CN106928248B - A kind of method preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol - Google Patents

A kind of method preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol Download PDF

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CN106928248B
CN106928248B CN201710064302.9A CN201710064302A CN106928248B CN 106928248 B CN106928248 B CN 106928248B CN 201710064302 A CN201710064302 A CN 201710064302A CN 106928248 B CN106928248 B CN 106928248B
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step
ethylene glycol
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CN106928248A (en
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滕大为
仇中选
黄龙江
龙中柱
晏桂刚
安娜
蔡水洪
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青岛科技大学
启东东岳药业有限公司
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    • YGENERAL 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
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    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
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    • Y02P20/55Synthetic design, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of chemical synthesis, a kind of method for preparing darunavir intermediate (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is disclosed.With (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) for raw material; Stereoselective reacts to obtain intermediate (II) with ethylene glycol derivative under the action of catalyst; it is cyclized (3R in acid condition after gained intermediate (II) deprotection base; 3aS; 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol.The preparation method raw material is cheap and easy to get, and reaction stereoselectivity is high, and easy to operate, route is short, at low cost, is suitble to the industrialized production of darunavir.

Description

A kind of method preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol

Technical field

It is the present invention relates to the field of chemical synthesis, in particular to a kind of to prepare (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] The method of furan-3-ol.

Background technique

Darunavir (structural formula such as formula IV) also known as Da Lunawei are that a kind of new non-peptides for treating AIDS are anti- Reversal of viral protease inhibitors.Darunavir is researched and developed into for the first time by Tai Boteke (Tibotec) drugmaker of Johnson & Johnson's pharmacy Function is biological in current 6 kinds of protease inhibitors (inverase, Ritonavir, indinavir, nafenavir, An Ruinawei) Availability is highest, it is by blocking the formation from infected host cell surface release new, mature virion Journey inhibits the protease of virus and works.

Simultaneously [2,3-b] furan-3-ol (III) (structural formula is as shown in formula III) is synthetically to (3R, 3aS, 6aR) hexahydro furyl One of key intermediate of Rui Nawei, hexahydro furyl is simultaneously in the molecular structure of [2,3-b] furan-3-ol there are three chiral centre, Theoretically there are eight kinds of possible stereoisomers, due to the influence of bicyclic rigid structure, only there are four types of cis- and ring solids Isomers is thermodynamically stable.The method of a variety of prepare compounds (III) has been disclosed in the prior art, these methods are summarized Get up and be broadly divided into two major classes, first kind method is all then to pass through reductive ring open and again cyclization system by a lactone intermediate Standby (such as WO03022853, US20040162340, US6867321, WO2005095410, JOC 2004,69,7822-29, OL, 2005,26,5917-20, CN201210552770, CN201210588083), such method is all walked using longer reaction substantially Suddenly, need to use dangerous material nitromethane in Part Methods, the most key be these methods stereoselectivity it is poor, greatly Part requires to obtain single target isomer by splitting, and its by-product (i.e. the enantiomer of target product) is difficult to pass through Short-cut method is then converted to target product, so as to cause high production cost;Second class method is introduced at 3-, dihydrofuran ring The structure fragment of vicinal diamines, then be cyclized prepare target product (such as WO2004033462, WO2012070057, WO2013114382, WO2008055970, WO2004002975, TL, 1986,32,3715-18), such methods equally exist synthetic route length, reaction Condition is harsh, is industrially not easy to realize and the problems such as the stereoselectivity of target product (III) is poor.Therefore, the present invention provides A kind of easy to operate, route is short, the side of preparation at low cost (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol Method.

Summary of the invention

In order to solve the problems, such as that synthetic line in the prior art is long, complicated for operation and at high cost, the present invention provides one The method for kind preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol.

In order to solve the above-mentioned technical problem, the invention adopts the following technical scheme:

A kind of method preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, including following synthetic route In step b or step a~step b:

R therein1、R2For methyl, cyclohexyl or cyclopenta, R3For benzyl, THP or MOM.

The step (a) is with (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) for raw material, under the action of catalyst Stereoselective reacts to obtain intermediate (II) with alkylating reagent ethylene glycol derivative, and the step (b) is in described (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is cyclized after mesosome (II) deprotection base in acid condition.

In preparation method provided by the invention, step (a) used catalyst is selected from AMP, nafoxidine, piperidines, dried meat ammonia Acid or proline derivative, prolinol or prolinol derivative;Catalyst and (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) Molar ratio be 0.1:1~2:1.

In preparation method provided by the invention, alkylating reagent used in step (a) is ethylene glycol derivative, alkylation examination Agent dosage is 1.0-2.0 times of (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I);Preferably, halogenated (chlorine, bromine, iodine) ethyl alcohol spreads out The ethylene glycol derivative that biology or list OMs, OTs, OTf replace.

In preparation method provided by the invention, solvent used in step (a) be selected from methylene chloride, chloroform, toluene, DMF, DMSO or DMA;Alkali used in step (a) is selected from triethylamine, DIPEA, DABCO, DBU, DBN, pyridine, methyl piperidine, bicarbonate Sodium or sodium carbonate.

In preparation method provided by the invention, in the step (a), it is added into alkylating reagent ethylene glycol derivative Catalyst and temperature when (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) are -20~0 DEG C, and reaction temperature when reaction is 25 ~80 DEG C.

Preferably, acid used in step (b) is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid or p-methyl benzenesulfonic acid.

Preferably, solvent used in step (b) is alcohols or ethers;The alcohols is selected from methanol, ethyl alcohol, isopropanol or second Glycol, the ethers are selected from tetrahydrofuran, 2- methyltetrahydrofuran, methyl tertiary butyl ether(MTBE) or dioxane.

Preferably, the reaction temperature of step (b) is 20~100 DEG C.

It is further preferable that the reaction temperature of step (b) is 50~80 DEG C.

(3R, 3aS, the 6aR) hexahydro furyl being prepared the present invention also provides such as above method simultaneously [2,3-b] furans- 3- alcohol.

It should be noted that step (b) is cyclized or is removed under acid condition after deprotection base by compound (II) Protecting group and cyclisation are carried out at " in one pot ".

Further, work as R3When for benzyl and its derivative protecting group, step (b) includes two-step reaction, that is, hydrogenates de- R3It protects Protect base reaction and cyclization reaction;Wherein, catalyst used by hydrogenation is Raney Ni or Pd/C, Hydrogen Vapor Pressure 1- 5atm, solvent are the common hydrogenation solvents such as methanol, ethyl alcohol, tetrahydrofuran, ethyl acetate;Acid used by cyclization reaction is salt Acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, phosphoric acid and nitric acid, cyclization reaction temperature are 20-100 DEG C, more preferably 50-80 ℃。

And work as R3For removed under the acid conditions such as THP, MOM protecting group when, Deprotection and cyclization exist in step (b) " in one pot " is completed, and solvent used in the step is ethers (such as tetrahydrofuran, dioxane), alcohols (such as methanol, ethyl alcohol) Equal hydrophilic solvents;The acid used is hydrochloric acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, phosphoric acid and nitric acid etc., reaction temperature 20- 100 DEG C, more preferably 50-80 DEG C.

The preparation method of compound used in the present invention (I) can be obtained by two methods, and concrete technology route is as follows:

Process route one:

Process route two:

The present invention provides a kind of method for preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, the party Compared with prior art, there are following advantages for method: (one) raw material is cheap and easy to get, and reaction stereoselectivity is high, and by-product is few, thus Cause production cost low, the yield of (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is greatly improved; (2) preparation method is easy to operate, and reaction route is short, is suitble to the industrialized production of darunavir.

Specific embodiment

The invention discloses a kind of method for preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, abilities Field technique personnel can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that all similar replaces Change and change apparent to those skilled in the art, they are considered as including in the present invention.The present invention Method and application be described by preferred embodiment, related personnel can obviously not depart from the content of present invention, essence Method described herein and application are modified or appropriate changes and combinations in mind and range, carry out implementation and application skill of the present invention Art.

In order to enable those skilled in the art to better understand the present invention, With reference to embodiment to the present invention It is described in further detail.

Embodiment 1

Step (a): 2- benzyloxy 1- iodoethane (31.4g, 0.12mol) and DABCO (16.1g, 0.13mol) are dissolved in In 300mL methylene chloride, -20 DEG C are cooled to after being stirred at room temperature 30 minutes, (R) -2,2- diformazan is sequentially added into the mixed liquor Base -1,3-dioxolane -4- acetaldehyde (14.4g, 0.1mol) and nafoxidine (7.1g, 0.1mol).Gained reaction solution is heated up After being stirred to react 24 hours to 25 DEG C and at such a temperature, the hydrochloric acid of 100 milliliters of water and 100 milliliters of 1N is added, stirs 30 minutes After separate organic phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing dries, filters, and filtrate decompression is concentrated to give II, point Sterling 19.5g, yield 70% are obtained from after.

Step (b): compound (II) (30g, 0.11mol), 3.0 grams of 10%Pd/C and 200mL methanol are placed in round bottom and are burnt In bottle, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressure.It filters, 100 milliliters of hydrochloric acid of 3N is added in filtrate, It after gained mixture is heated to 60 DEG C of reactions 3 hours, is cooled to room temperature, triethylamine neutralization reaction liquid is added to alkalinity.Concentration is anti- It answers liquid to doing, ethyl acetate, filtering is added, filter cake is washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate phase concentration 12.9g compound III is obtained to dry rear column chromatography for separation.Yield is 90%.

Embodiment 2

Step (a): 2- benzyloxy 1- iodoethane (52.3g, 0.20mol) and triethylamine (13.1g, 0.13mol) are dissolved in In 300mL methylene chloride, -20 DEG C are cooled to after being stirred at room temperature 30 minutes;(R) -2,2- diformazan is sequentially added into the mixed liquor Base -1,3-dioxolane -4- acetaldehyde (14.4g, 0.1mol) and nafoxidine (1.42g, 0.02mol), by gained reaction solution liter After temperature is stirred to react 24 hours to 25 DEG C and at such a temperature, the hydrochloric acid of 100mL water and 100mL1N is added, after stirring 30 minutes Organic phase is separated, organic phase anhydrous magnesium sulfate after saturated common salt water washing dries, filters, and filtrate decompression is concentrated to give II, separation Sterling 17.5g, yield: 63% are obtained afterwards.

Step (b): compound (II) (35g, 0.13mol), 3.5g10%Pd/C and 250mL tetrahydrofuran are placed in round bottom In flask, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressure.It filters, 100mL water and 30mL first is added in filtrate Sulfonic acid is cooled to room temperature after gained mixture is heated to 50 DEG C of reactions 5 hours, and triethylamine neutralization reaction liquid is added to alkalinity.It is dense Contracting reaction liquid to dry, addition ethyl acetate, filtering, filter cake is washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate phase 14.7g compound III is separated to obtain after being concentrated to dryness.Yield: 87%.

Embodiment 3

Step (a): by 2- (2- iodine ethyoxyl) tetrahydro -2H- pyrans (51.2g, 0.20mol) and triethylamine (21.2g, It 0.21mol) is dissolved in 300mL chloroform, is cooled to 0 DEG C after being stirred at room temperature 30 minutes;Sequentially added into the mixed liquor (14.4g, 0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L- prolinol derivative L-2- (diphenyl-triphen silicon oxygen Methyl) nafoxidine (25.5g, 0.05mol), after gained reaction solution rises to 40 DEG C and is stirred to react 10 hours at such a temperature, The hydrochloric acid of 100mL water and 100mL1N is added, stirring separated organic phase, organic phase nothing after saturated common salt water washing after 30 minutes Water magnesium sulfate dries, filters, and filtrate decompression is concentrated to give compound II crude product.

Step (b): the hydrochloric acid 100mL of tetrahydrofuran 200mL, 3N being added into the crude product, and gained reaction solution is heated to 65 DEG C reaction 6 hours.Triethylamine is added until reaction liquid is in alkalinity, ethyl acetate, filtering is added to doing in concentration of reaction solution body. Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, and compound III crude product is obtained, and crude product obtains after column chromatography for separation 9.1g compound III sterling, yield 70%.

Embodiment 4

Step (a): 2- benzyloxy 1- iodoethane (31.4g, 0.12mol) and triethylamine (13.1g, 0.13mol) are dissolved in In 300mL methylene chloride, -10 DEG C are cooled to after being stirred at room temperature 30 minutes;(R) -2,2- diformazan is sequentially added into the mixed liquor Base -1,3-dioxolane -4- acetaldehyde (14.4g, 0.1mol) and L- prolinol (10.1g, 0.1mol), gained reaction solution rise to 80 DEG C and after being stirred to react 15 hours at such a temperature, the hydrochloric acid of 100mL water and 100mL1N is added, stirring has separated after 30 minutes Machine phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing dry, filter, and filtrate decompression is concentrated to give II, obtain after separation pure Product 22.8g, yield: 82%.

Step (b): compound (II) (30g, 0.11mol), 3.0g10%Pd/C and 200mL isopropanol are placed in round bottom and burnt In bottle, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressure.It filters, the p-methyl benzenesulfonic acid of 3N is added in filtrate 100mL is cooled to room temperature after gained mixture is heated to 20 DEG C of reactions 3 hours, and triethylamine neutralization reaction liquid is added to alkalinity. Concentration of reaction solution body to dry, addition ethyl acetate, filtering, filter cake is washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate 12.9g compound III is separated to obtain after being mutually concentrated to dryness.Yield: 90%.

Embodiment 5

Step (a): by 2- benzyloxy 1- chloroethanes (20.4g, 0.12mol) and 1,11 carbon -7- alkene of 8- diazabicylo (abbreviation DBU) (16.1g, 0.13mol) is dissolved in 300mL toluene, is cooled to -20 DEG C after being stirred at room temperature 30 minutes;To the mixing (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde (14.4g, 0.1mol) and L- diphenylprolinol are sequentially added in liquid After gained reaction solution rises to 40 DEG C and is stirred to react 20 hours at such a temperature, 100 milliliters of water are added in (38.0g, 0.15mol) With the hydrochloric acid of 100 milliliters of 1N, stirring separates organic phase after 30 minutes, organic phase anhydrous magnesium sulfate after saturated common salt water washing is dry Dry, filtering, filtrate decompression is concentrated to give II, and sterling 14.2g, yield: 51% are obtained after separation.

Step (b): compound (II) (30g, 0.11mol), 3.0g10%Pd/C and 200mL isopropanol are placed in round bottom and burnt In bottle, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressure.It filters, 100 milliliters of sulfuric acid of 3N is added in filtrate, It after gained mixture is heated to 80 DEG C of reactions 3 hours, is cooled to room temperature, triethylamine neutralization reaction liquid is added to alkalinity.Concentration is anti- It answers liquid to doing, ethyl acetate, filtering is added, filter cake is washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate phase concentration 12.9g compound III is separated to obtain to after doing.Yield is 90%.

Embodiment 6

Step (a): by 2- (2- iodine ethyoxyl) tetrahydro -2H- pyrans (30.7g, 0.12mol) and triethylamine (13.1g, It 0.13mol) is dissolved in 300mL DMF, is cooled to 0 DEG C after being stirred at room temperature 30 minutes;Sequentially added into the mixed liquor (14.4g, 0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L- prolinol derivative (L-2- (diphenyl-triphen silicon Oxygen methyl) nafoxidine) (102g, 0.2mol), gained reaction solution rises to 25 DEG C and is stirred to react at such a temperature 17 hours Afterwards, the hydrochloric acid of 100mL water and 100mL1N is added, stirring separated organic phase after 30 minutes, and organic phase is through saturated common salt water washing Anhydrous magnesium sulfate dries, filters afterwards, and filtrate decompression is concentrated to give compound II crude product.

Step (b): the hydrochloric acid 100mL of tetrahydrofuran 200mL, 3N being added into the crude product, and gained reaction solution is heated to 60 DEG C reaction 6 hours.Triethylamine is added until reaction liquid is in alkalinity, ethyl acetate, filtering is added to doing in concentration of reaction solution body. Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, and compound III crude product is obtained, and crude product obtains after column chromatography for separation 9.1g compound III sterling, yield 72%.

Embodiment 7

Step (a): by 2- benzyloxy 1- bromoethane (25.7g, 0.12mol) and 1,5- diazabicyclo [4.3.0] -5- nonyl Alkene (DBN) (16.1g, 0.13mol) is dissolved in 300 milliliters of methylene chloride, is cooled to -10 DEG C after being stirred at room temperature 30 minutes;To this (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde (14.4g, 0.1mol) and 1- amino -2- first are sequentially added in mixed liquor Oxygen methyl nafoxidine (AMP) (2.6g, 0.02mol).Gained reaction solution is warming up to 25 DEG C and is stirred to react at such a temperature After 24 hours, the hydrochloric acid of 100mL water and 100mL1N is added, stirring separated organic phase after 30 minutes, and organic phase is through saturated salt solution Anhydrous magnesium sulfate dries, filters after washing, separates to obtain intermediate sterling 13.9g, yield: 50% after filtrate decompression concentration.

Step (b): by midbody compound (II) (35g, 0.13mol), 3.5g10%Pd/C and 250mL2- methyl tetrahydro Furans is set in a round bottom flask, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressure.It filters, is added in filtrate 100mL water and 30mL methanesulfonic acid are cooled to room temperature after gained mixture is heated to 100 DEG C of reactions 5 hours, are added in triethylamine With reaction solution to alkalinity.Concentration of reaction solution body to dry, addition ethyl acetate, filtering, filter cake is washed with ethyl acetate, merges acetic acid Ethyl ester phase, ethyl acetate phase are separated to obtain 14.7g compound III after being concentrated to dryness.Yield: 87%.

Embodiment 8

Step (a): the iodohydrin (25.9g, 0.12mol) and diisopropyl ethyl amine (DIPEA) that MOM is protected (16.8g, 0.13mol) is dissolved in 300mL DMSO, is cooled to 0 DEG C after being stirred at room temperature 30 minutes;Successively add into the mixed liquor Enter (14.4g, 0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L-2- (diphenyl-triphen silicon oxygen methyl) Nafoxidine (10.2g, 0.02mol).After gained reaction solution rises to 25 DEG C and is stirred to react 17 hours at such a temperature, it is added The hydrochloric acid of 100 milliliters of water and 100mL1N, stirring separated organic phase after 30 minutes, and organic phase is anhydrous after saturated common salt water washing Magnesium sulfate dries, filters, and filtrate decompression is concentrated to give compound II crude product.

Step (b): the hydrochloric acid 100mL of dioxane 200mL, 3N being added into the crude product, and gained reaction solution is heated to 50 DEG C reaction 6 hours.Triethylamine is added until reaction liquid is in alkalinity, ethyl acetate, filtering is added to doing in concentration of reaction solution body. Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, and compound III crude product is obtained, and crude product obtains after column chromatography for separation 9.8g compound III sterling, yield 75%.

Embodiment 9

Step (a): by THP protection ethylene glycol methanesulfonates (26.9g, 0.12mol) and triethylamine (13.1g, It 0.13mol) is dissolved in 300mL n,N-dimethylacetamide, is cooled to 0 DEG C after being stirred at room temperature 30 minutes;Into the mixed liquor according to Secondary addition (14.4g, 0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L- prolinol derivative L-2- (two Phenyl-triphen silicon oxygen methyl) nafoxidine (10.2g, 0.02mol).Gained reaction solution rises to 25 DEG C and stirs at such a temperature After reaction 17 hours, the hydrochloric acid of 100mL water and 100mL1N is added, stirring separated organic phase after 30 minutes, and organic phase is through being saturated Anhydrous magnesium sulfate dries, filters after brine It, and filtrate decompression is concentrated to give compound II crude product.

Step (b): the hydrochloric acid 100mL of ethyl alcohol 200mL, 3N being added into the crude product, and gained reaction solution is heated to 50 DEG C instead It answers 6 hours.Triethylamine is added until reaction liquid is in alkalinity, ethyl acetate, filtering is added to doing in concentration of reaction solution body.Filter cake It is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, obtain compound III crude product, crude product obtains 7.9g after column chromatography for separation Compound III sterling, yield 61%.

Embodiment 10

Step (a): 2- benzyloxy 1- iodoethane (31.4g, 0.12mol) and methyl piperidine (13.9g, 0.14mol) is molten In 300mL dimethyl sulfoxide, 0 DEG C is cooled to after being stirred at room temperature 30 minutes;(R) -2- (Isosorbide-5-Nitrae-is sequentially added into the mixed liquor Dioxo spiro [4,5] decane acetaldehyde (18.4g, 0.1mol) and L- prolinol (2.02g, 0.02mol).Gained reaction solution rises to 50 DEG C and after being stirred to react 15 hours at such a temperature, the hydrochloric acid of 100mL water and 100mL1N is added, stirring has separated after 30 minutes Machine phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing dry, filter, and filtrate decompression is concentrated to give II, obtain after separation pure Product 23.9g, yield: 75%.

Step (b): compound (II) (32g, 0.1mol), 3.0g10%Pd/C and 200mL methanol are placed in round-bottomed flask In, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressure.It filters, the hydrochloric acid 100mL of 3N, gained is added in filtrate It after mixture is heated to 50 DEG C of reactions 3 hours, is cooled to room temperature, triethylamine neutralization reaction liquid is added to alkalinity.Concentration of reaction solution Body to dry, addition ethyl acetate, filtering, filter cake is washed with ethyl acetate, and combined ethyl acetate phase, ethyl acetate phase is concentrated to dryness By separating to obtain 11.8g compound III.Yield: 91%.

Embodiment 11

Step (a): the sodium carbonate of the iodohydrin (25.9g, 0.12mol) of MOM protection and (13.8g, 0.13mol) is dissolved in In 300mL methylene chloride, 0 DEG C is cooled to after being stirred at room temperature 30 minutes;(R) -2- (Isosorbide-5-Nitrae-dioxy is sequentially added into the mixed liquor Miscellaneous spiral shell [4,5] nonane acetaldehyde (17.0g, 0.1mol) and L-2- (diphenyl-triphen silicon oxygen methyl) nafoxidine (10.2g, 0.02mol).After gained reaction solution rises to 25 DEG C and is stirred to react 17 hours at such a temperature, 100mL water and 100mL1N is added Hydrochloric acid, stirring 30 minutes after separate organic phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing dries, filters, filter Compound II crude product is concentrated under reduced pressure to obtain in liquid.

Step (b): the hydrochloric acid 100mL of tetrahydrofuran 200mL, 3N being added into above-mentioned crude product, and gained reaction solution is heated to 50 DEG C are reacted 6 hours.Triethylamine is added until reaction liquid is in alkalinity, ethyl acetate, mistake is added to doing in concentration of reaction solution body Filter.Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, obtains compound III crude product, crude product is after column chromatography for separation Obtain 10.0g compound III sterling, yield 77%.

The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered It is considered as protection scope of the present invention.

Claims (9)

1. a kind of method for preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, which is characterized in that including such as Step b or step a~step b in lower synthetic route:
Wherein, R1、R2For methyl, cyclohexyl or cyclopenta, R3For benzyl, THP trtrahydropyranyl (THP) or methoxyl methyl (MOM);
The step (a) is with (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) for raw material, under alkali and catalyst action Stereoselective reacts to obtain intermediate (II) with alkylating reagent ethylene glycol derivative, and the step (b) is in described (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is cyclized after mesosome (II) deprotection base in acid condition; The catalyst of the step (a) is selected from nafoxidine, 1- amino -2- methoxyl methyl nafoxidine (AMP), L-2- (diphenyl - Triphen silicon oxygen methyl) nafoxidine, L- prolinol or L- diphenylprolinol.
2. the method as described in claim 1, which is characterized in that the molar ratio of compound shown in the catalyst and the formula I For 0.1:1~2:1.
3. the method as described in claim 1, which is characterized in that the alkylating reagent ethylene glycol derivative of the step (a) is The ethylene glycol derivative that halogenated ethylene glycol derivative or list OMs, OTs, OTf replace, the halogenated ethylene glycol derivative are fluoro Ethylene glycol derivative, bromo ethylene glycol derivative or iodo ethylene glycol derivative;The alkylating reagent dosage is the formula I 1.0-2.0 times of the molar ratio of shown compound.
4. the method as described in claim 1, which is characterized in that the solvent of the step (a) is selected from methylene chloride, chloroform, first Benzene, n,N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or n,N-dimethylacetamide (DMA);The step (a) Alkali be selected from triethylamine, diisopropyl ethyl amine (DIPEA), triethylenediamine (DABCO), 1,8- diazabicylo 11 Carbon -7- alkene (DBU), 1,5- diazabicyclo [4.3.0] -5- nonene (DBN), pyridine, methyl piperidine, sodium bicarbonate or carbonic acid Sodium.
5. the method as described in claim 1, which is characterized in that derivative to alkylating reagent ethylene glycol in the step (a) It is -20~0 DEG C that catalyst and temperature when (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) are added in object, reaction when reaction Temperature is 25~80 DEG C.
6. the method as described in claim 1, which is characterized in that acid used in the step (b) is selected from hydrochloric acid, sulfuric acid, methylsulphur Acid or p-methyl benzenesulfonic acid.
7. the method as described in claim 1, which is characterized in that the solvent of the step (b) is alcohols or ethers;The alcohol Class is selected from methanol, ethyl alcohol, isopropanol or ethylene glycol, and the ethers is selected from tetrahydrofuran, 2- methyltetrahydrofuran, methyl- tert fourth Base ether or dioxane.
8. the method as described in claim 1, which is characterized in that the reaction temperature of the step (b) is 20~100 DEG C.
9. method according to claim 8, which is characterized in that the reaction temperature of the step (b) is 50~80 DEG C.
CN201710064302.9A 2017-02-04 2017-02-04 A kind of method preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol CN106928248B (en)

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