CN107235872A - A kind of preparation method of the red sugar alcohol of two sulphur - Google Patents
A kind of preparation method of the red sugar alcohol of two sulphur Download PDFInfo
- Publication number
- CN107235872A CN107235872A CN201611235712.7A CN201611235712A CN107235872A CN 107235872 A CN107235872 A CN 107235872A CN 201611235712 A CN201611235712 A CN 201611235712A CN 107235872 A CN107235872 A CN 107235872A
- Authority
- CN
- China
- Prior art keywords
- formula
- nitrae
- isosorbide
- sugar alcohol
- red sugar
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/06—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols from sulfides, hydropolysulfides or polysulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Abstract
The invention discloses a kind of method for preparing the red sugar alcohol of two sulphur, including step：(a) by initiation material along the butylene of Isosorbide-5-Nitrae dichloro 2 under cryogenic, occur cis dihydroxylation reaction with potassium permanganate, obtain the butanol of 1.4 dichloro of formula (I) 2,3 two；(b) butanol of formula (I) Isosorbide-5-Nitrae dichloro 2,3 two is added into organic base, carries out esterification with acetic anhydride, obtain the diacetate esters of formula (II) Isosorbide-5-Nitrae dichloro 2,3；(c) with thioacetic acid potassium under the catalytic action of sodium iodide nucleophilic substitution occurs for the diacetate esters of formula (II) Isosorbide-5-Nitrae dichloro 2,3, obtains the acetic acid esters of two ethanethioyl of formula (III) Isosorbide-5-Nitrae 2,3；(d) acetic acid esters of two ethanethioyl of formula (III) Isosorbide-5-Nitrae 2,3 is hydrolyzed in acid condition, obtains the red sugar alcohol of sulphur of target product formula (IV) two.Synthesis cost of the invention is low, synthetic route is short, easy to operate, security is good, product quality is high, yield is high, meet the requirement of industrialized production.
Description
Technical field
The present invention relates to technical field of compound preparation, and in particular to the preparation method of the red sugar alcohol of two sulphur.
Background technology
The red sugar alcohol of two sulphur (DTE) is a stereoisomer of dithiothreitol (DTT) (DTT).DTT two hydroxyls are Soviet Union's formulas
Configuration, DTE two hydroxyls are erythro form configurations.DTE can as sulfhydrylation DNA reducing agent and deprotection agent, be also commonly used for egg
The reduction of disulfide bond in white matter, in the protein molecule that prevents to be formed between the cysteine in protein or intermolecular
Disulfide bond, its structural formula is：
The double hydroxyls for building erythro form configuration are to synthesize one of DTE difficult point, and the synthetic method on the red sugar alcohol of two sulphur rarely has
Document report.The present invention carries out the product that cis addition obtains erythro form configuration on cis-form olefin, successfully develops a system
The synthetic method of the red sugar alcohol of standby two sulphur.The synthetic method route is short, can obtain preferable yield, with applying valency well
Value.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of method for preparing the red sugar alcohol of two sulphur, with cheap and easy to get
Cis- Isosorbide-5-Nitrae-dichloro-2-butene is raw material, occurs cis dihydroxylation reaction with potassium permanganate first, obtains the centre of erythro form configuration
Body (I), then again by steps such as esterification (acetyl group protection), nucleophilic substitution, hydrolysis, prepares the red sugar of two sulphur
Alcohol.This method synthetic route is brief, easy to operate, cost is low, yield is high, be easy to the advantage of industrialized production.
To achieve these goals, the technical solution adopted by the present invention is：
A kind of method for preparing the red sugar alcohol of two sulphur, comprises the following steps：
(a) cis- Isosorbide-5-Nitrae-dichloro-2-butene is dissolved in the first reaction dissolvent, under cryogenic, occurred with potassium permanganate
Cis dihydroxylation reaction, obtains the chloro- butanol of 2,3- bis- of formula (I) Isosorbide-5-Nitrae-two；
(b) the chloro- butanol of 2,3- bis- of formula (I) Isosorbide-5-Nitrae-two for preparing step (a) is dissolved in the second reaction dissolvent, and it is appropriate to add
Organic base, with acetic anhydride occur esterification, obtain chloro- 2, the 3- diacetate esters of formula (II) Isosorbide-5-Nitrae-two；
(c) in the 3rd reaction dissolvent, by step (b) prepare chloro- 2, the 3- diacetate esters of formula (II) Isosorbide-5-Nitrae-two with it is thio
Under the catalytic action of sodium iodide nucleophilic substitution occurs for potassium acetate, obtains formula (III) ethanethioyl -2,3- second of Isosorbide-5-Nitrae-two
Acid esters；
(d) in the 4th reaction dissolvent, step (c) prepare formula (III) ethanethioyl -2,3- of Isosorbide-5-Nitrae-two acetic acid esters with
Hydrolysis occurs for acid reagent, obtains the red sugar alcohol of sulphur of target product formula (IV) two.
Shown in course of reaction such as route (1)：
Wherein, in step (a)：
First reaction dissolvent is selected from：The mixed liquor of the mixed liquor of water and acetone, water and the tert-butyl alcohol.Preferably water and
The mixed liquor of acetone, volume ratio is 1：1.5~3；Or the preferably mixed liquor of water and the tert-butyl alcohol, volume ratio is 1：1.5~3；
The ratio between mole of the cis- Isosorbide-5-Nitrae-dichloro-2-butene and potassium permanganate is 1：1.0~1.5；Preferably, 1:
1.2；Preferably, the feed postition of potassium permanganate is to be added portionwise.
The cryogenic conditions of the cis dihydroxylation reaction are -5 DEG C~5 DEG C；Preferably, 0 DEG C~5 DEG C.
The time of the cis dihydroxylation reaction is 3~5 hours；Preferably, it is 5 hours.
Preferably, described in step (a) after the completion of dihydroxylation reaction, step can also be included：Add after diatomite stirring
Suction filtration, is extracted with appropriate solvent, is washed, and is dried, is evaporated, and uses ethyl acetate with petroleum ether volume ratio for 1：5 progress mashing are pure
Change.Extracting the solvent used includes dichloromethane, chloroform, ethyl acetate.
Wherein, in step (b)：
Second reaction dissolvent be dichloromethane, chloroform, toluene, N,N-dimethylformamide, acetonitrile, tetrahydrofuran or
Acetic anhydride；Preferably, it is dichloromethane.
The organic base is pyridine, triethylamine, DMAP or N, N- DIC；Preferably,
For triethylamine.
The ratio between the chloro- butanol of 2,3- bis- of formula (I) Isosorbide-5-Nitrae-two and organic base, the mole of acetic anhydride are 1：1.0-1.5：
2.0~2.5；Preferably, the ratio between the chloro- butanol of 2,3- bis- of formula (I) Isosorbide-5-Nitrae-two and organic base, the mole of acetic anhydride are 1：
1.0：2.2.
The temperature of the esterification is 50 DEG C~80 DEG C；Preferably, it is 70 DEG C.
The time of the esterification is 5~8 hours；Preferably, it is 8 hours.
Preferably, in step (b), after the completion of the reaction, in addition to step：The solvent is steamed, is extracted with appropriate solvent
Take, wash, drying is evaporated.
Wherein, in step (c)：
3rd reaction dissolvent is DMF or absolute ethyl alcohol；Preferably, it is N, N- dimethyl formyls
Amine.
The ratio between chloro- 2, the 3- diacetate esters of formula (II) Isosorbide-5-Nitrae-two, thioacetic acid potassium, mole of sodium iodide are 1：2.0
~3.0：0.05；Preferably, chloro- 2, the 3- diacetate esters of formula (II) Isosorbide-5-Nitrae-two, thioacetic acid potassium, sodium iodide mole it
Than for 1:2.20:0.05.
The temperature of the nucleophilic substitution is 60 DEG C~90 DEG C；Preferably, it is 80 DEG C~90 DEG C.
The time of the nucleophilic substitution is 3~5 hours；Preferably, it is 5 hours.
Preferably, described in step (c) after the completion of nucleophilic substitution, in addition to step：Extracted with appropriate solvent, water
Wash, organic layer activated carbon decolorizing, dry, be evaporated, use ethyl acetate with petroleum ether volume ratio for 1：5 carry out mashing purifying.
Extracting the solvent used includes dichloromethane, chloroform, ethyl acetate.
Wherein, in step (d)：
4th reaction dissolvent is methanol or ethanol；Preferably, it is methanol.
The acid reagent is hydrochloric acid, chloroacetic chloride or acetic acid；Preferably, it is chloroacetic chloride.
The ratio between mole of ethanethioyl -2, the 3- acetic acid esters of formula (III) 1.4- bis- and acid reagent is 1：2.0~
3.0；Preferably, the ratio between mole of ethanethioyl -2, the 3- acetic acid esters of formula (III) 1.4- bis- and acid reagent is 1:3.
The temperature of the hydrolysis is 20 DEG C~25 DEG C；Preferably, it is 25 DEG C.
The time of the hydrolysis is 4~7 hours；Preferably, it is 7h.
Preferably, after the completion of being reacted described in step (d), in addition to step：Solvent evaporated, using ethyl acetate and oil
Ether volume ratio is 1：3 carry out mashing purifying.
The beneficial effects of the present invention are：(1) present invention uses cis- Isosorbide-5-Nitrae-dichloro-2-butene for raw material, by double hydroxyls
The reaction such as change, esterification, nucleophilic displacement of fluorine, hydrolysis obtains the red sugar alcohol of the sulphur of compound two, and synthetic route is brief, and high income, yield is reachable
78%；(2) present invention is not related to the use of expensive reagent, and cost is low；That (3) synthetic method of the invention is related to is easy to operate,
Condition is easily-controllable, it is easy to industrialized production.
Embodiment
With reference to specific examples below, the present invention is described in further detail.Implement the present invention process, condition,
Experimental method etc., is the universal knowledege and common knowledge of this area in addition to the following content specially referred to, the present invention does not have
Especially limit content.
Embodiment 1
It is in there-necked flask that the cis- Isosorbide-5-Nitrae-dichloro-2-butenes of 10g (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) is molten
In 60mL acetone and 20mL water, fall into frozen water to warm for 0 DEG C -5 DEG C in system, 15.16g potassium permanganate is added in three batches
(Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure).Reaction 5 hours, complete with TLC monitoring raw material reactions, suction filtration removes solid
Body, adds suction filtration after proper amount of active carbon stirring, and decompression boils off acetone, adds ethyl acetate, is washed with saturated nacl aqueous solution, point
Go out organic phase, anhydrous sodium sulfate drying is evaporated, use ethyl acetate with petroleum ether volume ratio for 1：6 temperature rising reflux are beaten
Purifying.Obtain the chloro- butanol 8.5g of 2,3- bis- of product formula (I) Isosorbide-5-Nitrae-two, yield 67%.
1HNMR(400MHz,CDCl3):δ=2.39 (s, 2H), 3.79-3.84 (m, 4H), 3.89 (d, 2H) .MS (ESI):
calculated for[C4H8Cl2O2H]+(M+H)+Requires m/z=159.99, found:159.99.
It is in there-necked flask that the cis- Isosorbide-5-Nitrae-dichloro-2-butenes of 10g (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) is molten
In 60mL acetone and 20mL water, fall into frozen water to warm for 0 DEG C -5 DEG C in system, 15.16g potassium permanganate is added in three batches
(Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure).Reaction 3 hours, complete with TLC monitoring raw material reactions, suction filtration removes solid
Body, adds suction filtration after proper amount of active carbon stirring, and decompression boils off acetone, adds ethyl acetate, is washed with saturated nacl aqueous solution, point
Go out organic phase, anhydrous sodium sulfate drying is evaporated, use ethyl acetate with petroleum ether volume ratio for 1：6 temperature rising reflux are beaten
Purifying.Obtain the chloro- butanol 7.87g of 2,3- bis- of product formula (I) Isosorbide-5-Nitrae-two, yield 62%.
1HNMR(400MHz,CDCl3):δ=2.39 (s, 2H), 3.79-3.84 (m, 4H), 3.89 (d, 2H) .MS (ESI):
calculated for[C4H8Cl2O2H]+(M+H)+Requires m/z=159.99, found:159.99.
It is in there-necked flask that the cis- Isosorbide-5-Nitrae-dichloro-2-butenes of 10g (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) is molten
In 60mL acetone and 30mL water, fall into frozen water to warm for 0 DEG C -5 DEG C in system, 15.16g potassium permanganate is added in three batches
(Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure).Reaction 5 hours, complete with TLC monitoring raw material reactions, suction filtration removes solid
Body, adds suction filtration after proper amount of active carbon stirring, and decompression boils off acetone, adds ethyl acetate, is washed with saturated nacl aqueous solution, point
Go out organic phase, anhydrous sodium sulfate drying is evaporated, use ethyl acetate with petroleum ether volume ratio for 1：6 temperature rising reflux are beaten
Purifying.The chloro- butanol 6.7g of 2,3- bis- of product formula (I) Isosorbide-5-Nitrae-two are obtained, yield is 53%.
1HNMR(400MHz,CDCl3):δ=2.39 (s, 2H), 3.79-3.84 (m, 4H), 3.89 (d, 2H) .MS (ESI):
calculated for[C4H8Cl2O2H]+(M+H)+Requires m/z=159.99, found:159.99.
It is in there-necked flask that the cis- Isosorbide-5-Nitrae-dichloro-2-butenes of 10g (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) is molten
In 60mL acetone and 20mL water, fall into frozen water to warm for 0 DEG C -5 DEG C in system, 12.64g potassium permanganate is added in three batches
(Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure).Reaction 5 hours, complete with TLC monitoring raw material reactions, suction filtration removes solid
Body, adds suction filtration after proper amount of active carbon stirring, and decompression boils off acetone, adds ethyl acetate, is washed with saturated nacl aqueous solution, point
Go out organic phase, anhydrous sodium sulfate drying is evaporated, use ethyl acetate with petroleum ether volume ratio for 1：6 temperature rising reflux are beaten
Purifying.The chloro- butanol 6.2g of 2,3- bis- of product formula (I) Isosorbide-5-Nitrae-two are obtained, yield is 49%.
1HNMR(400MHz,CDCl3):δ=2.39 (s, 2H), 3.79-3.84 (m, 4H), 3.89 (d, 2H) .MS (ESI):
calculated for[C4H8Cl2O2H]+(M+H)+Requires m/z=159.99, found:159.99.
It is in there-necked flask that the cis- Isosorbide-5-Nitrae-dichloro-2-butenes of 10g (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) is molten
In 60mL acetone and the 20mL tert-butyl alcohols, fall into frozen water to warm for 0 DEG C -5 DEG C in system, 15.16g permanganic acid is added in three batches
Potassium (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure).Reaction 5 hours, complete with TLC monitoring raw material reactions, suction filtration is removed
Solid, adds suction filtration after proper amount of active carbon stirring, and decompression boils off acetone, adds ethyl acetate, is washed with saturated nacl aqueous solution,
Organic phase is separated, anhydrous sodium sulfate drying is evaporated, use ethyl acetate with petroleum ether volume ratio for 1：6 temperature rising reflux are beaten
Slurry purifying.Obtain the chloro- butanol 7.61g of 2,3- bis- of product formula (I) Isosorbide-5-Nitrae-two, yield 60%.
1HNMR(400MHz,CDCl3):δ=2.39 (s, 2H), 3.79-3.84 (m, 4H), 3.89 (d, 2H) .MS (ESI):
calculated for[C4H8Cl2O2H]+(M+H)+Requires m/z=159.99, found:159.99.
Embodiment 2
The chloro- butanol of 2,3- bis- of 2g formulas (I) Isosorbide-5-Nitrae-two is dissolved in 20mL dichloromethane in single port bottle, 1.27g tri- is added
Ethamine (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), adds 2.8mL acetic anhydrides (Chinese medicines group Solution on Chemical Reagents in Shanghai
Company, chemistry is pure), under nitrogen protection, it is heated to reflux (70 DEG C) reactions.Reaction 8 hours, TLC detection raw material reactions are complete.Steam
Acetic anhydride, adds ethyl acetate, is washed, washed with the aqueous solution with saturated sodium bicarbonate solution, separate organic phase, anhydrous sodium sulfate
Dry, be evaporated, use ethyl acetate with petroleum ether volume ratio for 1：5 carry out mashing purifying.Obtain formula (II) Isosorbide-5-Nitrae-two chloro- 2,3-
Diacetate esters 2.15g, yield is 71%.
1H NMR(400MHz,CDCl3):δ=2.07 (s, 6H), 3.61 (dd, J=12.0,4.0Hz, 2H), 3.75 (dd, J
=12.0,4.0Hz, 2H), 5.25 (s, 2H) .MS (ESI):calculated for[C8H12Cl2O4H]+(M+H)+requires
M/z=244.01, found:243.08.
The chloro- butanol of 2,3- bis- of 2g formulas (I) Isosorbide-5-Nitrae-two is dissolved in 20mL dichloromethane in single port bottle, 1.49mL pyrroles are added
Pyridine (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), adding 2.8mL acetic anhydrides, (Chinese medicines group Solution on Chemical Reagents in Shanghai is public
Department, chemistry is pure), under nitrogen protection, it is heated to reflux (70 DEG C) reactions.Reaction 8 hours, TLC detection raw material reactions are complete.Steam second
Acid anhydrides, adds ethyl acetate, is washed, washed with the aqueous solution with saturated sodium bicarbonate solution, separates organic phase, and anhydrous sodium sulfate is done
It is dry, it is evaporated, uses ethyl acetate with petroleum ether volume ratio for 1：5 carry out mashing purifying.Obtain chloro- 2, the 3- bis- of formula (II) Isosorbide-5-Nitrae-two
Acetic acid esters 1.97g, yield is 65%.
1H NMR(400MHz,CDCl3):δ=2.07 (s, 6H), 3.61 (dd, J=12.0,4.0Hz, 2H), 3.75 (dd, J
=12.0,4.0Hz, 2H), 5.25 (s, 2H) .MS (ESI):calculated for[C8H12Cl2O4H]+(M+H)+requires
M/z=244.01, found:243.08.
The chloro- butanol of 2,3- bis- of 2g formulas (I) Isosorbide-5-Nitrae-two is dissolved in 20mL dichloromethane in single port bottle, 1.27g tri- is added
Ethamine (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), adds 3.2mL acetic anhydrides (Chinese medicines group Solution on Chemical Reagents in Shanghai
Company, chemistry is pure), under nitrogen protection, it is heated to reflux (70 DEG C) reactions.Reaction 8 hours, TLC detection raw material reactions are complete.Steam
Acetic anhydride, adds ethyl acetate, is washed, washed with the aqueous solution with saturated sodium bicarbonate solution, separate organic phase, anhydrous sodium sulfate
Dry, be evaporated, use ethyl acetate with petroleum ether volume ratio for 1：5 carry out mashing purifying.Obtain formula (II) Isosorbide-5-Nitrae-two chloro- 2,3-
Diacetate esters 2.09g, yield is 69%.
1H NMR(400MHz,CDCl3):δ=2.07 (s, 6H), 3.61 (dd, J=12.0,4.0Hz, 2H), 3.75 (dd, J
=12.0,4.0Hz, 2H), 5.25 (s, 2H) .MS (ESI):calculated for[C8H12Cl2O4H]+(M+H)+requires
M/z=244.01, found:243.08.
The chloro- butanol of 2,3- bis- of 2g formulas (I) Isosorbide-5-Nitrae-two is dissolved in 20mL tetrahydrofurans in single port bottle, 1.27g tri- is added
Ethamine (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), adds 2.8mL acetic anhydrides (Chinese medicines group Solution on Chemical Reagents in Shanghai
Company, chemistry is pure), under nitrogen protection, it is heated to reflux (70 DEG C) reactions.Reaction 8 hours, TLC detection raw material reactions are complete.Steam
Acetic anhydride, adds ethyl acetate, is washed, washed with the aqueous solution with saturated sodium bicarbonate solution, separate organic phase, anhydrous sodium sulfate
Dry, be evaporated, use ethyl acetate with petroleum ether volume ratio for 1：5 carry out mashing purifying.Obtain formula (II) Isosorbide-5-Nitrae-two chloro- 2,3-
Diacetate esters 2.03g, yield is 67%.
1H NMR(400MHz,CDCl3):δ=2.07 (s, 6H), 3.61 (dd, J=12.0,4.0Hz, 2H), 3.75 (dd, J
=12.0,4.0Hz, 2H), 5.25 (s, 2H) .MS (ESI):calculated for[C8H12Cl2O4H]+(M+H)+requires
M/z=244.01, found:243.08.
Embodiment 3
Chloro- 2, the 3- diacetate esters of 5g formulas (II) Isosorbide-5-Nitrae-two are dissolved in 20mL DMFs in single port bottle,
0.2g sodium iodides (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) are added, 5.85g thioacetic acid potassiums (traditional Chinese medicines collection is added
Solution on Chemical Reagents in Shanghai company of group, chemistry is pure), it is heated to reflux (80-90 DEG C) reaction.Reaction 3~5 hours, TLC detection raw material reactions
Completely.Ethyl acetate is added, is washed with water, separates organic phase, with suction filtration after activated carbon decolorizing 1 hour, anhydrous sodium sulfate is added
Dry, be evaporated.Formula (III) Isosorbide-5-Nitrae-two ethanethioyl -2,3- acetic acid esters 4.65g is obtained, yield is 70%.
1H NMR:(500MHz,CDCl3):δ=2.07 (s, 6H), 2.36 (s, 6H), 3.07 (dd, J=14.0,6.5Hz,
2H), 3.11 (dd, J=14.0,3.0Hz, 2H), 5.15 (s, 2H) .MS (ESI):calculated for[C12H18O6S2H]+(M
+H)+Requires m/z=323.06, found:323.05.
Chloro- 2, the 3- diacetate esters of 5g formulas (II) Isosorbide-5-Nitrae-two are dissolved in 20mL absolute ethyl alcohols in single port bottle, 0.2g is added
Sodium iodide (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), adds 5.85g thioacetic acid potassiums (Chinese medicines group Shanghai
Reagent Company is learned, chemistry is pure), it is heated to reflux (80-90 DEG C) reaction.Reaction 3~5 hours, TLC detection raw material reactions are complete.Plus
Enter ethyl acetate, be washed with water, separate organic phase, with suction filtration after activated carbon decolorizing 1 hour, add anhydrous sodium sulfate drying, steam
It is dry.Formula (III) Isosorbide-5-Nitrae-two ethanethioyl -2,3- acetic acid esters 4.19g is obtained, yield is 63%.
1H NMR:(500MHz,CDCl3):δ=2.07 (s, 6H), 2.36 (s, 6H), 3.07 (dd, J=14.0,6.5Hz,
2H), 3.11 (dd, J=14.0,3.0Hz, 2H), 5.15 (s, 2H) .MS (ESI):calculated for[C12H18O6S2H]+(M
+H)+Requires m/z=323.06, found:323.05.
Chloro- 2, the 3- diacetate esters of 5g formulas (II) Isosorbide-5-Nitrae-two are dissolved in 20mL DMFs in single port bottle,
0.2g sodium iodides (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure) are added, 4.63g thioacetic acid potassiums (traditional Chinese medicines collection is added
Solution on Chemical Reagents in Shanghai company of group, chemistry is pure), it is heated to reflux (80-90 DEG C) reaction.Reaction 3~5 hours, TLC detection raw material reactions
Completely.Ethyl acetate is added, is washed with water, separates organic phase, with suction filtration after activated carbon decolorizing 1 hour, anhydrous sodium sulfate is added
Dry, be evaporated.Formula (III) Isosorbide-5-Nitrae-two ethanethioyl -2,3- acetic acid esters 3.92g is obtained, yield is 59%.
1H NMR:(500MHz,CDCl3):δ=2.07 (s, 6H), 2.36 (s, 6H), 3.07 (dd, J=14.0,6.5Hz,
2H), 3.11 (dd, J=14.0,3.0Hz, 2H), 5.15 (s, 2H) .MS (ESI):calculated for[C12H18O6S2H]+(M
+H)+Requires m/z=323.06, found:323.05.
Embodiment 4
5g formulas (III) ethanethioyl -2,3- acetic acid esters of Isosorbide-5-Nitrae-two is dissolved in 15mL methanol solutions in single port bottle, added
5mL concentrated hydrochloric acid solutions (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), nitrogen protection is lower to react, and reaction temperature is 25 DEG C.
Reaction 4~7 hours, after TLC detection raw material reactions completely, solvent evaporated uses ethyl acetate with petroleum ether volume ratio for 1：3
Carry out mashing purifying.The red sugar alcohol 1.68g of sulphur of formula (IV) two is obtained, yield is 70%.
1H NMR:(400MHz,d6-DMSO):δ=1.95-2.10 (dd, J=9.2,7.2Hz, 2H), 2.66-2.83 (dd,
J=12.0,10.0Hz, 2H), 4.97 (s, 2H) .MS (ESI):calculated for[C4H10O2S2H]+(M+H)+requires
M/z=155.02, found:155.02.
5g formulas (III) ethanethioyl -2,3- acetic acid esters of Isosorbide-5-Nitrae-two is dissolved in 15mL methanol solutions in single port bottle, added
2.03mL chloroacetic chlorides (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), nitrogen protection is lower to react, and reaction temperature is 25 DEG C.
Reaction 4~7 hours, after TLC detection raw material reactions completely, solvent evaporated uses ethyl acetate with petroleum ether volume ratio for 1：3
Carry out mashing purifying.The red sugar alcohol 1.46g of sulphur of formula (IV) two is obtained, yield is 61%.
1H NMR:(400MHz,d6-DMSO):δ=1.95-2.10 (dd, J=9.2,7.2Hz, 2H), 2.66-2.83 (dd,
J=12.0,10.0Hz, 2H), 4.97 (s, 2H) .MS (ESI):calculated for[C4H10O2S2H]+(M+H)+requires
M/z=155.02, found:155.02.
5g formulas (III) ethanethioyl -2,3- acetic acid esters of Isosorbide-5-Nitrae-two is dissolved in 15mL ethanol solutions in single port bottle, added
3.05mL chloroacetic chlorides (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), nitrogen protection is lower to react, and reaction temperature is 25 DEG C.
Reaction 4~7 hours, after TLC detection raw material reactions completely, solvent evaporated uses ethyl acetate with petroleum ether volume ratio for 1：3
Carry out mashing purifying.The red sugar alcohol 1.73g of sulphur of formula (IV) two is obtained, yield is 72%.
1H NMR:(400MHz,d6-DMSO):δ=1.95-2.10 (dd, J=9.2,7.2Hz, 2H), 2.66-2.83 (dd,
J=12.0,10.0Hz, 2H), 4.97 (s, 2H) .MS (ESI):calculated for[C4H10O2S2H]+(M+H)+requires
M/z=155.02, found:155.02.
5g formulas (III) ethanethioyl -2,3- acetic acid esters of Isosorbide-5-Nitrae-two is dissolved in 15mL methanol solutions in single port bottle, added
3.05mL chloroacetic chlorides (Chinese medicines group Solution on Chemical Reagents in Shanghai company, chemistry is pure), nitrogen protection is lower to react, and reaction temperature is 25 DEG C.
Reaction 4~7 hours, after TLC detection raw material reactions completely, solvent evaporated uses ethyl acetate with petroleum ether volume ratio for 1：3
Carry out mashing purifying.The red sugar alcohol 1.87g of sulphur of formula (IV) two is obtained, yield is 78%.
1H NMR:(400MHz,d6-DMSO):δ=1.95-2.10 (dd, J=9.2,7.2Hz, 2H), 2.66-2.83 (dd,
J=12.0,10.0Hz, 2H), 4.97 (s, 2H) .MS (ESI):calculated for[C4H10O2S2H]+(M+H)+requires
M/z=155.02, found:155.02.
In summary, the method for the red sugar alcohol of the sulphur of preparation two of the invention has that synthetic route is brief, easy to operate, cost
Low, yield is high, be easy to the advantage of industrialized production.
The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, this
Art personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect
Protect scope.
Claims (11)
1. a kind of method for preparing the red sugar alcohol of two sulphur, it is characterised in that comprise the following steps：
(a) cis- Isosorbide-5-Nitrae-dichloro-2-butene is dissolved in the first reaction dissolvent, occurs cis dihydroxylation reaction with potassium permanganate, obtain
To the chloro- butanol of 2,3- bis- of formula (I) 1,4- bis-；
(b) the chloro- butanol of 2,3- bis- of formula (I) Isosorbide-5-Nitrae-two for preparing step (a) is dissolved in the second reaction dissolvent, adds organic base,
Occur esterification with acetic anhydride, obtain chloro- 2, the 3- diacetate esters of formula (II) Isosorbide-5-Nitrae-two；
(c) in the 3rd reaction dissolvent, chloro- 2, the 3- diacetate esters of formula (II) Isosorbide-5-Nitrae-two and thioacetic acid prepared by step (b)
Under the catalytic action of sodium iodide nucleophilic substitution occurs for potassium, obtains formula (III) ethanethioyl -2,3- acetic acid of Isosorbide-5-Nitrae-two
Ester；
(d) in the 4th reaction dissolvent, formula (III) ethanethioyl -2,3- of Isosorbide-5-Nitrae-two acetic acid esters prepared by step (c) and acidity
Hydrolysis occurs for reagent, the red sugar alcohol of two sulphur is obtained, shown in its structure such as formula (IV)；Shown in course of reaction such as route (1)：
2. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that described in the step (a)
The ratio between mole of cis- 1,4- dichloro-2-butenes and potassium permanganate is 1：1.0~1.5.
3. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that described suitable in the step (a)
The temperature of formula dihydroxylation reaction is -5 DEG C~5 DEG C, and the time of reaction is 3~5 hours.
4. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that described to have in the step (b)
Machine alkali is pyridine, triethylamine, DMAP or N, N- DIC.
5. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that in the step (b), the formula
(I) the ratio between the chloro- butanol of 2,3- bis- of Isosorbide-5-Nitrae-two and organic base, the mole of acetic anhydride are 1：1.0-1.5：2.0~2.5.
6. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that in the step (b), the ester
The temperature for changing reaction is 50 DEG C~80 DEG C, and the time of the esterification is 5~8 hours.
7. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that in the step (c), the parent
The temperature of core substitution reaction is 60 DEG C~90 DEG C, and the time of the nucleophilic substitution is 3~5 hours.
8. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that in the step (c), the formula
(II) the ratio between chloro- 2, the 3- diacetate esters of Isosorbide-5-Nitrae-two, thioacetic acid potassium, mole of sodium iodide are 1：2.0~3.0：0.05.
9. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that in the step (d), the acid
Property reagent be hydrochloric acid, chloroacetic chloride or acetic acid.
10. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that described in the step (d)
The ratio between mole of formula (III) ethanethioyl -2,3- of Isosorbide-5-Nitrae-two acetic acid esters and acid reagent is 1：2.0~3.0.
11. the preparation method of the red sugar alcohol of two sulphur according to claim 1, it is characterised in that described in the step (d)
The temperature of hydrolysis is 20 DEG C~25 DEG C, and the time of the hydrolysis is 4~7 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611235712.7A CN107235872A (en) | 2016-12-28 | 2016-12-28 | A kind of preparation method of the red sugar alcohol of two sulphur |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611235712.7A CN107235872A (en) | 2016-12-28 | 2016-12-28 | A kind of preparation method of the red sugar alcohol of two sulphur |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107235872A true CN107235872A (en) | 2017-10-10 |
Family
ID=59982971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611235712.7A Pending CN107235872A (en) | 2016-12-28 | 2016-12-28 | A kind of preparation method of the red sugar alcohol of two sulphur |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107235872A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100096A (en) * | 2019-12-30 | 2020-05-05 | 新乡医学院 | Intermediate compound for synthesizing dithioerythritol, application of intermediate compound and synthetic method of dithioerythritol |
| CN115093352A (en) * | 2022-07-05 | 2022-09-23 | 湖南汇百益新材料有限公司 | Preparation method of dithiothreitol |
| CN115093352B (en) * | 2022-07-05 | 2024-04-26 | 湖南汇百益新材料有限公司 | Preparation method of dithiothreitol |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU182566B (en) * | 1979-11-30 | 1984-02-28 | Reanal Finomvegyszergyar | Process for preparing 1,4-dimercapto-2,3-autane-diola |
| CN101503384A (en) * | 2009-03-18 | 2009-08-12 | 重庆铂宁化工有限公司 | Method for synthesizing dithiothreitol |
| CN103073462A (en) * | 2013-01-12 | 2013-05-01 | 江西师范大学 | DDT (dithiothreitol) reparation method |
-
2016
- 2016-12-28 CN CN201611235712.7A patent/CN107235872A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU182566B (en) * | 1979-11-30 | 1984-02-28 | Reanal Finomvegyszergyar | Process for preparing 1,4-dimercapto-2,3-autane-diola |
| CN101503384A (en) * | 2009-03-18 | 2009-08-12 | 重庆铂宁化工有限公司 | Method for synthesizing dithiothreitol |
| CN103073462A (en) * | 2013-01-12 | 2013-05-01 | 江西师范大学 | DDT (dithiothreitol) reparation method |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100096A (en) * | 2019-12-30 | 2020-05-05 | 新乡医学院 | Intermediate compound for synthesizing dithioerythritol, application of intermediate compound and synthetic method of dithioerythritol |
| CN111100096B (en) * | 2019-12-30 | 2021-09-14 | 新乡医学院 | Intermediate compound for synthesizing dithioerythritol, application of intermediate compound and synthetic method of dithioerythritol |
| CN115093352A (en) * | 2022-07-05 | 2022-09-23 | 湖南汇百益新材料有限公司 | Preparation method of dithiothreitol |
| CN115093352B (en) * | 2022-07-05 | 2024-04-26 | 湖南汇百益新材料有限公司 | Preparation method of dithiothreitol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2009076627A2 (en) | Conversion of carbohydrates to hydroxy-methylfurfural (hmf) and derivatives | |
| CN105461777B (en) | A kind of purification process of Abiraterone acetate | |
| CN103910777B (en) | Steroid ester preparation method | |
| CN102395591B (en) | Method for preparing prasugrel | |
| CN107011404A (en) | A kind of method using cholic acid as Material synthesis lithocholic acid | |
| CN103113333A (en) | Synthesizing method of vitamin C ethyl ether | |
| CN102863408B (en) | Preparation method of andrographolide | |
| CN106083961A (en) | A kind of preparation method of (2 ' R) 2 ' deoxidation 2 ' fluorine 2 ' MU glycosides | |
| CN103864866B (en) | Synthetic method and the midbody compound thereof of a kind of morphine-6-β-D-Glucose aldehydic acid glycosides | |
| CN106939030A (en) | A kind of synthetic method of the keto lithcholic acid of intermediate 7 of shellfish cholic acid difficult to understand | |
| CN107235872A (en) | A kind of preparation method of the red sugar alcohol of two sulphur | |
| CN111559995B (en) | Preparation process of ascorbic acid ethyl ether | |
| CN103288890B (en) | One prepares 3-O-benzyl-1, the new method of 2-O-isopropylidene-β-L-furan idose | |
| CN105732648B (en) | The nitrogen-containing heterocycle compound and synthetic method of a kind of pyrrolo- furans | |
| CN109988220B (en) | Preparation method of green synthetic tanshinone IIA sodium sulfonate | |
| CN107383137A (en) | A kind of synthetic method of chenodeoxycholic acid | |
| CN105130972B (en) | Benzoic acid emtricitabine salt, its preparation method and the method for preparing emtricitabine with benzoic acid emtricitabine salt | |
| CN110204557B (en) | Preparation method of cefamandole nafate derivative | |
| CN106674330A (en) | 34-Dimethyl apratoxin A/E preparation method | |
| CN107382785A (en) | One planting sand storehouse must bent key intermediate preparation method | |
| CN113416220B (en) | Thiosulfoglycan compound and preparation method thereof | |
| CN110746471B (en) | Preparation method of fondaparinux sodium disaccharide intermediate | |
| CN107686495B (en) | A kind of synthetic method of Fondaparinux sodium intermediate | |
| CN102453068B (en) | Improvement preparation method for oxabolone cipionate | |
| CN111100096B (en) | Intermediate compound for synthesizing dithioerythritol, application of intermediate compound and synthetic method of dithioerythritol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171010 |
|
| WD01 | Invention patent application deemed withdrawn after publication |