CN110396072A - (s) preparation method of -3- hydroxyl tetrahydrofuran - Google Patents
(s) preparation method of -3- hydroxyl tetrahydrofuran Download PDFInfo
- Publication number
- CN110396072A CN110396072A CN201910821576.7A CN201910821576A CN110396072A CN 110396072 A CN110396072 A CN 110396072A CN 201910821576 A CN201910821576 A CN 201910821576A CN 110396072 A CN110396072 A CN 110396072A
- Authority
- CN
- China
- Prior art keywords
- catalyst
- solvent
- hydroxyl
- chloro
- tetrahydrofuran
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
Abstract
The present invention provides the preparation methods of one kind (s) -3- hydroxyl tetrahydrofuran, use 4- chloroacetyl acetacetic ester for starting material, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared first, substrate is dissolved in the first solvent, alkali is added, asymmetric hydrogenation occurs with hydrogen under the catalytic action of the first catalyst and the second catalyst and generates (s) -4- chloro-3-hydroxyl-n-butyl alcohol, then it prepares chiral 3-hydroxy tetrahydrofuran: the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- obtained is dissolved in the second solvent, acid is added and is used as catalyst, reaction obtains (s) -3- hydroxyl tetrahydrofuran, first catalyst is [Ir (COD) Cl]2The complex compound generated is reacted with phosphine-pyridine ligand, second catalyst is Ru-MACHO complex compound, reaction route of the present invention is short, simple process, raw material is cheap and easy to get, production cost is low, reaction process environmental pollution is small, and product optical purity is high, is suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to the preparation method of one kind (s) -3- hydroxyl tetrahydrofuran.
Background technique
Optically pure (S) -3- hydroxyl tetrahydrofuran is an important pharmaceutical intermediate, can be used for diabetes medicament grace lattice
Arrange net (Empagliflozin), breast cancer medicines Afatinib (Afatinb), anti-aids drug amprenavir
(Amprenavir) and the synthesis of Fosamprenavir (Fosamprenavir) etc., the huge market demand, before there is good application
Scape.
Synthetic method about chiral 3-hydroxy tetrahydrofuran is by widespread reports.Nineteen eighty-three, Tadon are put forward for the first time chirality
The synthetic route (J.Org.Chem, 1983,48,2767-2769) of 3- hydroxyl tetrahydrofuran.The route is with chiral malic acid
Beginning raw material needs to be not appropriate for large-scale production using a large amount of lithium aluminium hydride reduction.Many published synthetic methods are to Tadon
Synthetic route improve, if patent CN107935971 and CN109503523 use improved route, with chiral malic acid
For starting material, chiral apple dimethyl phthalate is generated by esterification, is then reduced into chiral 1,2,4-butanetriol, then in acid item
Dehydration ring closure obtains product chiral 3-hydroxy tetrahydrofuran under part, and the route steps are long, and yield is low, is unable to satisfy industrialized production.
Document (apply chemical industry [J], 2008,37,191-194), CN102477019, CN107098872,
WO2008093955, WO2000063199, EP761663 etc. are used is with optically pure (S) -4- chloro-3-hydroxyl ethyl butyrate
Raw material obtains intermediate (S) -4- chloro-3-hydroxyl butanediol after sodium borohydride reduction, then obtains (S) -3- in acid condition
Hydroxyl tetrahydrofuran.This method expensive starting materials need a large amount of sodium borohydride, and waste water is more, are not suitable for large-scale production.
Patent CN104961711 discloses a kind of preparation method of chiral 3-hydroxy tetrahydrofuran.This method is with chiral meat
Alkali is starting material, and chirality 2,4- dihydroxy-N, N, N- trimethyl butylamine accordingly is obtained after reduction.Then it is acidified into salt,
Cyclization obtains chiral 3- hydroxyl tetrahydrofuran again.It is starting material this process employs expensive chiral carnitine, is not suitable for scale
Production.
Document (Synthesis, 2013,45,931-935) describes a kind of light using azo acid dimethyl ester and prolongs instead
The method that (S) -3- hydroxyl tetrahydrofuran should be converted by (R) -3- hydroxyl tetrahydrofuran.The azoformic acid two that this method utilizes
Methyl esters is expensive, is not suitable for large-scale production.
Catalyzed by biological enzyme is widely paid close attention to and is studied.Document (FEBS Journal, 2013,280,3084-3093),
(Tetrahedron Letters,2008,49,6752-6755)、(Angew.Chem.Int.Ed,2008,47,741-745)、
(Tetrahedron:Asymmetry, 2012,23,583-586), patent JP10337197 and CN106957287 are using life
The 3- hydroxyl tetrahydrofuran and derivative or fractionation epoxide of object enzyme hydrolysis fractionation racemization prepare optically pure (s) -3- hydroxyl
Base tetrahydrofuran.The biological enzyme that these methods use is expensive, and reaction time is long, and yield is low, is unable to satisfy large-scale production.
Summary of the invention
The present invention is to carry out to solve the above-mentioned problems, and it is an object of the present invention to provide a kind of cost of material is low, reaction step
Short, product optical purity height, efficient, green (s) -3- hydroxyl tetrahydrofuran suitable for industrialized production preparation method.
The present invention provides the preparation methods of one kind (s) -3- hydroxyl tetrahydrofuran characterized by comprising step 1, system
The chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- shown in standby formula II: 4- chloroacetyl acetacetic ester shown in formula I is dissolved in the first solvent, is added
Enter alkali, occurs shown in asymmetric hydrogenation production II under the catalytic action of the first catalyst and the second catalyst with hydrogen
(s) -4- chloro-3-hydroxyl-n-butyl alcohol,
Step 2, it prepares chiral 3-hydroxy tetrahydrofuran: the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 is dissolved in
In two solvents, acid being added and is used as catalyst, reaction obtains (s) -3- hydroxyl tetrahydrofuran shown in formula V,
Wherein, first catalyst is [Ir (COD) Cl]2The network generated is reacted with phosphine-pyridine ligand shown in formula III
Object is closed,
Second catalyst is Ru-MACHO complex compound shown in formula IV.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: the pressure of hydrogen is 1~8MPa in step 1, and reaction temperature is 20~150 DEG C, and the reaction time is 5~6 hours；Step 2
In reaction temperature be 0~100 DEG C, the reaction time be 3~4 hours.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: the pressure of hydrogen is 2~4MPa in step 1, and reaction temperature is 80~120 DEG C；Reaction temperature in step 2 is 50~80
℃。
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: in step 2, (s) the chloro- 3 hydroxyls-n-butyl alcohol of -4- is dissolved in the second solvent, and acid is added and is used as catalyst reaction 3~4 hours
Afterwards, short-path distillation is carried out, distillate is cooled down, revolving removes the second solvent, and vacuum distillation obtains (s) -3- hydroxy tetrahydro
Furans.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: it in step 1, before being passed through hydrogen, is replaced 3~5 times with hydrogen, after the reaction was completed, it is molten to remove first for slow release hydrogen
Then silicagel column isolated (s) -4- chloro-3-hydroxyl-n-butyl alcohol is used in agent.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: first catalyst is prepared method particularly includes: under nitrogen protection, by [Ir (COD) Cl]2With phosphine-pyridine ligand
It is dissolved in the first solvent, stirs 8~12min at room temperature.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: the volume ratio of first solvent and 4- chloroacetyl acetacetic ester is 10:1~1:1 in step 1, wherein the volume of the first solvent
Volume including the first solvent being added when the first catalyst of the first solvent for being added in 4- chloroacetyl acetacetic ester and preparation it
It is 1:100~1:5 with the molar ratio of, alkali and 4- chloroacetyl acetacetic ester, theoretically the first catalyst and 4- chloracetyl obtained
The molar ratio of ethyl acetate is 1:10000~1:1000, and the molar ratio of the second catalyst and 4- chloroacetyl acetacetic ester is 1:
1000~1:100；
In step 2 in second solvent and step 1 volume ratio of (s) -4- chloro-3-hydroxyl-n-butyl alcohol obtained be 10:1~
1:1, the amount of sour substance are 10:1 with the ratio of the amount of (s) -4- chloro-3-hydroxyl-n-butyl alcohol substance made from theory in step 1
~1:1.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: the volume ratio of first solvent and 4- chloroacetyl acetacetic ester is 5:1~2:1 in step 1, wherein the volume of the first solvent
Volume including the first solvent being added when the first catalyst of the first solvent for being added in 4- chloroacetyl acetacetic ester and preparation it
It is 1:20~1:10 with the molar ratio of, alkali and 4- chloroacetyl acetacetic ester, theoretically the first catalyst and 4- chloracetyl obtained
The molar ratio of ethyl acetate is 1:5000~1:2000, and the molar ratio of the second catalyst and 4- chloroacetyl acetacetic ester is 1:500
~1:200；
The volume ratio of second solvent and (s) -4- chloro-3-hydroxyl-n-butyl alcohol obtained in step 1 is 5:1~2 in step 2:
1, in the amount of sour substance and step 1 ratio of the amount of (s) -4- chloro-3-hydroxyl-n-butyl alcohol substance made from theory be 5:1~
2:1。
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: first solvent is anhydrous methylene chloride, anhydrous dichloroethanes, methanol, ethyl alcohol, anhydrous tetrahydro furan, dry toluene
In any one；
Second solvent is deionized water, methanol, ethyl alcohol, isopropanol, tetrahydrofuran, any one in dioxane
Kind；
The alkali is sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, any one in potassium carbonate；
Any one sour in hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid.
Further, in the preparation method of (s) provided by the invention -3- hydroxyl tetrahydrofuran, can also have such
Feature: first solvent is methanol or ethyl alcohol；Second solvent is deionized water or methanol；The alkali is sodium methoxide or uncle
Butanol potassium；The acid is hydrochloric acid or sulfuric acid.
The present invention provides following advantages:
The preparation method of (s) according to the present invention -3- hydroxyl tetrahydrofuran, using 4- chloracetyl second that is cheap and being easy to get
Acetoacetic ester passes through the catalytic action of catalyst as starting material under alkaline condition, and asymmetric hydrogenation occurs and generates
(s) the chloro- 3 hydroxyls-n-butyl alcohol of -4-, then the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is cyclized generation under acidic catalyst catalytic action
(s) -3- hydroxyl tetrahydrofuran, reaction route of the present invention is short, simple process, raw material is cheap and easy to get, production cost is low, reaction process
Environmental pollution is small, and product optical purity is high, is suitable for industrialized production.
Specific embodiment
In order to be easy to understand the technical means, the creative features, the aims and the efficiencies achieved by the present invention, tie below
Embodiment is closed to be specifically addressed the preparation method of (s) -3- hydroxyl tetrahydrofuran of the invention.
<embodiment one>
Step 1, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared:
Step 1-1, under nitrogen protection, by [Ir (COD) Cl]2, chiral phosphine-pyridine ligand be dissolved in ethyl alcohol, at room temperature
The first catalyst is made in stirring 10 minutes.
Step 1-2, the amount of the substance of the first catalyst according to made from theory in step 1-1, according to the first catalyst
The amount of the substance of the amount and 4- chloroacetyl acetacetic ester of substance is the ratio of 1:3000, and substrate 4- chloroacetyl acetacetic ester is taken to be dissolved in
In ethyl alcohol.Wherein, the total volume of ethyl alcohol used in ethyl alcohol and step 1-2 used in step 1-1 and substrate 4- chloracetyl second
The volume ratio of acetoacetic ester is 3:1.Then the ethanol solution of above-mentioned 4- chloroacetyl acetacetic ester is added obtained the in step 1-1
In one catalyst.
Step 1-3, the molar ratio according to potassium tert-butoxide and 4- chloroacetyl acetacetic ester be 1:15, Ru-MACHO complex compound with
The molar ratio of 4- chloroacetyl acetacetic ester is the dosage of 1:300, and potassium tert-butoxide and Ru-MACHO complex compound are placed in reaction under high pressure
In kettle, hydrogen is replaced 3 times, is then passed to hydrogen to 2MPa and is kept pressure constant, reacts 5 hours at 100 DEG C, then, slowly
Hydrogen is discharged, uses the isolated product chirality 4- chloro-3-hydroxyl-n-butyl alcohol of silicagel column after removing etoh solvent.
Step 2, chiral 3-hydroxy tetrahydrofuran is prepared:
By the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 according to the body of ethyl alcohol and the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4-
Product is than being that the dosage of 3:1 is dissolved in ethyl alcohol, according to the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from theory in hydrochloric acid and step 1
Concentrated hydrochloric acid is added as catalyst in the dosage that the ratio of the amount of substance is 3:1, after reacting 3 hours at 60 DEG C, carries out to reaction solution
Then short-path distillation will distillate liquid cooling and cool down, revolving removes ethyl alcohol, and finally vacuum distillation obtains (s) -3- hydroxy tetrahydro furan
It mutters.(s) -3- hydroxyl tetrahydrofuran total recovery is 91.3%.(s) obtained -3- hydroxyl tetrahydrofuran chemical purity is 98.5%,
Optical purity is 99%.
<embodiment two>
Step 1, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared:
Step 1-1, under nitrogen protection, by [Ir (COD) Cl]2, chiral phosphine-pyridine ligand be dissolved in methanol, at room temperature
The first catalyst is made in stirring 10 minutes.
Step 1-2, the amount of the substance of the first catalyst according to made from theory in step 1-1, according to the first catalyst
The amount of the substance of the amount and 4- chloroacetyl acetacetic ester of substance is the ratio of 1:2000, and substrate 4- chloroacetyl acetacetic ester is taken to be dissolved in
In methanol.Wherein, the total volume of methanol used in methanol and step 1-2 used in step 1-1 and substrate 4- chloracetyl second
The volume ratio of acetoacetic ester is 5:1.Then the methanol solution of above-mentioned 4- chloroacetyl acetacetic ester is added obtained the in step 1-1
In one catalyst.
Step 1-3 is 1:20, Ru-MACHO complex compound and 4- according to the molar ratio of sodium methoxide and 4- chloroacetyl acetacetic ester
The molar ratio of chloroacetyl acetacetic ester is the dosage of 1:500, and sodium methoxide and Ru-MACHO complex compound are placed in autoclave,
Hydrogen is replaced 5 times, is then passed to hydrogen to 3MPa and is kept pressure constant, 5 hours, then, slow release hydrogen are reacted at 80 DEG C
Gas uses the isolated product chirality 4- chloro-3-hydroxyl-n-butyl alcohol of silicagel column after removing solvent methanol.
Step 2, chiral 3-hydroxy tetrahydrofuran is prepared:
By the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 according to the body of methanol and the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4-
Product is than being that the dosage of 5:1 is dissolved in methanol, according to the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from theory in hydrochloric acid and step 1
Concentrated hydrochloric acid is added as catalyst in the dosage that the ratio of the amount of substance is 2:1, after reacting 4 hours at 50 DEG C, carries out to reaction solution
Then short-path distillation will distillate liquid cooling and cool down, revolving removes methanol, and finally vacuum distillation obtains (s) -3- hydroxy tetrahydro furan
It mutters.(s) -3- hydroxyl tetrahydrofuran total recovery is 94.6%.(s) obtained -3- hydroxyl tetrahydrofuran chemical purity is 98.3%,
Optical purity is 99%.
<embodiment three>
Step 1, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared:
Step 1-1, under nitrogen protection, by [Ir (COD) Cl]2, chiral phosphine-pyridine ligand be dissolved in anhydrous methylene chloride
In, it stirs 10 minutes at room temperature, the first catalyst is made.
Step 1-2, the amount of the substance of the first catalyst according to made from theory in step 1-1, according to the first catalyst
The amount of the substance of the amount and 4- chloroacetyl acetacetic ester of substance is the ratio of 1:5000, and substrate 4- chloroacetyl acetacetic ester is taken to be dissolved in
In anhydrous methylene chloride.Wherein, anhydrous methylene chloride used in anhydrous methylene chloride and step 1-2 used in step 1-1
Total volume and substrate 4- chloroacetyl acetacetic ester volume ratio be 2:1.Then by the anhydrous of above-mentioned 4- chloroacetyl acetacetic ester
In first catalyst made from dichloromethane solution addition step 1-1.
Step 1-3 is 1:10, Ru-MACHO complex compound and 4- according to the molar ratio of sodium ethoxide and 4- chloroacetyl acetacetic ester
The molar ratio of chloroacetyl acetacetic ester is the dosage of 1:200, and sodium ethoxide and Ru-MACHO complex compound are placed in autoclave,
Hydrogen is replaced 4 times, is then passed to hydrogen to 4MPa and is kept pressure constant, 5 hours, then, slow release hydrogen are reacted at 120 DEG C
Gas uses the isolated product chirality 4- chloro-3-hydroxyl-n-butyl alcohol of silicagel column after removing solvent anhydrous methylene chloride.
Step 2, chiral 3-hydroxy tetrahydrofuran is prepared:
By the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 according to deionized water and the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4-
Volume ratio be 2:1 dosage be dissolved in deionized water, according to chloro- 3 hydroxyl-of chirality 4- made from theory in hydrochloric acid and step 1
The dosage addition concentrated hydrochloric acid that the ratio of the amount of the substance of n-butyl alcohol is 5:1 is right after reacting 3.5 hours at 80 DEG C as catalyst
Reaction solution carries out short-path distillation, then will distillate liquid cooling and cool down, and revolving removes deionized water, and finally vacuum distillation obtains
(s) -3- hydroxyl tetrahydrofuran.(s) -3- hydroxyl tetrahydrofuran total recovery is 90%.(s) obtained -3- hydroxyl tetrahydrofuran
Learning purity is 98.9%, optical purity 99%.
<example IV>
Step 1, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared:
Step 1-1, under nitrogen protection, by [Ir (COD) Cl]2, chiral phosphine-pyridine ligand be dissolved in anhydrous dichloroethanes
In, it stirs 8 minutes at room temperature, the first catalyst is made.
Step 1-2, the amount of the substance of the first catalyst according to made from theory in step 1-1, according to the first catalyst
The amount of the substance of the amount and 4- chloroacetyl acetacetic ester of substance is the ratio of 1:7000, and substrate 4- chloroacetyl acetacetic ester is taken to be dissolved in
In anhydrous dichloroethanes.Wherein, anhydrous dichloroethanes used in anhydrous dichloroethanes and step 1-2 used in step 1-1
Total volume and substrate 4- chloroacetyl acetacetic ester volume ratio be 7:1.Then by the anhydrous of above-mentioned 4- chloroacetyl acetacetic ester
In first catalyst made from dichloroethane solution addition step 1-1.
Step 1-3 is 1:40, Ru-MACHO complex compound and 4- according to the molar ratio of sodium carbonate and 4- chloroacetyl acetacetic ester
The molar ratio of chloroacetyl acetacetic ester is the dosage of 1:600, and sodium carbonate and Ru-MACHO complex compound are placed in autoclave,
Hydrogen is replaced 3 times, is then passed to hydrogen to 6MPa and is kept pressure constant, 5.5 hours, then, slow release are reacted at 60 DEG C
Hydrogen uses the isolated product chirality 4- chloro-3-hydroxyl-n-butyl alcohol of silicagel column after removing the anhydrous dichloroethanes of solvent.
Step 2, chiral 3-hydroxy tetrahydrofuran is prepared:
By the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 according to isopropanol and the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4-
Volume ratio is that the dosage of 8:1 is dissolved in isopropanol, according to the chloro- 3 hydroxyl -1- fourth of chirality 4- made from theory in sulfuric acid and step 1
The ratio of the amount of the substance of alcohol be 7:1 dosage be added sulfuric acid as catalyst, after being reacted 4 hours at 40 DEG C, to reaction solution into
Then row short-path distillation will distillate liquid cooling and cool down, revolving removes isopropanol, and finally vacuum distillation obtains (s) -3- hydroxyl four
Hydrogen furans.(s) -3- hydroxyl tetrahydrofuran total recovery is 82.5%.(s) obtained -3- hydroxyl tetrahydrofuran chemical purity is
97.6%, optical purity 99%.
<embodiment five>
Step 1, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared:
Step 1-1, under nitrogen protection, by [Ir (COD) Cl]2, chiral phosphine-pyridine ligand be dissolved in anhydrous tetrahydro furan
In, it stirs 12 minutes at room temperature, the first catalyst is made.
Step 1-2, the amount of the substance of the first catalyst according to made from theory in step 1-1, according to the first catalyst
The amount of the substance of the amount and 4- chloroacetyl acetacetic ester of substance is the ratio of 1:10000, takes substrate 4- chloroacetyl acetacetic ester molten
In anhydrous tetrahydro furan.Wherein, anhydrous tetrahydro furan used in anhydrous tetrahydro furan and step 1-2 used in step 1-1
The volume ratio of the total volume and substrate 4- chloroacetyl acetacetic ester muttered is 10:1.Then by the nothing of above-mentioned 4- chloroacetyl acetacetic ester
In first catalyst made from water tetrahydrofuran solution addition step 1-1.
Step 1-3, the molar ratio according to sodium bicarbonate and 4- chloroacetyl acetacetic ester be 1:5, Ru-MACHO complex compound with
The molar ratio of 4- chloroacetyl acetacetic ester is the dosage of 1:100, and sodium bicarbonate and Ru-MACHO complex compound are placed in reaction under high pressure
In kettle, hydrogen is replaced 3 times, is then passed to hydrogen to 8MPa and is kept pressure constant, reacts 6 hours at 20 DEG C, then, slowly release
Hydrogen release gas uses the isolated product chirality 4- chloro-3-hydroxyl-n-butyl alcohol of silicagel column after removing solvent anhydrous tetrahydro furan.
Step 2, chiral 3-hydroxy tetrahydrofuran is prepared:
By the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 according to tetrahydrofuran and the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4-
Volume ratio be 1:1 dosage be dissolved in tetrahydrofuran, according to chloro- 3 hydroxyl-of chirality 4- made from theory in phosphoric acid and step 1
Phosphoric acid is added as catalyst, after reacting 3 hours at 100 DEG C, to anti-in the dosage that the ratio of the amount of the substance of n-butyl alcohol is 10:1
It answers liquid to carry out short-path distillation, then will distillate liquid cooling and cool down, revolving removes tetrahydrofuran, and finally vacuum distillation obtains (s)-
3- hydroxyl tetrahydrofuran.(s) -3- hydroxyl tetrahydrofuran total recovery is 36.8%.(s) obtained -3- hydroxyl tetrahydrofuran chemistry
Purity is 98.0%, optical purity 99%.
<embodiment six>
Step 1, the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- is prepared:
Step 1-1, under nitrogen protection, by [Ir (COD) Cl]2, chiral phosphine-pyridine ligand be dissolved in dry toluene, room
Temperature lower stirring 11 minutes, the first catalyst is made.
Step 1-2, the amount of the substance of the first catalyst according to made from theory in step 1-1, according to the first catalyst
The amount of the substance of the amount and 4- chloroacetyl acetacetic ester of substance is the ratio of 1:1000, and substrate 4- chloroacetyl acetacetic ester is taken to be dissolved in
In dry toluene.Wherein, the total volume of dry toluene used in dry toluene and step 1-2 used in step 1-1 and bottom
The volume ratio of object 4- chloroacetyl acetacetic ester is 1:1.Then the anhydrous toluene solution of above-mentioned 4- chloroacetyl acetacetic ester is added
In first catalyst made from step 1-1.
Step 1-3, the molar ratio according to potassium carbonate and 4- chloroacetyl acetacetic ester be 1:100, Ru-MACHO complex compound with
The molar ratio of 4- chloroacetyl acetacetic ester is the dosage of 1:1000, and potassium carbonate and Ru-MACHO complex compound are placed in autoclave
In, hydrogen is replaced 3 times, is then passed to hydrogen to 1MPa and is kept pressure constant, reacts 6 hours at 150 DEG C, then, slowly release
Hydrogen release gas uses the isolated product chirality 4- chloro-3-hydroxyl-n-butyl alcohol of silicagel column after removing solvent dry toluene.
Step 2, chiral 3-hydroxy tetrahydrofuran is prepared:
By the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 according to dioxane and the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4-
Volume ratio be 10:1 dosage be dissolved in dioxane, it is chloro- according to p-methyl benzenesulfonic acid and chirality 4- made from theory in step 1
P-methyl benzenesulfonic acid is added as catalyst in the dosage that the ratio of the amount of the substance of 3 hydroxyls-n-butyl alcohol is 1:1, reacts 3.5 at 0 DEG C
After hour, short-path distillation is carried out to reaction solution, liquid cooling then will be distillated and cool down, revolving removes dioxane, finally depressurizes
Distillation obtains (s) -3- hydroxyl tetrahydrofuran.(s) -3- hydroxyl tetrahydrofuran total recovery is 35%.(s) obtained -3- hydroxyl four
Hydrogen furans chemical purity is 98.2%, optical purity 99%.
The preparation method of (s) according to the present invention -3- hydroxyl tetrahydrofuran is not limited to the range of specific embodiment.With
Upper content is only basic explanation of the invention, and any equivalent transformation made by technical solution according to the present invention, be should belong to
Protection scope of the present invention.
Claims (10)
1. the preparation method of one kind (s) -3- hydroxyl tetrahydrofuran, which comprises the following steps:
Step 1,4- chloroacetyl acetacetic ester shown in formula I the chloro- 3 hydroxyls-n-butyl alcohol of (s) -4- shown in preparation formula II: is dissolved in
In one solvent, alkali is added, asymmetric hydrogenation occurs with hydrogen under the catalytic action of the first catalyst and the second catalyst
The chloro-3-hydroxyl of (s) -4- shown in production II-n-butyl alcohol,
Step 2, prepare chiral 3-hydroxy tetrahydrofuran: it is molten that the chloro- 3 hydroxyls-n-butyl alcohol of chirality 4- made from step 1 is dissolved in second
In agent, acid being added and is used as catalyst, reaction obtains (s) -3- hydroxyl tetrahydrofuran shown in formula V,
Wherein, first catalyst is [Ir (COD) Cl]2The complex compound generated is reacted with phosphine-pyridine ligand shown in formula III,
Second catalyst is Ru-MACHO complex compound shown in formula IV.
The preparation method of (s) 2. according to claim 1-3- hydroxyl tetrahydrofuran, it is characterised in that:
The pressure of hydrogen is 1~8MPa in step 1, and reaction temperature is 20~150 DEG C, and the reaction time is 5~6 hours；
Reaction temperature in step 2 is 0~100 DEG C, and the reaction time is 3~4 hours.
The preparation method of (s) 3. according to claim 2-3- hydroxyl tetrahydrofuran, it is characterised in that:
The pressure of hydrogen is 2~4MPa in step 1, and reaction temperature is 80~120 DEG C；
Reaction temperature in step 2 is 50~80 DEG C.
The preparation method of (s) 4. according to claim 3-3- hydroxyl tetrahydrofuran, it is characterised in that:
In step 2, (s) the chloro- 3 hydroxyls-n-butyl alcohol of -4- is dissolved in the second solvent, and acid is added and is used as catalyst reaction 3~4 hours
Afterwards, short-path distillation is carried out, distillate is cooled down, revolving removes the second solvent, and vacuum distillation obtains (s) -3- hydroxy tetrahydro
Furans.
The preparation method of (s) 5. according to claim 1-3- hydroxyl tetrahydrofuran, it is characterised in that:
In step 1, before being passed through hydrogen, replaced 3~5 times with hydrogen,
After the reaction was completed, slow release hydrogen removes the first solvent, then uses silicagel column isolated (s) -4- chloro-3-hydroxyl -
N-butyl alcohol.
The preparation method of (s) 6. according to claim 5-3- hydroxyl tetrahydrofuran, it is characterised in that:
Prepare first catalyst method particularly includes: under nitrogen protection, by [Ir (COD) Cl]2It is molten with phosphine-pyridine ligand
In the first solvent, 8~12min is stirred at room temperature.
The preparation method of (s) 7. according to claim 6-3- hydroxyl tetrahydrofuran, it is characterised in that:
The volume ratio of first solvent and 4- chloroacetyl acetacetic ester is 10:1~1:1 in step 1, wherein the volume of the first solvent
Volume including the first solvent being added when the first catalyst of the first solvent for being added in 4- chloroacetyl acetacetic ester and preparation it
It is 1:100~1:5 with the molar ratio of, alkali and 4- chloroacetyl acetacetic ester, theoretically the first catalyst and 4- chloracetyl obtained
The molar ratio of ethyl acetate is 1:10000~1:1000, and the molar ratio of the second catalyst and 4- chloroacetyl acetacetic ester is 1:
1000~1:100；
The volume ratio of second solvent and (s) -4- chloro-3-hydroxyl-n-butyl alcohol obtained in step 1 is 10:1~1:1 in step 2,
The ratio of the amount of (s) -4- chloro-3-hydroxyl-n-butyl alcohol substance made from theory is 10:1~1 in the amount and step 1 of the substance of acid:
1。
The preparation method of (s) 8. according to claim 7-3- hydroxyl tetrahydrofuran, it is characterised in that:
The volume ratio of first solvent and 4- chloroacetyl acetacetic ester is 5:1~2:1 in step 1, wherein the volume packet of the first solvent
The sum of the volume for the first solvent being added when including the first catalyst of the first solvent being added in 4- chloroacetyl acetacetic ester and preparation,
The molar ratio of alkali and 4- chloroacetyl acetacetic ester is 1:20~1:10, theoretically the first catalyst and 4- chloroethene ethyl acetoacetic acid obtained
The molar ratio of ethyl ester is 1:5000~1:2000, and the molar ratio of the second catalyst and 4- chloroacetyl acetacetic ester is 1:500~1:
200；
The volume ratio of second solvent and (s) -4- chloro-3-hydroxyl-n-butyl alcohol obtained in step 1 is 5:1~2:1, acid in step 2
Substance amount and step 1 in the ratio of amount of (s) -4- chloro-3-hydroxyl-n-butyl alcohol substance made from theory be 5:1~2:1.
The preparation method of (s) 9. according to claim 1-3- hydroxyl tetrahydrofuran, it is characterised in that:
First solvent is anhydrous methylene chloride, in anhydrous dichloroethanes, methanol, ethyl alcohol, anhydrous tetrahydro furan, dry toluene
Any one；
Second solvent is deionized water, methanol, ethyl alcohol, isopropanol, tetrahydrofuran, any one in dioxane；
The alkali is sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, sodium bicarbonate, any one in potassium carbonate；
Any one sour in hydrochloric acid, sulfuric acid, phosphoric acid, p-methyl benzenesulfonic acid.
The preparation method of (s) 10. according to claim 9-3- hydroxyl tetrahydrofuran, it is characterised in that:
First solvent is methanol or ethyl alcohol；
Second solvent is deionized water or methanol；
The alkali is sodium methoxide or potassium tert-butoxide；
The acid is hydrochloric acid or sulfuric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910821576.7A CN110396072B (en) | 2019-09-02 | 2019-09-02 | Method for producing(s) -3-hydroxytetrahydrofuran |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910821576.7A CN110396072B (en) | 2019-09-02 | 2019-09-02 | Method for producing(s) -3-hydroxytetrahydrofuran |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110396072A true CN110396072A (en) | 2019-11-01 |
| CN110396072B CN110396072B (en) | 2022-09-13 |
Family
ID=68329672
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910821576.7A Active CN110396072B (en) | 2019-09-02 | 2019-09-02 | Method for producing(s) -3-hydroxytetrahydrofuran |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110396072B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248461A (en) * | 2021-05-17 | 2021-08-13 | 青岛化赫医药科技有限公司 | Preparation method of hydroxyl oxygen heterocyclic alkane derivative |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2456937A1 (en) * | 1973-12-03 | 1975-06-26 | Monsanto Co | ASYMMETRIC CATALYSIS |
| CA1070711A (en) * | 1975-05-03 | 1980-01-29 | Hoechst Aktiengesellschaft | Process for preparing butanediol-(1.4) |
| CN101163656A (en) * | 2004-07-01 | 2008-04-16 | 英尼奥斯美国有限责任公司 | Catalysts for maleic acid hydrogenation to 1,4-butanediol |
| CN102040625A (en) * | 2010-11-19 | 2011-05-04 | 南开大学 | Chiral spiro pyridylamidophosphine ligand compounds and synthesis method and application thereof |
| CN102177170A (en) * | 2009-10-23 | 2011-09-07 | 高砂香料工业株式会社 | Novel ruthenium carbonyl complex having a tridentate ligand and manufacturing method and usage therefor |
| CN103347844A (en) * | 2011-02-03 | 2013-10-09 | 中央硝子株式会社 | Method for producing ss-fluoroalcohol |
| CN105153229A (en) * | 2015-06-18 | 2015-12-16 | 武汉凯特立斯科技有限公司 | Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation |
| CN106853378A (en) * | 2015-12-08 | 2017-06-16 | 中国科学院大连化学物理研究所 | The ternary catalyst systems of the part of structural framework containing PNN and its application |
| CN107098872A (en) * | 2017-03-23 | 2017-08-29 | 苏州华道生物药业股份有限公司 | A kind of production technology of the hydroxyl tetrahydrofuran of high-optical-purity 3 |
| CN108101785A (en) * | 2016-11-24 | 2018-06-01 | 中国科学院大连化学物理研究所 | A kind of method that iridium catalysis asymmetric hydrogenation prepares chiral beta-hydroxy ester |
| CN110003005A (en) * | 2019-04-22 | 2019-07-12 | 上海欣海国际贸易有限公司 | The method for preparing chiral beta-hydroxy carboxylate compound |
-
2019
- 2019-09-02 CN CN201910821576.7A patent/CN110396072B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2456937A1 (en) * | 1973-12-03 | 1975-06-26 | Monsanto Co | ASYMMETRIC CATALYSIS |
| CA1070711A (en) * | 1975-05-03 | 1980-01-29 | Hoechst Aktiengesellschaft | Process for preparing butanediol-(1.4) |
| CN101163656A (en) * | 2004-07-01 | 2008-04-16 | 英尼奥斯美国有限责任公司 | Catalysts for maleic acid hydrogenation to 1,4-butanediol |
| CN102177170A (en) * | 2009-10-23 | 2011-09-07 | 高砂香料工业株式会社 | Novel ruthenium carbonyl complex having a tridentate ligand and manufacturing method and usage therefor |
| CN102040625A (en) * | 2010-11-19 | 2011-05-04 | 南开大学 | Chiral spiro pyridylamidophosphine ligand compounds and synthesis method and application thereof |
| CN103347844A (en) * | 2011-02-03 | 2013-10-09 | 中央硝子株式会社 | Method for producing ss-fluoroalcohol |
| CN105153229A (en) * | 2015-06-18 | 2015-12-16 | 武汉凯特立斯科技有限公司 | Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation |
| CN106853378A (en) * | 2015-12-08 | 2017-06-16 | 中国科学院大连化学物理研究所 | The ternary catalyst systems of the part of structural framework containing PNN and its application |
| CN108101785A (en) * | 2016-11-24 | 2018-06-01 | 中国科学院大连化学物理研究所 | A kind of method that iridium catalysis asymmetric hydrogenation prepares chiral beta-hydroxy ester |
| CN107098872A (en) * | 2017-03-23 | 2017-08-29 | 苏州华道生物药业股份有限公司 | A kind of production technology of the hydroxyl tetrahydrofuran of high-optical-purity 3 |
| CN110003005A (en) * | 2019-04-22 | 2019-07-12 | 上海欣海国际贸易有限公司 | The method for preparing chiral beta-hydroxy carboxylate compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248461A (en) * | 2021-05-17 | 2021-08-13 | 青岛化赫医药科技有限公司 | Preparation method of hydroxyl oxygen heterocyclic alkane derivative |
| CN113248461B (en) * | 2021-05-17 | 2022-07-22 | 上海巽田科技股份有限公司 | Preparation method of hydroxyl oxygen heterocyclic alkane derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110396072B (en) | 2022-09-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lu et al. | Sustainable routes for quantitative green selenocyanation of activated alkynes | |
| CN114605366B (en) | Synthesis method and synthesis system for preparing hydroxypropyl pyrantriol by continuous flow | |
| CN109534975A (en) | A kind of efficient catalytic synthetic method of 2- hydroxy benzophenone ketone compound | |
| CN102336723A (en) | Preparation method of L-chloperastine fendizoic acid | |
| CN110396072A (en) | (s) preparation method of -3- hydroxyl tetrahydrofuran | |
| CN110003005A (en) | The method for preparing chiral beta-hydroxy carboxylate compound | |
| CN104710402A (en) | Dicyclohexyl crown ether synthesis method | |
| CN112250611B (en) | Synthesis method of-2- (2, 5-difluorophenyl) pyrrolidine hydrochloride | |
| CN101519351B (en) | Method for preparing high allyl alcohol ester | |
| CN110317170B (en) | Green synthesis method of 3-phenanthridinyl propyl formate compound | |
| CN109942432B (en) | Triaryl methanol compound and synthetic method thereof | |
| CN113996339A (en) | Catalyst for preparing cyclic carbonate and preparation method of cyclic carbonate | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN103183592B (en) | The preparation method of chloro-1,1, the 1-tri-alkoxy ethane of 2- | |
| CN102850270A (en) | Method for preparing hydroxy substituted-3,4-dihydro-2(1H)-quinolinone compound by one-pot method | |
| CN112680497A (en) | Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme | |
| CN111499497A (en) | Preparation method of thymol | |
| CN112321399A (en) | Preparation method of chemical intermediate | |
| CN103664743A (en) | Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate | |
| CN109879775A (en) | A kind of environment-friendly preparation method of 5-ALA hydrochloride intermediate | |
| CN110330429A (en) | A kind of preparation method of chiral beta-hydroxy ester compound | |
| CN114716341B (en) | Method for preparing dimethenamid by one-pot method | |
| CN109232224B (en) | Preparation method of 2-phenylpropionic acid | |
| CN115536494B (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol | |
| CN111018701B (en) | Method for preparing decanediol dicarboxylate and derivatives thereof |
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 | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: Room 308, 2000 Dongming Road, Pudong New Area, Shanghai 200123 Applicant after: Shanghai Xinhai Jianwei Industrial Co.,Ltd. Address before: Room 308, 2000 Dongming Road, Pudong New Area, Shanghai 200123 Applicant before: SHANGHAI SHINE HIGH INTERNATIONAL TRADE Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |