CN112300186B - Process for preparing hexahydrofurofuranol derivative, intermediate and process for preparing the same - Google Patents

Process for preparing hexahydrofurofuranol derivative, intermediate and process for preparing the same Download PDF

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CN112300186B
CN112300186B CN201910706770.0A CN201910706770A CN112300186B CN 112300186 B CN112300186 B CN 112300186B CN 201910706770 A CN201910706770 A CN 201910706770A CN 112300186 B CN112300186 B CN 112300186B
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ethyl acetate
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concentrating
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CN112300186A (en
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刘声民
林荆鑫
郑辉
叶美其
高照波
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of hexahydrofurofuranol derivatives, intermediates thereof and a preparation method thereof. The preparation method comprises condensation reaction, deprotection and cyclization reaction,Wherein R 1 and R 2 are hydrogen or hydroxyl protecting groups, R 3 is alkyl, acyl, ether, ester or aryl, and X is oxygen, sulfur or nitrogen. In the preparation process of hexahydrofurofuranol derivatives, the compound of the formula I can prepare a product with very high optical purity by adopting the way through condensation reaction. The preparation method can realize commercial production of the key intermediate (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol of darunavir, and is a very economical route suitable for industrial production.

Description

Process for preparing hexahydrofurofuranol derivative, intermediate and process for preparing the same
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of hexahydrofurofuranol derivatives, intermediates thereof and a preparation method thereof.
Background
The compound having the structure of formula IV below is the chemical name (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol:
Belonging to one of hexahydrofurofuranol derivatives, and being an intermediate of darunavir as an anti-AIDS drug.
The racemization structure of the darunavir belongs to an intermediate of the darunavir which is an anti-AIDS drug.
Chinese patent application CN101541775 discloses the reaction of glyoxylate derivatives of formula (III) wherein n is 0, 1, 2 or 3 and R is alkyl or arylalkyl, using 2, 3-dihydrofuran of formula (II) in the presence of a titanium salt of formula Ti (Hal) n(OR)4-n, and subsequently reacting the resulting reaction product with an alcohol of formula (IV) to form a compound of formula (V):
Wherein R 1 is alkyl or arylalkyl and R 2 is alkyl or arylalkyl;
reducing the resulting compound of formula (V) to form a compound of formula (VI);
cyclizing the compound of formula (VI) to form a compound of formula (I);
Chiral separation is carried out to obtain (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol.
The invention prepares (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol and the report of the preparation method of hexahydrofuro [2,3-b ] -3-alcohol by condensation, deprotection and cyclization reaction is basically in a blank state, and the method has simple operation, relatively high yield and strong applicability of industrialized amplification production. The method brings great help to both the economic benefit and the operation flow of the drug synthesis.
Disclosure of Invention
The process for the preparation of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol and-hexahydrofuro [2,3-b ] -3-ol of the present invention starts with reaction with methoxy alcohol and has been studied to develop a process for the preparation of key intermediates of darunavir which is different from the starting materials in the existing patent applications. The preparation method provided by the invention has the advantages of low cost and mild reaction conditions, and provides another route suitable for industrialization for the preparation of the darunavir key intermediate.
In order to achieve the technical purpose of the invention, the invention provides the following technical scheme:
In a first aspect the present invention provides an intermediate compound for the preparation of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol having the structural formula:
Wherein, R 1 and R 2 are hydrogen or hydroxyl protecting groups, and R 3 is alkyl, acyl, ether, ester or aryl; x is oxygen, sulfur or nitrogen. The hydroxyl protecting group is alkyl, silyl, acyl of C 2-11, cycloalkenyl of C 4-9, aryl, aralkyl, aroyl, phenyl, substituted phenyl, ether of C 2-11, ester of C 2-11; the silane group is tetramethylsilane group, trimethylsilane group, triethylsilane group, tri-n-butylsilane group and tert-butyldimethylsilyl group; the alkyl is C 1-C8 alkyl; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxyalkyl substituted phenyl, nitroalkyl substituted phenyl or halogen substituted phenyl; the phenyl substituted by the alkyl is benzyl, benzhydryl and trityl; the phenyl substituted by the alkoxyalkyl is p-methoxybenzyl; the nitroalkyl-substituted phenyl is p-nitrobenzyl; the halogen substituted phenyl is p-chlorophenyl, and the ether group is oxyether or thioether; the ester group is carbonyl ester, sulfate or phosphate.
In a second aspect, the invention provides a process for the preparation of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol of formula IV by cyclization of a compound of formula II' in the presence of an acid,
Wherein R 2、R3 and X are as defined above;
The acid in the cyclization reaction step is organic acid, inorganic acid or Lewis acid.
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid and m-nitrobenzenesulfonic acid, the m-nitrobenzoic acid, the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and the Lewis acid is selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, and is preferably hydrochloric acid;
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The third aspect of the invention provides a preparation method of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol formula IV, which is prepared by deprotection of the compound of the formula II under the existence of acid, alkali or metal catalyst to obtain the compound of the formula II ', and then cyclizing the compound of the formula II' under the existence of acid,
Wherein R 1,R2、R3 and X are as defined above;
The alkali in the deprotection step is organic alkali or inorganic alkali;
the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium borohydride, lithium aluminum hydride and red aluminum, the metal catalyst is selected from palladium reagent and nickel reagent, and preferably sodium carbonate;
The reaction temperature of the deprotection step is 10-50 ℃, preferably 15-35 ℃;
The acid in the cyclization reaction step is organic acid, inorganic acid or Lewis acid;
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid and m-nitrobenzoic acid, the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and the Lewis acid is selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, and is preferably hydrochloric acid;
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The fourth aspect of the invention provides a preparation method of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol formula IV, which is prepared by condensation reaction of a compound of formula I in the presence of acid to obtain a compound of formula II, deprotection of the compound of formula II in the presence of acid or alkali to obtain a compound of formula II ', cyclization of the compound of formula II in the presence of acid to obtain the compound of formula II',
Wherein, R 1,R2、R3 and X are defined as above.
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid and m-nitrobenzoic acid, and the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, preferably p-toluenesulfonic acid;
The reaction temperature of the condensation reaction step is 10-50 ℃, preferably 15-35 ℃;
the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium borohydride, lithium aluminum hydride and red aluminum, the metal catalyst is selected from palladium reagent and nickel reagent, and preferably sodium carbonate;
The reaction temperature of the deprotection step is 10-50 ℃, preferably 15-35 ℃;
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid and m-nitrobenzene, the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and the Lewis acid is selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, preferably hydrochloric acid;
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The preparation method of the (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol has the advantages of low cost and mild reaction conditions, and provides another route suitable for industrialization for the preparation of the darunavir key intermediate.
In a fifth aspect the present invention provides hexahydrofuro [2,3-b ] -3-ol intermediate compounds of formula V having the formula:
Or an isomer thereof.
Wherein, R 1 and R 2 are hydrogen or hydroxyl protecting groups, and R 3 is alkyl, acyl, ether, ester or aryl; x is oxygen, sulfur or nitrogen. The hydroxyl protecting group is alkyl, silyl, acyl of C 2-11, cycloalkenyl of C 4-9, aryl, aralkyl, aroyl, phenyl, substituted phenyl, ether of C 2-11, ester of C 2-11; the silane group is tetramethylsilane group, trimethylsilane group, triethylsilane group, tri-n-butylsilane group and tert-butyldimethylsilyl group; the alkyl is C 1-C8 alkyl; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxyalkyl substituted phenyl, nitroalkyl substituted phenyl or halogen substituted phenyl; the phenyl substituted by the alkyl is benzyl, benzhydryl and trityl; the phenyl substituted by the alkoxyalkyl is p-methoxybenzyl; the nitroalkyl-substituted phenyl is p-nitrobenzyl; the halogen substituted phenyl is p-chlorophenyl, and the ether group is oxyether or thioether; the ester group is carbonyl ester, sulfate or phosphate.
The sixth aspect of the invention provides a process for preparing hexahydrofuro [2,3-b ] -3-ol of formula VI, which comprises cyclizing an intermediate compound of formula V' in the presence of an acid,
Wherein R 2、R3 and X are as defined above;
The acid in the cyclization reaction step is organic acid, inorganic acid or Lewis acid.
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid and m-nitrobenzenesulfonic acid, the m-nitrobenzoic acid, the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and the Lewis acid is selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, and is preferably hydrochloric acid;
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The seventh aspect of the invention provides a method for preparing hexahydrofuro [2,3-b ] -3-alcohol formula VI, which comprises the steps of preparing a compound of formula V 'from an intermediate formula V through deprotection under the condition of acid, alkali or metal catalyst, and then preparing the compound of formula V' through cyclization reaction in the presence of acid,
Wherein R 1,R2、R3 and X are as defined above;
The alkali in the deprotection step is organic alkali or inorganic alkali;
the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium borohydride, lithium aluminum hydride and red aluminum, the metal catalyst is selected from palladium reagent and nickel reagent, and preferably sodium carbonate;
The reaction temperature of the deprotection step is 10-50 ℃, preferably 15-35 ℃;
The acid in the cyclization reaction step is organic acid, inorganic acid or Lewis acid;
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid and m-nitrobenzoic acid, the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and the Lewis acid is selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, and is preferably hydrochloric acid;
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The eighth aspect of the invention provides a method for preparing hexahydrofuro [2,3-b ] -3-alcohol formula VI, which comprises the steps of preparing a compound of formula V by condensation reaction of a compound of formula I in the presence of acid, preparing a compound of formula V 'by deprotection of the compound of formula V in the presence of acid, alkali or metal catalyst, preparing the compound of formula V' by cyclization reaction of the compound of formula V in the presence of acid,
Wherein, R 1,R2、R3 and X are defined as above.
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid and m-nitrobenzoic acid, and the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, preferably p-toluenesulfonic acid;
The reaction temperature of the condensation reaction step is 10-50 ℃, preferably 15-35 ℃;
the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine and imidazole, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium borohydride, lithium aluminum hydride and red aluminum, the metal catalyst is selected from palladium reagent and nickel reagent, and preferably sodium carbonate;
The reaction temperature of the deprotection step is 10-50 ℃, preferably 15-35 ℃;
The organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid and m-nitrobenzene, the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid and phosphoric acid, and the Lewis acid is selected from aluminum chloride, ferric chloride, boron trifluoride and niobium pentachloride, preferably hydrochloric acid;
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The reaction temperature of the cyclization reaction step is-10-20 ℃, preferably-5-15 ℃.
The method for preparing hexahydrofuro [2,3-b ] -3-alcohol has low cost and mild reaction conditions, and provides another route suitable for industrialization for preparing the darunavir key intermediate
Detailed Description
For a further understanding of the present invention, the preparation of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol and-hexahydrofuro [2,3-b ] -3-ol by the process provided in the present invention is described in detail below in connection with examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1:
to a dry four-necked flask, compound I (1.0 g,3.96 mmol), ethylene glycol methyl ether 4g and p-toluenesulfonic acid monohydrate (0.038 g,0.22 mmol) were added, and after the reaction was carried out at 20 to 25℃with stirring for about 1 hour, sampling and detection were carried out, and after the reaction was completed, sodium carbonate was neutralized, and concentrated to dryness at 60 to 70℃under reduced pressure to give oily Compound II.
To the compound II, 4g of methanol and sodium carbonate (0.21 g,1.98 mmol) were added, and the mixture was reacted at 20 to 25℃for 5 to 8 hours with sampling. After the reaction is finished, filtering, leaching a filter cake by using a proper amount of methanol, decompressing and concentrating filtrate at 40-50 ℃ until the filtrate is dried, and obtaining a sticky substance. 3ml of water and 1ml of toluene were added and stirred, and the mixture was allowed to stand for delamination, and an aqueous layer was collected, which was an aqueous solution of Compound III.
The temperature of the aqueous solution of the compound III is reduced by 0 to 5 ℃, concentrated hydrochloric acid (0.45 g,4.38 mmol) is added, the temperature is kept for about 8 hours at 0 to 5 ℃, and sampling GC detection is carried out. After the reaction, the pH value is adjusted to be slightly alkaline with sodium carbonate=7-8, and the mixture is concentrated to be dry under reduced pressure at 60-70 ℃ to obtain a sticky substance. Ethyl acetate was added to stir, filter, the filter cake was rinsed with ethyl acetate, and the filtrate was collected. Concentrating under reduced pressure until no liquid flows out, 0.54g of oily compound IV is obtained, the yield is 89.4%, and the GC purity is 86.3%.
Example 2:
to a dry four-necked flask, compound I '(1.3 g,5.15 mmol), ethylene glycol methyl ether 5g and p-toluenesulfonic acid monohydrate (0.049 g,0.26 mmol) were added, the mixture was stirred at 25 to 30℃under constant temperature, the reaction was carried out for 1 hour, sampling and detection were carried out, sodium carbonate was neutralized after the completion of the reaction, and the mixture was concentrated to dryness under reduced pressure at 60 to 70℃to obtain oily Compound II'.
To the compound II', 5g of methanol and sodium carbonate (0.27 g,2.55 mmol) were added, and the mixture was reacted at 22 to 28℃with a constant temperature for 10 hours, followed by sampling and detection. The raw materials disappear, the reaction is stopped, the filter cake is leached by methanol, and the filtrate is decompressed and concentrated to dryness at 45-50 ℃ to obtain viscous oily matter. 3ml of water and 1ml of toluene were added and stirred, and the mixture was allowed to stand for delamination, and an aqueous layer was collected, which was an aqueous solution of compound III'.
The temperature of the aqueous solution of the compound III' is reduced to-2 to 3 ℃, concentrated hydrochloric acid (0.58 g,5.66 mmol) is added, and the temperature is kept at-2 to 3 ℃ for about 6 to 9 hours, and sampling GC detection is carried out. After the reaction, the pH value is adjusted to be slightly alkaline by sodium carbonate=7-8, and the mixture is concentrated to be dry at 55-70 ℃ under reduced pressure to obtain a sticky substance. Ethyl acetate was added to stir, filter, the filter cake was rinsed with ethyl acetate, and the filtrate was collected. Concentrating under reduced pressure until no liquid flows out, 0.68g of oily compound IV' is obtained, the yield is 85.6%, and the GC purity is 88.1%.
Example 3:
To a dry four-necked flask, compound 10 (1.8 g,7.13 mmol), ethylene glycol methyl ether 7.2g and p-toluenesulfonic acid monohydrate (0.068 g,0.36 mmol) were added, the mixture was stirred at 22 to 26℃under constant temperature, the reaction was carried out for about 0.5 to 1 hour, sampling and detection were carried out, sodium carbonate was neutralized after completion of the reaction, and the mixture was concentrated to dryness under reduced pressure at 60 to 70℃to give oily compound 20.
7G of methanol and sodium carbonate (0.38 g,3.56 mmol) are added into the compound 20, the temperature is kept between 22 and 26 ℃ for reaction, and sampling and detection are carried out for 6 to 10 hours. After the reaction is finished, filtering, leaching with a proper amount of methanol, decompressing and concentrating the filtrate at 40-50 ℃ until the filtrate is dried, and obtaining a sticky substance. 5ml of toluene and 2ml of toluene were added thereto, and the mixture was stirred, allowed to stand for delamination, and an aqueous layer was collected, which was an aqueous solution of Compound 30.
The temperature of the aqueous solution of the compound 30 is reduced to-2 to 5 ℃, concentrated hydrochloric acid (0.85 g,8.5 mmol) is added, the temperature is kept at 0 to 5 ℃ for 5 to 8 hours, and sampling GC detection is carried out. After the reaction, the pH=7-8 was adjusted with sodium carbonate, and concentrated to dryness under reduced pressure at 50-70℃to give an oil. Ethyl acetate was added to stir, filter, the filter cake was rinsed with ethyl acetate, and the filtrate was collected. Concentrating under reduced pressure until no liquid flows out, 0.95g of oily compound 40 is obtained, the yield is 90.4%, and the GC purity is 87.5%.
Example 4:
To a dry four-necked flask, compound 10 '(1.5 g,5.95 mmol), ethylene glycol methyl ether 6g and p-toluenesulfonic acid monohydrate (0.057 g,0.3 mmol) were added, and after the reaction was carried out at 20 to 25℃with stirring and with stirring for about 1 hour, sampling and detection were carried out, and after the reaction was completed, sodium carbonate was neutralized, and then concentrated to dryness under reduced pressure at 60 to 70℃was started to obtain an oily compound 20'.
6G of methanol and sodium carbonate (0.32 g,2.98 mmol) were added to the compound 20', and the mixture was reacted at 25 to 30℃for 8 to 10 hours with sampling. After the reaction is finished, filtering, eluting with methanol, decompressing and concentrating filtrate at 40-50 ℃ until the filtrate is dried to obtain oily matter. 5ml of toluene and 2ml of toluene were added thereto, and the mixture was stirred, allowed to stand for delamination, and an aqueous layer was collected, which was an aqueous solution of Compound 30'.
The temperature of the 30' aqueous solution of the compound is reduced to-1 to 5 ℃, concentrated hydrochloric acid (0.67 g,6.54 mmol) is added, and the temperature is kept for about 8 to 10 hours at 0 to 5 ℃. After the reaction, the pH=7-8 is adjusted by sodium carbonate, and the mixture is concentrated to dryness under reduced pressure at 50-70 ℃ to obtain a sticky substance. Ethyl acetate was added to stir, filter, the filter cake was rinsed with ethyl acetate, and the filtrate was collected. Concentrating under reduced pressure until no liquid flows out, 0.8g of oily compound 40' is obtained, the yield is 85.0%, and the GC purity is 80.2%.
Example 5:
To a dry four-necked flask, compound 10 '(1.5 g,5.95 mmol), ethylene glycol methyl ether 6g and p-toluenesulfonic acid monohydrate (0.057 g,0.3 mmol) were added, and after the reaction was carried out at 20 to 25℃with stirring and with stirring for about 1 hour, sampling and detection were carried out, and after the reaction was completed, sodium carbonate was neutralized, and then concentrated to dryness under reduced pressure at 60 to 70℃was started to obtain an oily compound 20'.
6G of methanol and sodium carbonate (0.32 g,2.98 mmol) were added to the compound 20', and the mixture was reacted at 25 to 30℃for 8 to 10 hours with sampling. After the reaction is finished, filtering, eluting with methanol, decompressing and concentrating filtrate at 40-50 ℃ until the filtrate is dried to obtain oily matter. 5ml of toluene and 2ml of toluene were added thereto, and the mixture was stirred, allowed to stand for delamination, and an aqueous layer was collected, which was an aqueous solution of Compound 30'.
The temperature of the 30' aqueous solution of the compound is reduced to-1 to 5 ℃, concentrated hydrochloric acid (0.67 g,6.54 mmol) is added, and the temperature is kept for about 8 to 10 hours at 0to 5 ℃. After the reaction, the pH=7-8 is adjusted by sodium carbonate, and the mixture is concentrated to dryness under reduced pressure at 50-70 ℃ to obtain a sticky substance. Ethyl acetate was added to stir, filter, the filter cake was rinsed with ethyl acetate, and the filtrate was collected. Concentrating under reduced pressure until no liquid flows out, 0.8g of oily compound 40' is obtained, the yield is 84.0%, and the GC purity is 80%.

Claims (4)

1. A process for preparing (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -furan-3-ol IV is characterized in that methanol and sodium carbonate are added into a compound II, the reaction is carried out at 20-25 ℃ for 5-8 h, sampling and detection are carried out, after the reaction is finished, filtering, leaching filter cake with a proper amount of methanol, decompressing and concentrating the filtrate at 40-50 ℃ until dryness to obtain a sticky substance, adding water and toluene, stirring, standing for layering, collecting a water layer, the water layer is a compound II 'aqueous solution, cooling the compound II' aqueous solution by 0-5 ℃, adding concentrated hydrochloric acid, preserving heat for about 8h at 0-5 ℃, sampling GC detection, adjusting pH value to 7-8 with sodium carbonate after the reaction is finished, decompressing and concentrating to dryness at 60-70 ℃ to obtain the sticky substance, adding ethyl acetate, stirring, filtering, leaching filter cake with ethyl acetate, collecting filtrate, decompressing and concentrating until no liquid flows out,
The compound II is:
the compound II' is:
2. A process for preparing (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -furan-3-ol IV is characterized in that a dry four-mouth flask is added with a compound I, ethylene glycol methyl ether and p-toluenesulfonic acid, the mixture is stirred at a temperature of 20-25 ℃, after the reaction is carried out for about 1 hour, sampling detection is carried out, sodium carbonate is neutral after the reaction is finished, the mixture is concentrated to dryness at 60-70 ℃ under reduced pressure to obtain an oily compound II, methanol and sodium carbonate are added into the compound II, the mixture is subjected to heat preservation reaction at 20-25 ℃ for 5-8 hours, after the reaction is finished, a filter cake is leached by a proper amount of methanol, the filtrate is subjected to reduced pressure and concentrated to dryness at 40-50 ℃ to obtain a sticky substance, water and toluene are added and stirred, the mixture is kept for layering, a water layer is collected, the water layer is an aqueous solution of the compound II', the aqueous solution is cooled to 0-5 ℃, concentrated hydrochloric acid is added at 0-5 ℃ and the temperature of about 8 hours, the sample is carried out after the reaction is finished, sodium carbonate is subjected to reduced pressure concentration to pH=7-8, the mixture is subjected to reduced pressure and alkaline pH=60-70 ℃, the mixture is leached to obtain a sticky filter cake, ethyl acetate is concentrated, ethyl acetate is obtained, the sticky filter cake is obtained, ethyl acetate is concentrated, ethyl acetate is obtained, and ethyl acetate is not filtered, and concentrated, and ethyl acetate is obtained, and the sticky filtrate is obtained, and ethyl acetate is filtered,
The compound I is:
The compound II is:
the compound II' is:
3. A process for preparing hexahydrofuro [2,3-b ] -furan-3-ol type VI includes such steps as adding methanol and sodium carbonate to intermediate type V compound, thermal insulating reaction at 25-30 deg.C, sampling for 8-10 hr, detecting, filtering, eluting with methanol, concentrating filtrate at 40-50 deg.C to obtain oily substance, adding water and toluene, stirring, laying aside, collecting water layer, cooling to-2-5 deg.C, adding concentrated hydrochloric acid at 0-5 deg.C, thermal insulating for 5-8 hr, sampling, GC detecting, regulating pH value to 7-8 with sodium carbonate, concentrating at 50-70 deg.C to obtain oily substance, stirring with ethyl acetate, filtering, concentrating filter cake with ethyl acetate, concentrating under reduced pressure until no liquid flows out,
The formula V is:
The formula V' is:
4. A process for preparing hexahydrofuro [2,3-b ] -furan-3-ol VI includes such steps as adding compound I, glycol methyl ether and p-toluenesulfonic acid in four-mouth dry flask, stirring at 20-25 deg.C, sampling, detecting, regulating pH value to 7-8 by sodium carbonate, concentrating at 50-70 deg.C, filtering, eluting with methanol, concentrating filtrate at 40-50 deg.C to obtain oily substance, stirring with water and toluene, collecting water layer, cooling to-2-5 deg.C, adding concentrated hydrochloric acid, sampling, GC, regulating pH value to 7-8 by sodium carbonate, concentrating to obtain oily substance, adding ethyl acetate, stirring, filtering, eluting with ethyl acetate, concentrating until no liquid is reacted,
The formula I is:
The formula V is:
The formula V' is:
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CN1753898A (en) * 2002-12-27 2006-03-29 住友化学株式会社 Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
CN101541775A (en) * 2006-11-09 2009-09-23 泰博特克药品有限公司 Methods for the preparation of hexahydrofuro[2,3-b]furan-3-ol
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CN103896886A (en) * 2012-12-31 2014-07-02 上海迪赛诺化学制药有限公司 Darunavir midbody as well as preparation method and application thereof
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CN1753898A (en) * 2002-12-27 2006-03-29 住友化学株式会社 Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
CN101541775A (en) * 2006-11-09 2009-09-23 泰博特克药品有限公司 Methods for the preparation of hexahydrofuro[2,3-b]furan-3-ol
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