CN111410607A - Process for producing hexahydrofurofuranol derivative, intermediate therefor, and process for producing the intermediate - Google Patents

Process for producing hexahydrofurofuranol derivative, intermediate therefor, and process for producing the intermediate Download PDF

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CN111410607A
CN111410607A CN202010282019.5A CN202010282019A CN111410607A CN 111410607 A CN111410607 A CN 111410607A CN 202010282019 A CN202010282019 A CN 202010282019A CN 111410607 A CN111410607 A CN 111410607A
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陈冲
朱国良
杜小华
徐立
罗力军
王程翔
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of hexahydrofurofuranol derivatives, an intermediate thereof and a preparation method thereof. The preparation method takes a compound of a formula A1 or a compound of a formula 0 as a starting material,
Figure DDA0002446961100000011
wherein R is1，R2The same or different is an alkyl group. This is different from the starting materials reported in the prior patent documents, and the specific preparation method is also different from the prior patent documents, but the preparation method can industrially produce the darunavir key intermediate (3R,3aS,6aR) -hexahydrofuro [2,3-b ]]-3-alcohols.

Description

Process for producing hexahydrofurofuranol derivative, intermediate therefor, and process for producing the intermediate
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of hexahydrofurofuranol derivatives, an intermediate thereof and a preparation method thereof.
Background
The compound having the structure of formula Z is (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol:
Figure BDA0002446961090000011
belongs to one of hexahydrofurofuranol derivatives, and is an intermediate of anti-AIDS drug darunavir.
A process for the preparation of the above (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol is provided in Chinese patent application No. 200580010400.X of Taibo Tec pharmaceuticals, Inc., wherein the starting material is a compound of the following formula (3),
Figure BDA0002446961090000012
the above-mentioned (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol is prepared by the method of preparing (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol aS described in the above-mentioned Japanese Sumitomo chemical Co., Ltd., China patent application No. 200380109926.4, wherein the starting material is a compound of the following formula VIII,
Figure BDA0002446961090000013
considering that (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-alcohol is a key intermediate for preparing darunavir medicaments, more preparation methods of the key intermediate are needed. This requires development from different starting materials.
Disclosure of Invention
The method for preparing (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-alcohol starts from the selection of the starting materials, and researches and develops a preparation method for preparing the key intermediate of darunavir from the starting materials in the prior patent application. The preparation method of the invention provides another route suitable for industrialization for the preparation of the darunavir key intermediate.
In order to realize the technical purpose of the invention, the invention provides the following technical scheme:
in a first aspect the present invention provides a compound of formula 1,
Figure BDA0002446961090000021
wave line
Figure BDA0002446961090000022
Can be represented as
Figure BDA0002446961090000023
S configuration, can also be
Figure BDA0002446961090000024
And R configuration. Wherein R isLIs hydrogen or a hydroxyl protecting group. The hydroxyl protecting group is alkyl, silyl, substituted phenyl or aryl.
The silyl is trimethylsilyl, triethylsilyl, tri-n-butylsilyl or tert-butyldimethylsilyl. The alkyl group is preferably a C1-C8 alkyl group. The aryl is phenyl, furyl, thienyl or indolyl. The substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl and nitro alkyl substituted phenyl. The alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl. The alkyl-substituted phenyl is preferably benzyl.
Specifically, provided are compounds of formula 1-1 or compounds of formula 1-2,
Figure BDA0002446961090000025
RLas defined above. Preferably, the compounds are selected from the group consisting of,
Figure BDA0002446961090000031
in a second aspect the present invention provides a compound of formula 2,
Figure BDA0002446961090000032
wave line
Figure BDA0002446961090000033
Can be represented as
Figure BDA0002446961090000034
S configuration, can also be
Figure BDA0002446961090000035
And R configuration. RLIn the same manner as defined above, the above-mentioned,
R3is an alkyl group. RL1Is hydrogen or p-chlorobenzoyl.
Specifically, provided are compounds of formula 2-1 or compounds of formula 2-2,
Figure BDA0002446961090000036
wherein R is3Is an alkyl group.
Preferably, the compounds are selected from the group consisting of,
Figure BDA0002446961090000037
in a third aspect the present invention provides a compound of formula B,
Figure BDA0002446961090000041
in particular, the compounds of formula B-1,
Figure BDA0002446961090000042
wherein R is1，R2Is hydrogen, the same or different is a carboxyl protecting group, such as alkyl, substituted phenyl such as alkyl-substituted phenyl, alkoxyalkyl-substituted phenyl, nitroalkyl-substituted phenyl or silyl; rLAs defined above.
The alkyl group is C1-C8Alkyl groups of (a), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl and the like, preferably methyl, isopropyl, tert-butyl and benzyl; the silyl is trimethylsilyl, triethylsilyl, tri-n-butylsilyl or tert-butyldimethylsilyl; the aryl is phenyl, furyl, thienyl or indolyl.
In a fourth aspect, the present invention provides a process for the preparation of compounds of formula B and formula B-1, wherein a compound of formula B-1 is prepared by reacting a compound of formula A1 with a compound of formula A2, the compound of formula B is identical thereto, the compound of formula A1 is adapted as a racemate,
Figure BDA0002446961090000043
wherein R is1，R2，RLAs defined above, X is a leaving group.
X may be a halogen atom, preferably an iodine atom, a bromine atom; methylsulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, phenylsulfonyloxy.
In particular, preparation of the protecting group RLA compound of formula B-1 which is a tert-butyl group,
Figure BDA0002446961090000051
wherein R is1，R2And X is as defined above.
In particular, preparation of the protecting group RLA compound of formula B-1 which is a trimethylsilyl group,
Figure BDA0002446961090000052
wherein R is1，R2And X is as defined above.
In particular, preparation of the protecting group RLA compound of formula B-1 which is a benzyl group,
Figure BDA0002446961090000053
wherein R is1，R2And X is as defined above.
In particular, preparation of the protecting group RLA compound of formula B-1 which is a benzhydryl group,
Figure BDA0002446961090000054
wherein R is1，R2And X is as defined above.
Wherein, the compound of formula B-1 with the protecting group of hydrogen can be prepared by deprotection of the protecting group of alkyl, benzyl or alkyl silicon. Such as acid hydrolysis of alkyl groups to hydroxyl groups, deprotection of benzyl, benzhydryl groups to hydroxyl groups over palladium on carbon, and deprotection of alkylsilyl groups to hydroxyl groups over acids such as trifluoroacetic acid.
The reaction for preparing the compound of formula B-1 is carried out in the presence of a base. The alkali is alkyl lithium or a compound with the following structure,
Figure BDA0002446961090000061
wherein, L1，L2Is alkyl, cycloalkyl or alkylsilyl, and M is a metal atom such as lithium, potassium, sodium, etc.
Specifically, the base is lithium diisopropylamide, lithium cyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or n-butyllithium.
Preferably, the base is lithium diisopropylamide.
The amount of the base used is usually 2.0 to 3.5mol, preferably 2.2 to 3.0mol, based on 1mol of the compound of the formula A1.
The reaction solvent is ether solvent such as diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc.
The reaction temperature is-78-70 ℃, and is preferably-78-0 ℃.
Wherein the compound of formula B-1 prepared by the reaction of the compound of formula A1 with the compound of formula A2 exists mostly as a compound of the following configuration,
Figure BDA0002446961090000062
at least partly in the form of their diastereoisomers,
Figure BDA0002446961090000063
the person skilled in the art can purify the compound of formula B-1 by column chromatography or the like,
Figure BDA0002446961090000071
more preferably, however, the compound of formula 1-2 is used in the following reaction without purification.
That is, the fifth aspect of the present invention provides a method for preparing a compound of formula 1-2, which is prepared from a compound of formula B-1 by reduction and cyclization.
Figure BDA0002446961090000072
Wherein, since the compound of the above formula B-1 exists mostly in the following configuration,
Figure BDA0002446961090000073
then, after the reaction, most of the compound of formula 1-2 is generated,
Figure BDA0002446961090000074
a minor portion exists in a configuration such that,
Figure BDA0002446961090000081
the reducing agent may be a reducing agent known in the art to reduce carbonyl groups to hydroxyl groups. Such as boron-based reducing agents or aluminum-based reducing agents. The cyclizing reagent can be an acid. The acid is an inorganic acid or an organic acid. The inorganic acid is hydrochloric acid or sulfuric acid, and the organic acid is trifluoroacetic acid.
In a sixth aspect, the present invention provides a process for preparing a compound of formula 1-1. Prepared by reacting a compound of formula 0 with a compound of formula a 2.
Figure BDA0002446961090000082
In particularPreparation of RLA compound of formula 1-1 which is tert-butyldimethylsilyl,
Figure BDA0002446961090000083
the reaction for preparing the compound of formula 1-1 is carried out in the presence of a base. The alkali is alkyl lithium or a compound with the following structure,
Figure BDA0002446961090000084
wherein, L1，L2Is alkyl, cycloalkyl or alkylsilyl, and M is a metal atom such as lithium, potassium, sodium, etc.
Specifically, the base is lithium diisopropylamide, lithium cyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, or n-butyllithium.
Preferably, the base is lithium hexamethyldisilazide or lithium diisopropylamide.
The amount of the base used is usually 2.0 to 3.5mol, preferably 2.2 to 3.0mol, based on 1mol of the compound of formula 0.
The reaction solvent is ether solvent such as diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc.
The reaction temperature is-78-70 ℃, and is preferably-78-0 ℃.
In a seventh aspect, the invention provides a compound of formula 2, in particular RL1A process for the preparation of a compound of formula 2-1 or formula 2-2 which is hydrogen. Prepared by substituting and reducing a compound of formula 1 or a compound of formula 1-2. The reaction formula is as follows:
Figure BDA0002446961090000091
the reducing agent may be any reducing agent known in the art for reducing a carbonyl group to a hydroxyl group. Such as boron-based reducing agents, aluminum-based reducing agents, and the like. The boron reducing agent can be boron trifluoride, sodium borohydride or boron trifluoride ethyl ether; the aluminum reducing agent can be lithium aluminum hydride, red aluminum, lithium diisobutyl aluminum hydride, and the like.
The reaction solvent is alcohol solvent such as methanol and ethanol.
The substitution in the above reduction reaction may be with p-chlorobenzoyl chloride, wherein RL1Is p-chlorobenzoyl.
In an eighth aspect, the invention provides a method for preparing (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol and (3R,3aS,6aS) -hexahydrofuro [2,3-b ] -3-ol which are key intermediates of darunavir. Prepared from the compound of formula 2 by hydrolysis. The reaction formula is as follows:
Figure BDA0002446961090000101
specifically, the compound of the formula 2-1 is prepared by hydrolysis reaction,
Figure BDA0002446961090000102
specifically, the compound of the formula 2-2 is prepared by hydrolysis reaction,
Figure BDA0002446961090000103
the hydrolysis reagent for the hydrolysis reaction may be an acid or a base well known in the art. The acid may be an inorganic acid or an organic acid. The inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is trifluoroacetic acid.
(3R,3aS,6aS) -hexahydrofuro [2,3-b ] -3-ol the darunavir key intermediate (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol) can be prepared by methods known in the literature, for example in journal literature Bioorganic & Medicinal Chemistry L ets (1996),6(23),2847 and 2852.
Figure BDA0002446961090000104
Wherein R is4Is phenyl, p-nitrophenyl, methyl, or-NH- (R) -1- (1-naphthalene) ethyl.
Further, the preparation of (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol and (3R,3aS,6aS) -hexahydrofuro [2,3-b ] -3-ol can be prepared by the compound of formula 1 via one-pot method. I.e., reduction, hydrolysis is carried out in one pot without isolation of the compound of formula 2.
One preferred embodiment of the present invention is:
Figure BDA0002446961090000111
another preferred embodiment of the present invention is:
Figure BDA0002446961090000112
wherein R isLPreferably tert-butyl or benzyl, RL1Preferably p-chlorobenzoyl.
In a ninth aspect the invention provides a compound of formula C,
Figure BDA0002446961090000113
including compounds of formula C1 and compounds of formula C2,
Figure BDA0002446961090000114
in a tenth aspect, the invention provides a process for the preparation of a compound of formula C, from a compound of formula B.
Since the compounds of formula B-1 above are present for the most part in the following configuration,
Figure BDA0002446961090000115
after the reaction, the resulting compound of formula C is also present in the following configuration,
Figure BDA0002446961090000121
a minor portion exists in a configuration such that,
Figure BDA0002446961090000122
wherein when R is2When hydrogen is used, the reaction can be completed by three processes of deprotection, cyclization and hydrolysis, or by three processes of hydrolysis, deprotection and cyclization, or by the processes of deprotection, hydrolysis and cyclization. I.e. the three processes in any order.
The deprotection reagent is acid or palladium carbon, and the cyclization reagent can be acid, wherein the acid is inorganic acid or organic acid; the hydrolysis reagent is inorganic base.
The inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is trifluoroacetic acid, and the inorganic base is sodium hydroxide, sodium carbonate and the like.
The compound of formula C can also be prepared by reacting a compound of formula A1 with a compound of formula A2, deprotecting, cyclizing and hydrolyzing in any order in one pot,
Figure BDA0002446961090000124
the invention discloses a method for preparing darunavir key intermediate (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-alcohol, which takes a compound of a formula A1 or a compound of a formula 0 aS a starting material,
Figure BDA0002446961090000131
wherein R is1，R2As defined above. This is in contrast to the starting materials reported in the prior patent literatureIn contrast, the specific preparation method is different from the prior patent literature, but the preparation method can be used for industrially producing the darunavir as the key intermediate.
Detailed Description
For further understanding of the present invention, the following examples are given to illustrate the preparation of hexahydrofurofuranol derivatives, intermediates thereof and the preparation thereof. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.
Example 1: preparation of (3R) -diisopropyl-2- (2- (tert-butoxy) -ethyl) -3-hydroxy
Figure BDA0002446961090000132
Adding 63ml of L DA (2.1eq) and 30ml of THF (tetrahydrofuran) into a 250ml four-mouth bottle provided with a magnetic stirrer and a thermometer under the protection of nitrogen, cooling to-60 to-70 ℃, dropwise adding isopropyl malate (13.1g and 60mmol), controlling the temperature not to exceed-60 ℃, keeping the internal temperature and stirring for 30min, slowly heating to-20 ℃, taking the mixture for half an hour, then cooling to-60 to-70 ℃, dropwise adding 2-iodoethyl tert-butyl ether (27.4g and 2.0eq), keeping the temperature and stirring for half an hour after dropwise adding, heating to-20 ℃, stirring overnight, adding 90ml of water and 40ml of ethyl acetate into a reaction system, stirring for 5min, standing for layering, extracting an aqueous phase with (40ml of × 3) ethyl acetate, combining organic layers, drying with magnesium sulfate, filtering, concentrating to obtain 28.54g of a product, separating part of the product through a column to obtain an oily substance, determining the target compound, wherein the yield is 80%. the product spectrogram data is as follows:
1H NMR(400.2MHz,CDCl3)5.10(1H,m),5.01(1H,m),4.31(1H,m)，3.54(1H,d，J＝7.2Hz),3.46(2H,m),3.06(1H,m)，2.13(1H,m),1.86(1H,m)，1.29(6H,d，J＝2.8Hz)，1.27(6H,d，J＝2.8Hz),1.18(9H,s)；
13C NMR(100.6MHz,CDCl3)172.8(d,J＝8.8Hz),171.45(d,J＝36.8Hz),72.83(d,J＝5.9Hz),71.18(d,J＝37.3Hz),69.48(t,J＝8.2Hz),68.1(d,J＝8.2Hz),58.88(s),45.67ppm(s), 28.59(s),27.34ppm(s), 21.58 ppm(s); mass Spectrometry (ESI method) C16H30O6(M)+Calculated value 318.20 measured value 319.2
Example 2: preparation of (3R) -diethyl-2- (2- (tert-butoxy) -ethyl) -3-hydroxy
Figure BDA0002446961090000141
Adding 42ml of L DA (2.1eq) and 20ml of THF (tetrahydrofuran) into a 250ml four-mouth bottle provided with a magnetic stirrer and a thermometer under the protection of nitrogen, cooling to-60 to-70 ℃, dropwise adding ethyl malate (7.5g and 40mmol), controlling the temperature not to exceed-60 ℃, after dropwise adding, maintaining the internal temperature and stirring for 30min, slowly heating to-20 ℃, taking for half an hour, then cooling to-60 to-70 ℃, dropwise adding 2-iodoethyl tert-butyl ether (9.58g and 2.0eq), after stirring for half an hour after dropwise adding, heating to-20 ℃, stirring overnight, adding 90ml of water and 40ml of ethyl acetate into a reaction system, stirring for 5min, standing for demixing, extracting an aqueous phase with (40ml of × 3) ethyl acetate, combining organic layers, drying with magnesium sulfate, filtering, concentrating to obtain 7.49g of a product, taking a part of the product to pass through a column for oily separation, determining the target compound to have the yield of 60%, wherein the product spectrogram data are as follows:
1H NMR(400.2MHz,CDCl3)4.30(1H,m),4.20(2H,m),4.11(2H,m)，3.52(1H,m),3.49(2H,m),3.10(1H,m)，2.12(1H,m),1.88(1H,m)，1.31(6H,d，J＝2.8Hz)，1.27(6H,d，J＝2.8Hz),1.15(9H,s)。
example 3: preparation of (3R) -diisopropylmethyl-2- (2- (trimethylsiloxy) -ethyl) -3-hydroxy
Figure BDA0002446961090000142
Compounds of formula B-1 wherein the protecting group is trimethylsilyl can be prepared as in example 1 or 2.
Example 4:
Figure BDA0002446961090000151
compounds of formula B-1 wherein the protecting group is benzyl can be prepared as in example 1 or 2.
Example 5:
Figure BDA0002446961090000152
the compound of formula B-1, wherein the protecting group is hydrogen, can be prepared by deprotection, and the product spectrogram data is as follows:
1H NMR(400.2MHz,CDCl3)5.14(1H,m),5.04(1H,m),4.53(2H,m)，4.28(1H,s),3.22(1H,m),3.02(1H,m)，2.60(1H,m),2.35(1H,m)，1.29(6H,m)，1.25(6H,m)；
mass Spectrometry (ESI method) C12H22O6(M)+Calculated 262.29, measured 263.2.
Example 6: preparation of Compounds of formula C
300mg of (3R) -diisopropyl-2- (2- (tert-butoxy) -ethyl) -3-hydroxy and 1ml of trifluoroacetic acid were added to a 50ml two-necked flask, and the mixture was cooled to-10 to-5 ℃ and stirred overnight, the trifluoroacetic acid was distilled off at low temperature, an aqueous sodium hydroxide solution and tetrahydrofuran were added thereto and stirred at room temperature for 6 hours, then diluted hydrochloric acid was used to adjust pH to 2, ethyl acetate was extracted, the solvent was evaporated, toluene was added thereto and evaporated to dryness at normal pressure, and this operation was repeated 2 times to obtain 127mg of a white solid with a yield of 80%, and the target compound was identified by nuclear magnetic resonance. The product spectrum data is as follows:
1H NMR(400.2MHz,DMSO-d6)4.25(3H,m),3.13(1H,m),2.33(1H,m)，2.13(1H,m)。
mass Spectrometry (ESI method) C6H8O5(M)-Calculated 160.1 measured 159.1.
Example 7:
Figure BDA0002446961090000153
RLis tert-butyl
Sodium borohydride and THF are put into a reaction bottle, stirred after being cooled to-10-15 ℃ under the protection of nitrogen, and R is dripped under the protection of nitrogenLA compound of formula B/THF solution which is tert-butyl,controlling the temperature to be minus 10 ℃ to minus 5 ℃, keeping the temperature, beginning to drip acetic acid, controlling the temperature to be minus 10 ℃ to minus 5 ℃, heating to 20 ℃ to 25 ℃, keeping the temperature, cooling to be minus 10 ℃ to minus 5 ℃, dripping water, controlling the temperature to be minus 10 ℃ to minus 5 ℃, stirring after the dripping is finished until the T L C raw material reacts, heating to be 0 ℃ to 5 ℃, adding dichloromethane for extraction, layering, and decompressing and concentrating the organic layer at 50 ℃ to 55 ℃ to obtain 16.5g of oily substance, putting the oily substance into a reaction bottle, adding THF (tetrahydrofuran) and p-toluenesulfonic acid, stirring, heating to be 75 ℃ to 80 ℃, refluxing for 16 h to 18h, and cooling T L C until the raw material reacts, decompressing and concentrating at 55 ℃ to 60 ℃ until no distillate drips, cooling the reaction liquid to be 0 ℃ to 5 ℃, adding water and DCM (DCM) for stirring, layering, collecting the organic layer, decompressing and concentrating until no distillate drips at 50 ℃ to 55 ℃, and obtaining the oily substance with the yield of 11.7 g.
Example 8:
Figure BDA0002446961090000161
RL1is p-chlorobenzoyl, RLIs tert-butyl
Adding the oily substance in example 7, DCM and p-chlorobenzoyl chloride into a reaction bottle, stirring, dropwise adding triethylamine, controlling the temperature to be 20-25 ℃, and controlling T L C until the raw materials react, cooling, adding 100ml of water, standing, layering to obtain an organic layer, concentrating under reduced pressure at 55-60 ℃ to remove the solvent, crystallizing with EA and hexane to obtain 20g of a product with the yield of 90%, adding the crystallized product into the reaction bottle, stirring and cooling to-65-70 ℃ under the protection of THF nitrogen, dropwise adding diisobutyl aluminum lithium hydride and T L C until the raw materials react, cooling, adding 100ml of methanol and boron ethyl ether 10g, stirring at 20-25 ℃ for 16-18h, concentrating under reduced pressure at 50-55 ℃ until no distillation liquid is obtained, obtaining 28g of the product, and directly preparing (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-alcohol without separation.
Example 9:
Figure BDA0002446961090000162
RL1is p-chlorobenzoyl, RLFeeding the compound of formula 2-2 (R) as a tert-butyl group into a reaction flaskL1Is p-chlorobenzoyl, RLIs tert-butyl), THF, hydrochloric acid and water are stirred and reacted at 0-5 ℃ until the raw materialsAfter the solution disappears, cooling, adding dichloromethane, extracting, layering, collecting organic layer, concentrating under reduced pressure at 50-55 deg.C until no distillate is dropped to obtain product (3R,3aS,6aR) -hexahydrofuro [2,3-b ]]7.8g of (E) -3-ol. The total yield was 87%.
Example 10:
Figure BDA0002446961090000171
a four-necked flask was charged with 15g of compound of formula 0, DMPU18.8g, THF10 ml. N is a radical of2Protecting, cooling to-78-80 ℃, dripping HMDS L i 407ml, controlling the temperature to-70-65 ℃, keeping the temperature for 1h after dripping, dripping 15.4g of 2-iodoethyl tert-butyl dimethyl silicon ether of the compound of the formula A, controlling the temperature to-65-60 ℃, keeping the temperature for 4h after dripping, finishing the reaction of the T L C raw material, quenching by using NaCl30ml saturated aqueous solution, extracting a water layer by layering 20ml of ethyl acetate, combining organic layers, concentrating until the target product is dried, obtaining the yield of 75 percent and the purity of 98 percent.
DMPU is 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidone, HMDS L i lithium hexamethyldisilazide
Example 11:
Figure BDA0002446961090000172
a reaction flask was charged with the compound of formula 1-1 (R)LTert-butyldimethylsilyl), THF, nitrogen protection, cooling to-65- -70 deg.C, dropwise adding diisobutyl lithium aluminum hydride, T L C until the reaction of the raw materials is completed, adding 100ml methanol and 10g boron trifluoride diethyl etherate, stirring at 20-25 deg.C for 16-18h, concentrating under reduced pressure at 50-55 deg.C to remove the solvent, and extracting with DCM to obtain 21.4g of the product with 85% yield.
DCM: methylene dichloride
Example 12:
Figure BDA0002446961090000173
a250 ml four-necked flask was charged with the 2-1 compound (R)LTert-butyldimethylsilyl), THF, cooling to 0-5 deg.C, adding 30% hydrochloric acid 10g, reacting at 0-5 deg.C until the raw material disappears, adding carbonic acidNeutralizing with sodium hydrogen to pH 7-8, filtering to remove solid, extracting with DCM and removing solvent to obtain (3R,3aS,6aS) -hexahydrofuro [2,3-b ]]7.99g of the (E) -3-ol was obtained in a yield of 85%.

Claims (16)

1. A compound having the following general formula B:
Figure FDA0002446961080000011
wherein R is1，R2Is hydrogen, the same or different is a carboxyl protecting group which is an alkyl, silyl or substituted phenyl group; rLIs hydrogen or a hydroxy protecting group; the hydroxyl protecting group is alkyl, silyl, substituted phenyl or aryl.
2. A compound according to claim 1, further being a compound of absolute stereoform B-1 and isomers thereof, or further being a compound of relative stereoform B,
Figure FDA0002446961080000012
wherein R is1，R2，RLAs defined in claim 1.
3. A compound according to claim 2, further a compound of the absolute stereoisomeric form B-1,
Figure FDA0002446961080000013
wherein R is1，R2，RLAs defined in claim 1.
4. A compound as claimed in claim 1, 2 or 3 wherein R1，R2Identical or different from hydrogen, benzyl, methyl, ethyl, n-propyl, isopropyl or tert-butylA group; the silyl is trimethylsilyl, triethylsilyl, tri-n-butylsilyl or tert-butyldimethylsilyl; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl and nitro alkyl substituted phenyl.
5. A preparation method of a compound shown in a formula 1-2 is characterized in that the compound is prepared by reduction and cyclization of a compound shown in a formula B-1,
Figure FDA0002446961080000021
wherein R is1，R2，RLAs defined in claim 1.
6. A preparation method of a compound shown in a formula 2 is characterized in that the compound shown in the formula B-1 is prepared by substitution and reduction after being prepared by reduction and cyclization,
Figure FDA0002446961080000022
wherein R isLAs defined in claim 1; r3Is an alkyl group; rL1Is hydrogen or p-chlorobenzoyl.
A process for preparing (3R,3aS) -hexahydrofuro [2,3-b ] -3-ol, characterized by comprising hydrolyzing the compound of formula 2 prepared according to claim 6,
Figure FDA0002446961080000023
wherein R isLAs defined in claim 1, RL1，R3As defined in claim 6; the wavy line is shown in either the R or S configuration.
A process for preparing (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol, characterized by hydrolyzing the compound of formula 2-2 prepared according to claim 6,
Figure FDA0002446961080000031
wherein R isLAs defined in claim 1, RL1As defined in claim 6; the wavy line is shown in either the R or S configuration.
A process for preparing (3R,3aS,6aS) -hexahydrofuro [2,3-b ] -3-ol, characterized by comprising hydrolyzing the compound of formula 2-1 prepared according to claim 6,
Figure FDA0002446961080000032
wherein R isLThe wavy line is shown in the R or S configuration, as defined in claim 1.
A process for producing (3R,3aS,6aR) -hexahydrofuro [2,3-b ] -3-ol, which comprises preparing from the (3R,3aS,6aS) -hexahydrofuro [2,3-b ] -3-ol according to claim 9,
Figure FDA0002446961080000033
wherein R is4Is phenyl, p-nitrophenyl, methyl, or-NH- (R) -1- (1-naphthalene) ethyl.
11. A compound of the absolute stereoisomeric form C and isomers thereof, or further a compound of the relative stereoisomeric form C,
Figure FDA0002446961080000034
12. the preparation method of the compound shown in the formula B is characterized in that the compound is prepared by reacting the compound shown in the formula A1 with the compound shown in the formula A2,
Figure FDA0002446961080000041
wherein R is1，R2，RLThe same as defined in claim 1, wherein X is a leaving group, and the leaving group is a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a benzenesulfonyloxy group.
13. The method according to claim 12, wherein X is an iodine atom and R is an iodine atom1，R2Identical or different methyl, ethyl, isopropyl, tert-butyl, benzyl; the R isLIs tert-butyl, trimethylsilyl, benzyl or benzhydryl.
14. The preparation method of the compound of the formula C is characterized in that the compound of the formula B is prepared by deprotection, cyclization and hydrolysis reaction in any order,
Figure FDA0002446961080000042
wherein R is1，R2，RLAs defined in claim 1.
15. The preparation method of the compound of the formula C is characterized in that the compound of the formula C is prepared by reacting a compound of a formula A1 with a compound of a formula A2, and then carrying out deprotection, cyclization and hydrolysis in any order in one-pot reaction,
Figure FDA0002446961080000043
wherein R is1，R2，RLAs defined in claim 1.
16. The method of claim 12, wherein the reaction of the A1 compound with the A2 compound is carried out in the presence of a base, wherein the base is an alkyl lithium or a compound of the structure,
Figure FDA0002446961080000044
wherein, L1，L2Is alkyl, cycloalkyl, silicon-substituted alkyl, M is a metal atom, wherein the metal atom is lithium, potassium or sodium.
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