业股份有限公司 | Synthetic method of five-membered cyclic derivative sulfate compounds |
| CN102656154B (en) * | 2009-12-18 | 2014-04-09 | 天秤医药股份有限公司 | Process for preparing substituted 1-O-acyl-2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranoses |
| WO2014059901A1 (en) * | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | 2'-cyano substituted nucleoside derivatives and methods of use thereof for treatment of viral diseases |
| CN106083773A (en) * | 2016-05-31 | 2016-11-09 | 杭州惠诺医药科技有限公司 | 3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones |
| CN106146433A (en) * | 2015-03-26 | 2016-11-23 | 常州制药厂有限公司 | A kind of preparation method of the intermediate of Suo Feibuwei |
-
2016
- 2016-12-30 CN CN201611253859.9A patent/CN106810541A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102656154B (en) * | 2009-12-18 | 2014-04-09 | 天秤医药股份有限公司 | Process for preparing substituted 1-O-acyl-2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranoses |
| CN103450148A (en) * | 2012-06-04 | 2013-12-18 | 浙江九洲药业股份有限公司 | Synthetic method of five-membered cyclic derivative sulfate compounds |
| WO2014059901A1 (en) * | 2012-10-17 | 2014-04-24 | Merck Sharp & Dohme Corp. | 2'-cyano substituted nucleoside derivatives and methods of use thereof for treatment of viral diseases |
| CN106146433A (en) * | 2015-03-26 | 2016-11-23 | 常州制药厂有限公司 | A kind of preparation method of the intermediate of Suo Feibuwei |
| CN106083773A (en) * | 2016-05-31 | 2016-11-09 | 杭州惠诺医药科技有限公司 | 3,5 dibenzoyls 2 deoxygenate the preparation method of 2 fluorine 2 methyl D ribose gamma lactones |
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Application publication date: 20170609 |