CN111410607B - 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 PDFInfo
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- CN111410607B CN111410607B CN202010282019.5A CN202010282019A CN111410607B CN 111410607 B CN111410607 B CN 111410607B CN 202010282019 A CN202010282019 A CN 202010282019A CN 111410607 B CN111410607 B CN 111410607B
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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 takes a compound of formula A1 or a compound of formula 0 as an initial raw material,wherein R is 1 ,R 2 The same or different are alkyl groups. This is different from the starting materials reported in the prior patent literature and the specific preparation method is different from the prior patent literature, but the preparation method can industrially produce darunavir key intermediate (3R, 3aS,6 aR) -hexahydrofuro [2, 3-b)]-3-alcohols.
Description
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 Z 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 Chinese patent application No. 200580010400.X of Taibolck pharmaceutical Co., ltd provides a preparation method of the (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol, wherein the starting material is a compound of the following formula (3),
a process for the preparation of the above-mentioned (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol is provided by Japanese Sumitomo chemical Co., ltd., chinese patent application No. 200380109926.4, wherein the starting material is a compound of the following formula VIII,
given that (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol is a key intermediate for the preparation of darunavir drugs, it is necessary to develop more preparation methods for the key intermediate. This requires development from different starting materials.
Disclosure of Invention
The method for preparing (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol starts from the selection of the starting materials, and researches and develops a preparation method for preparing darunavir key intermediates from the starting materials in the prior patent application. The preparation method 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:
the first aspect of the present invention provides a compound of formula 1,
wave lineThe representation can be +.>S-configuration, also can be +.>R configuration. Wherein R is L Is hydrogen or a hydroxyl protecting group. The hydroxyl protecting group is alkyl, silane, substituted phenyl or aryl.
The silane group is trimethylsilyl, triethylsilyl, tri-n-butylsilyl and 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, alkoxyalkyl substituted phenyl, nitroalkyl 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 alkyl-substituted phenyl is preferably benzyl.
In particular, there is provided a compound of formula 1-1 or a compound of formula 1-2,
R L the same definition as above. Preferably, the compound is a compound,
in a second aspect the present invention provides a compound of formula 2,
wave lineThe representation can be +.>S-configuration, also can be +.>R configuration. R is R L As in the case of the definition set forth above,
R 3 is alkyl. R is R L1 Is hydrogen or p-chlorobenzoyl.
In particular, compounds of formula 2-1 or compounds of formula 2-2 are provided,
wherein R is 3 Is alkyl.
Preferably, the compound is a compound,
in a third aspect the present invention provides a compound of formula B,
in particular, the following compounds of formula B-1,
wherein R is 1 ,R 2 Hydrogen, identical or different, being carboxyl protecting groups, e.g. alkylSubstituted phenyl groups such as alkyl-substituted phenyl, alkoxyalkyl-substituted phenyl, nitroalkyl-substituted phenyl or silane groups; r is R L The same definition as above.
The alkyl group being C 1 -C 8 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; 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 and the like, preferably methyl, isopropyl, tert-butyl and benzyl; the silane group is trimethylsilyl, triethylsilyl, tri-n-butylsilyl and tert-butyldimethylsilyl; the aryl is phenyl, furyl, thienyl or indolyl.
In a fourth aspect, the present invention provides a process for the preparation of a compound of formula B and a compound of formula B-1, wherein the compound of formula B-1 is prepared by reacting a compound of formula A1 with a compound of formula A2, wherein the compound of formula B is the same as the compound of formula A1, and the compound of formula A1 is adjusted to its racemate,
wherein R is 1 ,R 2 ,R L As defined above, X is a leaving group.
X may be a halogen atom, preferably an iodine atom, a bromine atom; methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy.
Specifically, the protecting group R is prepared L A compound of formula B-1 which is tert-butyl,
wherein R is 1 ,R 2 X is as defined above.
Specifically, the protecting group R is prepared L A compound of formula B-1 which is trimethylsilyl,
wherein R is 1 ,R 2 X is as defined above.
Specifically, the protecting group R is prepared L A compound of formula B-1 which is benzyl,
wherein R is 1 ,R 2 X is as defined above.
Specifically, the protecting group R is prepared L A compound of formula B-1 which is benzhydryl,
wherein R is 1 ,R 2 X is as defined above.
Wherein, the compound of the formula B-1 with the protecting group being hydrogen can be prepared by deprotection of a protecting group which is alkyl, benzyl or alkyl silicon base. For example, alkyl groups are hydrolyzed to hydroxyl groups by acid, benzyl groups are deprotected to hydroxyl groups by palladium on charcoal, and alkyl silicon groups are deprotected to hydroxyl groups by acid 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,
wherein L is 1 ,L 2 Is alkyl, cycloalkyl, alkylsilyl, M is a metal atom such as lithium, potassium, sodium, etc.
Specifically, the alkali 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 to be used is usually 2.0 to 3.5mol, preferably 2.2 to 3.0mol, relative to 1mol of the compound of the formula A1.
The reaction solvent is an ether solvent such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc.
The reaction temperature is-78 ℃ to 70 ℃, preferably-78 ℃ to 0 ℃.
Wherein the compound of formula B-1 prepared by the reaction of the compound of formula A1 and the compound of formula A2 exists in a majority of the following configuration,
in the form of its diastereoisomers,
the person skilled in the art can purify the compounds of formula B-1 herein by column chromatography or the like,
more preferably, however, the compounds of formulas 1-2 are prepared directly for the following reaction without purification.
That is, the fifth aspect of the present invention provides a process for preparing a compound of formula 1-2, from a compound of formula B-1 by reduction and cyclization.
Wherein, since the above compound of formula B-1 exists mostly in the following configuration,
after that, most of the compounds of the formula 1-2 are formed,
the minority is present in a configuration such that,
the reducing agent may be a reducing agent known in the art for reducing carbonyl groups to hydroxyl groups. Such as boron-based reducing agents or aluminum-based reducing agents. The cyclization reagent may 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 the preparation of a compound of formula 1-1. Is prepared by reacting a compound of formula 0 with a compound of formula A2.
In particular, R is prepared L A compound of formula 1-1 which is tert-butyldisilyl,
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,
wherein L is 1 ,L 2 Is alkyl, cycloalkyl, alkylsilyl, M is a metal atom such as lithium, potassium, sodium, etc.
Specifically, the alkali 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 to be used is usually 2.0 to 3.5mol, preferably 2.2 to 3.0mol, relative to 1mol of the compound of formula 0.
The reaction solvent is an ether solvent such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc.
The reaction temperature is-78 ℃ to 70 ℃, preferably-78 ℃ to 0 ℃.
In a seventh aspect the invention provides a compound of formula 2, in particular R L1 A process for the preparation of a compound of formula 2-1 or formula 2-2 which is hydrogen. Is prepared by substituting and reducing a compound of formula 1 or a compound of formula 1-2. The reaction formula is as follows:
wherein the reducing agent may be a reducing agent known in the art for reducing carbonyl groups to hydroxyl groups. Such as boron-based reducing agents, aluminum-based reducing agents, and the like. The boron-based reducing agent can be boron trifluoride, sodium borohydride or boron trifluoride diethyl 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 reacted with p-chlorobenzoyl chloride, wherein R L1 Is p-chlorobenzoyl.
In an eighth aspect, the present invention provides a process for the preparation of the key intermediate (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol of darunavir and (3R, 3aS,6 aS) -hexahydrofuro [2,3-b ] -3-ol. Is prepared from the compound of formula 2 through hydrolysis reaction. The reaction formula is as follows:
specifically, the compound is prepared by hydrolysis reaction of a compound of formula 2-1,
specifically, the compound is prepared by hydrolysis reaction of a compound of formula 2-2,
the hydrolysis reagents of the hydrolysis reaction may be acids or bases 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,6 aS) -hexahydrofuro [2,3-b ] -3-ol the key intermediate (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol of darunavir can be prepared by methods in the prior literature. Such as in journal literature Bioorganic & Medicinal Chemistry Letters (1996), 6 (23), 2847-2852.
Wherein R is 4 Is phenyl, p-nitrophenyl, methyl, or-NH- (R) -1- (1-naphthalene) ethyl.
Further, (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-ol and (3R, 3aS,6 aS) -hexahydrofuro [2,3-b ] -3-ol can be prepared by a one-pot method through the compound of the formula 1. I.e., reduction reaction, hydrolysis reaction is carried out in one pot without isolating the compound of formula 2.
One preferred embodiment of the present invention is:
another preferred embodiment of the present invention is:
wherein R is L Preferably t-butyl or benzyl, R L1 P-chlorobenzoyl is preferred.
In a ninth aspect the present invention provides a compound of formula C,
comprising a compound of formula C1 and a compound of formula C2,
in a tenth aspect the present invention provides a process for the preparation of a compound of formula C, from a compound of formula B.
Since the above-mentioned compounds of formula B-1 are present for the most part in the following configuration,
the resulting compound of formula C, after that reaction, is also present in the following configuration,
the minority is present in a configuration such that,
wherein when R is 2 In the case of hydrogen, the reaction can be completed through three processes of deprotection, cyclization and hydrolysis, or through hydrolysis, deprotection and cyclization, or through deprotection, hydrolysis and cyclization. I.e. these three processes are 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 an 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 the formula C can also be prepared by reacting the compound of the formula A1 with the compound of the formula A2, then deprotecting, cyclizing and hydrolyzing in any sequence,
the invention relates to a method for preparing darunavir key intermediate (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol, which takes a compound of formula A1 or a compound of formula 0 as a starting material,
wherein R is 1 ,R 2 The same definition as above. This is different from the starting materials reported in the prior patent literature, and the specific preparation method is also different from the prior patent literature, but the preparation method can industrially produce darunavir as the key intermediate.
Detailed Description
In order to further understand the present invention, the following describes in detail the preparation method of hexahydrofurofuranol derivative, its intermediate and its preparation method provided in the present invention with reference to 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: preparation of (3R) -diisopropyl-2- (2- (tert-butoxy) -ethyl) -3-hydroxy
63ml of LDA (2.1 eq) and 30ml of THF are added into a 250ml four-mouth bottle equipped with a magnetic stirrer and a thermometer under the protection of nitrogen, cooled to-60 ℃ to-70 ℃, isopropyl malate (13.1 g,60 mmol) is dropwise added, the temperature is controlled to be not higher than-60 ℃, the internal temperature is maintained for stirring for 30min after the dropwise addition, the temperature is slowly increased to-20 ℃ for half an hour, the temperature is reduced to-60 ℃ to-70 ℃, 2-iodoethyl tert-butyl ether (27.4 g,2.0 eq) is dropwise added after the dropwise addition, the temperature is maintained for half an hour after the dropwise addition, and the mixture is stirred overnight at-20 ℃. The reaction system was stirred for 5min with 90ml of water and 40ml of ethyl acetate, the layers were allowed to stand, the aqueous phase was extracted with (40 ml. Times.3) ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 28.54g of an oil, and the fractions were isolated by column to determine the title compound in 80% yield. The product spectrum data are as follows:
1 H NMR(400.2MHz,CDCl 3 )δ5.10(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);
13 C NMR(100.6MHz,CDCl 3 ) Delta 172.8 (d, j=8.8 Hz), 171.45 (d, j=36.8 Hz), 72.83 (d, j=5.9 Hz), 71.18 (d, j=37.3 Hz), 69.48 (t, j=8.2 Hz), 68.1 (d, j=8.2 Hz), 58.88(s), 45.67 ppm(s), 28.59(s), 27.34 ppm(s), 21.58 ppm(s); mass Spectrometry (ESI method) C 16 H 30 O 6 (M) + Calculated 318.20 measured 319.2
Example 2: preparation of (3R) -diethyl-2- (2- (tert-butoxy) -ethyl) -3-hydroxy
In a 250ml four-mouth bottle equipped with a magnetic stirrer and a thermometer, 42ml LDA (2.1 eq) and 20ml THF are added under the protection of nitrogen, cooled to-60 ℃ to-70 ℃, ethyl malate (7.5 g,40 mmol) is dropwise added, the temperature is controlled to be not more than-60 ℃, the internal temperature is maintained for stirring for 30min after the dropwise addition, the temperature is slowly increased to-20 ℃ for half an hour, the temperature is reduced to-60 ℃ to-70 ℃, 2-iodoethyl tert-butyl ether (9.58 g,2.0 eq) is dropwise added, the temperature is maintained for half an hour after the dropwise addition, and the temperature is increased to-20 ℃ after the dropwise addition and stirring is completed for overnight. The reaction system was stirred for 5min with 90ml of water and 40ml of ethyl acetate, the layers were allowed to stand, the aqueous phase was extracted with (40 ml. Times.3) ethyl acetate, the combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 7.49g of an oil, and the fractions were isolated by column to determine the title compound in 60% yield. The product spectrum data are as follows:
1 H NMR(400.2MHz,CDCl 3 )δ4.30(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
Compounds of formula B-1 wherein the protecting group is trimethylsilyl can be prepared as in example 1 or 2.
Example 4:
compounds of formula B-1 wherein the protecting group is benzyl can be prepared as in example 1 or 2.
Example 5:
the compound of the formula B-1 with the protecting group being hydrogen can be prepared through deprotection, and the product spectrogram data are as follows:
1 H NMR(400.2MHz,CDCl 3 )δ5.14(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) C 12 H 22 O 6 (M) + Calculated 262.29 measured 263.2.
Example 6: preparation of Compounds of formula C
To a 50ml two-necked flask were added 300mg of (3R) -diisopropyl-2- (2- (t-butoxy) -ethyl) -3-hydroxy and 1ml of trifluoroacetic acid, cooled to-10 ℃ to-5 ℃ and stirred overnight, the trifluoroacetic acid was distilled off at low temperature, aqueous sodium hydroxide solution and tetrahydrofuran were added and stirred at room temperature for 6 hours, then diluted hydrochloric acid was used to adjust pH=2, extraction was performed with ethyl acetate, the solvent was evaporated, toluene was added and evaporated to dryness at normal pressure, this operation was repeated 2 times to obtain 127mg of a white solid with a yield of 80%, and the nuclear magnetic resonance was identified as the target compound. The product spectrum data are as follows:
1 H NMR(400.2MHz,DMSO-d 6 )δ4.25(3H,m),3.13(1H,m),2.33(1H,m),2.13(1H,m)。
mass Spectrometry (ESI method) C 6 H 8 O 5 (M) - Calculated 160.1 measured 159.1.
Example 7:
Adding sodium borohydride, THF and nitrogen gas into a reaction bottle, cooling to-10-15 ℃ under the protection of nitrogen gas, stirring, and dropwise adding R under the protection of nitrogen gas L The temperature of the compound of formula B/THF solution is controlled to be-10 to-5 ℃. After the dripping is finished, preserving heat, beginning to drip acetic acid, controlling the temperature to-10 to-5 ℃, and heating to 20 to 25 ℃ for preserving heat. After heat preservation, coolDropwise adding water to-10-5 ℃, controlling the temperature to-10-5 ℃, stirring until the TLC raw materials are reacted, heating to 0-5 ℃, adding dichloromethane for extraction, layering, concentrating an organic layer at 50-55 ℃ under reduced pressure to obtain 16.5g of oily matter, adding the obtained oily matter into a reaction bottle, adding THF, p-toluenesulfonic acid, stirring, heating to 75-80 ℃ for reflux for 16-18h, and finishing the TLC raw materials reaction. Cooling, concentrating under reduced pressure at 55-60deg.C to obtain non-dripping distillate, cooling to 0-5deg.C, adding water and DCM, stirring, layering, and collecting organic layer, concentrating under reduced pressure at 50-55deg.C to obtain oily substance with yield of 11.7g and 80%.
Example 8:
The oil from example 7, DCM, p-chlorobenzoyl chloride and triethylamine were added dropwise while stirring in a reaction flask, the temperature was controlled at 20-25℃and TLC was run to completion. Cooled, 100ml of water was added, and the mixture was allowed to stand and delaminated. The organic layer was concentrated under reduced pressure at 55-60℃to remove the solvent, and then crystallized with EA and hexane to give 20g of the product in 90% yield. The crystallization product is put into a reaction bottle, stirred and cooled to-65 ℃ to-70 ℃ under the protection of THF nitrogen, lithium diisobutyl aluminum hydride is added dropwise, and TLC is carried out until the reaction of the raw materials is completed. Cooled, 100ml of methanol, 10g of boron trifluoride diethyl etherate are added, stirred for 16-18h at 20-25 ℃ and concentrated to a non-dripping distillation liquid at 50-55 ℃ under reduced pressure, 28g of product is obtained, and the (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] -3-alcohol can be directly prepared without separation.
Example 9:
R L1 r is p-chlorobenzoyl L Into a reaction flask was charged a compound of formula 2-2 (R L1 R is p-chlorobenzoyl L Tert-butyl), THF, hydrochloric acid and water at 0-5deg.C until the raw materials disappear, cooling, adding dichloromethane, extracting, layering, collecting organic layer, and concentrating under reduced pressure at 50-55deg.C until no dripping occursThe liquid is used to obtain the product (3R, 3aS,6 aR) -hexahydrofuro [2,3-b]-3-ol 7.8g. The total yield was 87%.
Example 10:
15g of the compound of formula 0, DMPU18.8g and THF10ml are placed in a four-necked flask. N (N) 2 And (3) protecting, cooling to-78 to-80 ℃, and dripping 407ml of HMDSLi. Controlling the temperature to be between 70 ℃ below zero and 65 ℃ below zero, and preserving the temperature for 1h after dripping. 15.4g of 2-iodoethyl tert-butyl disilyl ether as a compound of the formula A is added dropwise, and the temperature is controlled between-65 ℃ and-60 ℃. After incubation for 4h, TLC starting material was completed, quenched with 30ml of saturated aqueous NaCl and the aqueous layer was extracted with 20ml of ethyl acetate as a layer. The organic layers were combined and concentrated to dryness to give the desired product in 75% yield and 98% purity.
DMPU is 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2-pyrimidinone, HMDSLi: lithium hexamethyldisilazide
Example 11:
the compound of formula 1-1 (R) L Tertiary butyl disilyl group), THF, cooling to-65- -70 ℃ under the protection of nitrogen, dropwise adding diisobutyl aluminum lithium hydride, TLC until the reaction of the raw materials is finished, adding 100ml of methanol, 10g of boron trifluoride diethyl ether, stirring for 16-18h at 20-25 ℃, concentrating under reduced pressure at 50-55 ℃ to remove the solvent, and extracting 21.4g of the product with DCM to obtain the product with the yield of 85%.
DCM: dichloromethane (dichloromethane)
Example 12:
into a 250ml four-necked flask, 2-1 compound (R L Tertiary butyl disilyl group), THF, cooling to 0-5 ℃ and adding 10g of 30% hydrochloric acid, reacting at 0-5 ℃ until the raw material disappears, adding sodium bicarbonate to neutralize to ph=7-8, filtering to remove solidsAdding DCM, extracting and then removing the solvent to obtain (3R, 3aS,6 aS) -hexahydrofuro [2,3-b]7.99g of 3-ol, yield 85%.
Claims (4)
1. 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 in any order,
wherein R is 1 ,R 2 Is hydrogen or the same or different is carboxyl protecting group, wherein the carboxyl protecting group is alkyl, silane or substituted phenyl, R L Is hydrogen or a hydroxyl protecting group; the hydroxyl protecting group is alkyl, silane, substituted phenyl or aryl.
2. The preparation method of the compound of the formula C is characterized in that the compound of the formula A1 and the compound of the formula A2 are reacted and then subjected to deprotection, cyclization and hydrolysis in any sequence to prepare the compound of the formula C by one-pot reaction,
wherein R is 1 ,R 2 R is as defined in claim 1 L Is hydrogen or a hydroxyl protecting group; the hydroxyl protecting group is alkyl, silane, substituted phenyl or aryl.
3. The process of claim 1, wherein the compound of formula B is prepared by reacting a compound of formula A1 with a compound of formula A2,
wherein R is 1 ,R 2 ,R L As defined in claim 1Similarly, X is a leaving group, and the leaving group is a halogen atom, such as methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy.
4. The process according to claim 3, wherein X is an iodine atom and R 1 ,R 2 Methyl, ethyl, isopropyl, tert-butyl, benzyl, which are identical or different; the R is L Is tert-butyl, trimethylsilyl, benzyl, benzhydryl.
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