CN109982992B - Method for preparing eldecalcitol and intermediate for same - Google Patents
Method for preparing eldecalcitol and intermediate for same Download PDFInfo
- Publication number
- CN109982992B CN109982992B CN201780071892.6A CN201780071892A CN109982992B CN 109982992 B CN109982992 B CN 109982992B CN 201780071892 A CN201780071892 A CN 201780071892A CN 109982992 B CN109982992 B CN 109982992B
- Authority
- CN
- China
- Prior art keywords
- chemical formula
- compound
- following chemical
- reaction
- production method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C43/196—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of eldecalcitol and an intermediate used for the preparation method. According to the preparation method of the present invention, it is possible to economically and efficiently prepare the eldecalcitol without a complicated and long preparation process.
Description
Technical Field
The present invention relates to a method for preparing eldercalcitol (Eldecalcitol) and an intermediate therefor, and more particularly, to a method for economically and efficiently preparing eldercalcitol and an intermediate therefor.
Background
Various vitamin D derivatives have useful physiological activities, and in particular, U.S. Pat. No. 4,555,634 discloses that 1 α -hydroxyvitamin D3 derivatives represented by the following formula I are useful as therapeutic agents against diseases caused by abnormal calcium metabolism or as antitumor agents.
[ chemical formula I ]
The eldecalcitol ((1R,2R,3R,5Z,7E) -2- (3-hydroxypropoxy) -9, 10-ring-opened cholest-5, 7,10(19) -triene-1, 3, 25-triol) of the following chemical formula 1, which is one of the compounds represented by the above chemical formula I, is useful as a therapeutic agent for osteoporosis
The Active Pharmaceutical Ingredient (API) of (1).
[ chemical formula 1]
A method of preparing eldercalciferol from cholesterol derivatives using a photoreaction as vitamin D derivatives and a method of preparing and coupling an a-ring moiety (a-ring moiety) and a CD-ring moiety (CD-ring moiety) as main intermediates are known.
U.S. Pat. No. 5,334,740 discloses a method for preparing eldecalcitol by preparing the a-ring moiety of a cyclohexanetriol derivative as a main intermediate through a complicated process of 26 steps or more using 3,4:5,6-O-diisopropylidene-D-mannitol (3,4:5, 6-O-diisopropylidene-D-manitol) as a starting material and reacting it with the CD-ring moiety as shown in the following reaction formula 1, followed by deprotection reaction. However, the above-mentioned production method has a problem that a long production process is required for producing the a-ring moiety as an intermediate.
[ reaction formula 1]
Disclosure of Invention
Technical problem
The present inventors have conducted intensive studies to solve the above problems in the process of preparing eldecalcitol, and as a result, have found that an a-ring moiety, which is a main intermediate of eldecalcitol, can be prepared by using (3R,4R) -hexa-1, 5-diene-3, 4-diol as a starting material, and a Wittig-Horner (Wittig-Horner) reaction can be performed using the a-ring moiety, thereby economically and efficiently preparing eldecalcitol.
It is therefore an object of the present invention to provide an improved process for the economical and efficient preparation of digalciferol.
It is another object of the present invention to provide an intermediate for use in the above preparation process.
Technical scheme
One embodiment of the present invention relates to a method for preparing an eldecalcitol of the following chemical formula 1, the preparation method of the present invention comprising:
step i: reacting a compound of the following chemical formula 2 with p-anisaldehyde in the presence of an acid catalyst to obtain a compound of the following chemical formula 3;
step ii: subjecting acetyl group of the compound of the following chemical formula 3 to a reduction reaction to obtain a compound of the following chemical formula 4;
step iii: subjecting an allyl alcohol group of a compound of the following chemical formula 4 to an asymmetric epoxidation reaction to obtain a compound of the following chemical formula 5;
step iv: reacting a compound of the following chemical formula 5 with a compound of the following chemical formula 6 in the presence of a base to obtain a compound of the following chemical formula 7;
step v: reacting a compound of the following chemical formula 7 with a compound of the following chemical formula 8 to obtain a compound of the following chemical formula 9;
step vi: obtaining a compound of the following chemical formula 10 by protecting a secondary hydroxyl group of the compound of the following chemical formula 9;
step vii: selectively deprotecting a PMB group of a compound of the following chemical formula 10 to obtain a compound of the following chemical formula 11;
step viii: obtaining a compound of the following chemical formula 12 by protecting a secondary hydroxyl group of the compound of the following chemical formula 11;
step ix: selectively subjecting the THP group of the compound of the following chemical formula 12 to deprotection reaction to obtain a compound of the following chemical formula 13;
step x: obtaining a compound of the following chemical formula 14 by subjecting an ethynyl group of the compound of the following chemical formula 13 to a reduction reaction and reacting with iodine;
step xi: subjecting a compound of the following chemical formula 14 to a cyclization reaction to obtain a compound of the following chemical formula 15;
step xii: obtaining a compound of the following chemical formula 16 by subjecting a compound of the following chemical formula 15 to a halogenation reaction;
step xiii: reacting a compound of the following chemical formula 16 with diphenylphosphine and performing an oxidation reaction to obtain a compound of the following chemical formula 17;
step xiv: subjecting a compound of the following chemical formula 17 to wittig-horner reaction with a compound of the following chemical formula 18 to obtain a compound of the following chemical formula 19; and
step xv: a deprotection reaction is performed on the compound of the following chemical formula 19,
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
[ chemical formula 8]
[ chemical formula 9]
[ chemical formula 10]
[ chemical formula 11]
[ chemical formula 12]
[ chemical formula 13]
[ chemical formula 14]
[ chemical formula 15]
[ chemical formula 16]
[ chemical formula 17]
[ chemical formula 18]
[ chemical formula 19]
In the above-mentioned formula, the compound of formula,
PMP is p-methoxyphenyl and PMP is p-methoxyphenyl,
PMB is a p-methoxybenzyl group,
TBDPS is tert-butyl diphenyl silicon base,
TfO is a trifluoromethyl sulfonic acid group,
THP is tetrahydro-2H-pyran-2-yl,
TBS is tert-butyl dimethyl silicon base,
TMS is trimethylsilyl.
The production method of the present invention will be described in more detail below with reference to the following reaction formulae 2 and 3. The methods described in the following reaction formulae 2 and 3 are only typical examples of the methods used, and the reagents, reaction conditions, and the like may be changed as appropriate.
[ reaction formula 2]
[ reaction formula 3]
The first step is as follows: synthesis of the Compound of chemical formula 3
The compound of chemical formula 3 is prepared by reacting the compound of chemical formula 2 with p-anisaldehyde in the presence of an acid catalyst.
The acid catalyst may be sulfuric acid, camphorsulfonic acid, p-toluenesulfonic acid, etc., and p-toluenesulfonic acid is particularly preferably used.
Benzene, toluene, cyclohexane, etc. can be used as the reaction solvent, and cyclohexane is particularly preferable.
The reaction temperature is suitably from about 40 to 50 ℃ and the reaction time is preferably from about 4 to 6 hours.
The second step is as follows: synthesis of Compound of chemical formula 4
The compound of chemical formula 4 may be prepared by subjecting an acetyl group of the compound of chemical formula 3 to a reduction reaction.
The above reduction reaction may be performed in the presence of a reducing agent such as diisobutylaluminum hydride (DIBAL).
Tetrahydrofuran, dichloromethane, benzene, toluene or the like can be used as a reaction solvent, and toluene is particularly preferable.
The reaction temperature is suitably from about-10 to 10 deg.C, and the reaction time is preferably from about 1 to 5 hours.
The third step: synthesis of the Compound of chemical formula 5
The compound of chemical formula 5 may be prepared by subjecting an allyl alcohol group of the compound of chemical formula 4 to an asymmetric epoxidation reaction (Sharpless asymmetric epoxidation).
Can be found in isopropyl titanate (Ti (O-iPr)4) The above asymmetric epoxidation reaction was carried out in the presence of (+) -diisopropyl tartrate ((+) -DIPT) and t-butyl hydroperoxide (tBuOOH).
Toluene, benzene, methylene chloride and the like can be used as a reaction solvent, and methylene chloride is particularly preferable.
The reaction temperature is suitably from about 0 to 30 ℃ and the reaction time is preferably from about 5 to 10 hours.
The fourth step: synthesis of the Compound of chemical formula 7
The compound of chemical formula 7 may be prepared by reacting the compound of chemical formula 5 with the compound of chemical formula 6 in the presence of a base.
Sodium tert-butoxide, sodium tert-amylate, sodium hydride and the like can be used as the base, and sodium hydride is particularly suitable.
Dimethylformamide, tetrahydrofuran, acetonitrile and the like can be used as a reaction solvent, and acetonitrile is particularly preferable.
The reaction temperature is suitably from about-10 to 20 deg.c, and the reaction time is preferably from about 30 minutes to 2 hours.
The compound of chemical formula 6 may be prepared by reacting a compound of chemical formula 21 obtained by protecting only a portion of two hydroxyl groups of the compound of chemical formula 20 with a silicon group with anhydrous trifluoromethanesulfonic acid.
[ chemical formula 20]
[ chemical formula 21]
The fifth step: synthesis of the Compound of chemical formula 9
The compound of chemical formula 9 may be prepared by reacting the compound of chemical formula 7 with the compound of chemical formula 8.
The reaction may be carried out in the presence of n-butyllithium and boron trifluoride diethyl ether, but is not limited thereto.
Acetonitrile, dichloromethane, tetrahydrofuran, and the like can be used as the reaction solvent, and tetrahydrofuran is particularly preferable.
The reaction temperature is suitably from about-78 to 30 c, and the reaction time is preferably from about 2 to 4 hours.
A sixth step: synthesis of the Compound of chemical formula 10
The compound of chemical formula 10 may be prepared by protecting a secondary hydroxyl group of the compound of chemical formula 9.
The above protection reaction is performed by reacting the compound of chemical formula 9 with t-butyldimethylsilyl chloride in the presence of a base.
As the base, pyridine, triethylamine, imidazole and the like can be used, and imidazole is particularly suitable.
Acetonitrile, tetrahydrofuran, dimethylformamide and the like can be used as a reaction solvent, and dimethylformamide is particularly preferred.
The reaction temperature is suitably from about 20 to 80 ℃ and the reaction time is preferably from about 12 to 24 hours.
A seventh step of: synthesis of the Compound of chemical formula 11
The compound of chemical formula 11 may be prepared by selectively performing a deprotection reaction on the PMB group of the compound of chemical formula 10.
The deprotection reaction may be performed using 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), but is not limited thereto.
Chloroform, dichloromethane, water, or a mixed solvent thereof can be used as the reaction solvent, and a mixed solvent of dichloromethane and water is particularly preferable.
The reaction temperature is suitably from about 0 to 30 ℃ and the reaction time is preferably from about 30 minutes to 2 hours.
An eighth step: synthesis of Compound of chemical formula 12
The compound of chemical formula 12 may be prepared by protecting a secondary hydroxyl group of the compound of chemical formula 11.
The above protection reaction may be performed by reacting the compound of chemical formula 11 with tert-butyldimethylsilyl chloride in the presence of a base.
As the base, pyridine, triethylamine, imidazole and the like can be used, and imidazole is particularly suitable.
Acetonitrile, tetrahydrofuran, dimethylformamide and the like can be used as a reaction solvent, and dimethylformamide is particularly preferable.
The reaction temperature is suitably from about 20 to 80 ℃ and the reaction time is preferably from about 5 to 12 hours.
A ninth step: synthesis of the Compound of chemical formula 13
The compound of chemical formula 13 may be prepared by selectively performing a deprotection reaction on the THP group of the compound of chemical formula 12.
The deprotection reaction can be carried out in the presence of an acid, and as the acid, magnesium bromide, dimethylaluminum chloride, or the like can be used, with dimethylaluminum chloride being particularly suitable.
Tetrahydrofuran, diethyl ether, dichloromethane and the like can be used as a reaction solvent, and dichloromethane is particularly preferable.
The reaction temperature is suitably from about 0 to 30 ℃ and the reaction time is preferably from about 3 to 10 hours.
A tenth step: synthesis of Compound of chemical formula 14
The compound of chemical formula 14 may be prepared by subjecting the ethynyl group of the compound of chemical formula 13 to a reduction reaction and reacting it with iodine.
The above reduction reaction may be performed in the presence of a reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), etc., followed by using ethyl acetate to inhibit the action of the reducing agent and reacting with iodine.
As the reaction solvent, toluene, dichloromethane, tetrahydrofuran, diethyl ether, and the like can be used, and diethyl ether or tetrahydrofuran is particularly preferable.
The reaction temperature is suitably from about-78 to 30 ℃ and the reaction time is preferably from about 5 to 10 hours.
The 11 th step: synthesis of the Compound of chemical formula 15
The compound of chemical formula 15 may be prepared by subjecting the compound of chemical formula 14 to a cyclization reaction.
Can be used in alkali and palladium catalyst (Pd (PPh)3)4) In the presence of (a) to (b).
As the base, calcium carbonate, silver carbonate, triethylamine and the like can be used, and triethylamine is particularly preferable.
Dimethylformamide, tetrahydrofuran, acetonitrile and the like can be used as a reaction solvent, and acetonitrile is particularly preferable.
The reaction temperature is suitably from about 20 to 90 ℃ and the reaction time is preferably from about 1 to 10 hours.
Step 12: synthesis of the Compound of chemical formula 16
The compound of chemical formula 16 may be prepared by subjecting the compound of chemical formula 15 to a halogenation reaction and converting allyl alcohol into allyl chloride.
The halogenation reaction can be carried out using N-chlorosuccinimide, dimethyl sulfide, and the like, but is not limited thereto.
Tetrahydrofuran, diethyl ether, dichloromethane and the like can be used as a reaction solvent, and dichloromethane is particularly preferable.
The reaction temperature is suitably from about-30 to 30 ℃ and the reaction time is preferably from about 1 to 5 hours.
Step 13: synthesis of Compound of chemical formula 17
The compound of chemical formula 17 may be prepared by reacting the compound of chemical formula 16 with diphenylphosphine and performing an oxidation reaction.
The reaction with the above-mentioned diphenylphosphine may be carried out in the presence of a base, and n-butyllithium or the like may be used as the base, but is not limited thereto.
As the reaction solvent, dichloromethane, diethyl ether, tetrahydrofuran, and the like can be used, and tetrahydrofuran is particularly preferable.
The reaction temperature is suitably from about-78 to 0 deg.C, and the reaction time is preferably from about 1 to 5 hours.
The above oxidation reaction may be performed using an oxidizing agent such as hydrogen peroxide.
In this case, dichloromethane, chloroform or the like can be used as a reaction solvent, and chloroform is particularly preferable.
The reaction temperature is suitably from about 0 to 30 ℃ and the reaction time is preferably from about 1 to 5 hours.
Step 14: synthesis of the Compound of chemical formula 19
The compound of chemical formula 19 may be prepared by subjecting the compound of chemical formula 17 to wittig-horner reaction with the compound of chemical formula 18.
The wittig-horner reaction may be performed in the presence of a base, and n-butyllithium or the like may be used as the base, but is not limited thereto.
As the reaction solvent, dichloromethane, diethyl ether, tetrahydrofuran, and the like can be used, and tetrahydrofuran is particularly preferred.
The reaction temperature is suitably from about-78 to 30 ℃ and the reaction time is preferably from about 1 to 5 hours.
Step 15: preparation of the Compound of chemical formula 1
The compound of chemical formula 1 may be prepared by performing a deprotection reaction on the compound of chemical formula 19.
The deprotection reaction can be carried out in the presence of an acid catalyst, and camphorsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like can be used as the acid catalyst, with p-toluenesulfonic acid being particularly suitable.
The reaction solvent may be methanol, ethanol, dichloromethane, or a mixed solvent thereof, and a mixed solvent of methanol and dichloromethane is particularly preferable.
The reaction temperature is suitably from about 0 to 30 ℃ and the reaction time is preferably from about 2 to 10 hours.
One embodiment of the present invention relates to a compound of the following chemical formula 5 as a preparation intermediate of eldecalcitol.
[ chemical formula 5]
In the above-mentioned formula, the compound of formula,
PMB is p-methoxybenzyl.
Another embodiment of the present invention relates to a compound of the following chemical formula 7 as a preparation intermediate of eldecalcitol.
[ chemical formula 7]
In the above-mentioned formula, the compound of formula,
PMB is a p-methoxybenzyl group,
TBDPS is tert-butyl diphenyl silicon base.
Yet another embodiment of the present invention relates to a compound of the following chemical formula 9 as a preparation intermediate of eldecalcitol.
[ chemical formula 9]
In the above-mentioned formula, the compound of formula,
PMB is a p-methoxybenzyl group,
TBDPS is tert-butyl diphenyl silicon base,
THP is tetrahydro-2H-pyran-2-yl.
An embodiment of the present invention relates to a method for preparing a compound of the following chemical formula 17 as an intermediate for preparing an eldecalcitol, the method comprising:
step vi: obtaining a compound of the following chemical formula 10 by protecting a secondary hydroxyl group of the compound of the following chemical formula 9;
step vii: selectively deprotecting a PMB group of a compound of the following chemical formula 10 to obtain a compound of the following chemical formula 11;
step viii: obtaining a compound of the following chemical formula 12 by protecting a secondary hydroxyl group of the compound of the following chemical formula 11;
step ix: selectively subjecting the THP group of the compound of the following chemical formula 12 to deprotection reaction to obtain a compound of the following chemical formula 13;
step x: obtaining a compound of the following chemical formula 14 by subjecting an ethynyl group of the compound of the following chemical formula 13 to a reduction reaction and reacting with iodine;
step xi: subjecting a compound of the following chemical formula 14 to a cyclization reaction to obtain a compound of the following chemical formula 15;
step xii: obtaining a compound of the following chemical formula 16 by subjecting a compound of the following chemical formula 15 to a halogenation reaction; and
step xiii: a compound of the following chemical formula 16 is reacted with diphenylphosphine and subjected to an oxidation reaction,
[ chemical formula 9]
[ chemical formula 10]
[ chemical formula 11]
[ chemical formula 12]
[ chemical formula 13]
[ chemical formula 14]
[ chemical formula 15]
[ chemical formula 16]
[ chemical formula 17]
In the above-mentioned formula, the compound of formula,
PMB is a p-methoxybenzyl group,
TBDPS is tert-butyl diphenyl silicon base,
THP is tetrahydro-2H-pyran-2-yl,
TBS is tert-butyl dimethyl silicon base.
Since the detailed description of the preparation method of the compound of chemical formula 17 described above is associated with the preparation method of eldecalcitol and is the same as the sixth to thirteenth steps described above, the detailed description is omitted in order to avoid repetition.
Advantageous effects
According to the preparation method of the present invention, it is possible to economically and efficiently prepare the eldecalcitol without a complicated and long preparation process.
Detailed Description
The present invention will be described more specifically with reference to examples. It will be apparent to those skilled in the art that these examples are merely illustrative of the present invention and the scope of the present invention is not limited to these examples.
Example 1: preparation of the Compound of chemical formula 3
503g of (3R,4R) -hexa-1, 5-diene-3, 4-diol 2 are diluted in 5000ml of cyclohexane. 2027ml of p-anisaldehyde and 1170g of p-toluenesulfonic acid were added, and the temperature of the reaction solution was raised to about 45 to 50 ℃ and stirred for four hours. The progress of the reaction was observed by thin layer chromatography (ethane: ethyl acetate ═ 2: 1). After the reaction was completed, the reaction solution was cooled to room temperature, and 3000ml of a 5% aqueous sodium hydrogencarbonate solution was added thereto and stirred. The organic layer was separated, 6940ml of 10% sodium hydrogensulfite was added thereto, and the mixture was stirred. The organic layer was separated, 1780ml of a 5% aqueous sodium hydrogencarbonate solution was added, and the mixture was stirred. The organic layer was separated and dried over anhydrous sodium sulfate. After filtering the anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain (4R,5R) -2- (4-methoxyphenyl) -4, 5-divinyl-1, 3-dioxolan 3 containing impurities. The reaction of the next step was carried out without further purification process.
1H NMR(300MHz,CDCl3):δ7.45-7.43(2H,dd,J＝1.8,6.6Hz),6.92-6.89(2H,dd,J＝1.9,6.7Hz),6.00-5.85(2H,m),5.45-5.35(2H,m),4.37-4.19(2H,m),3.81(3H,s)。
Example 2: preparation of the Compound of chemical formula 4
200g of (4R,5R) -2- (4-methoxyphenyl) -4, 5-divinyl-1, 3-dioxolane 3 with impurities are diluted in 1800ml of toluene. The temperature of the reaction solution was cooled to about-5 to 0 ℃ and 1552ml of diisobutylaluminum hydride (DIBAL, 1.2M in toluene) was added dropwise while maintaining 0 ℃. The reaction solution was stirred at the same temperature for about 1 to 2 hours, and the progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 2: 1). After the reaction, 50.3ml of methanol was added dropwise to the reaction mixture to complete the reaction, and 50.3ml of a 5% aqueous NaOH solution was added dropwise while maintaining the temperature at 10 ℃ or lower. After the reaction solution was stirred for about 10 to 20 minutes, the organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, a mixture was obtained by concentrating the filtrate in vacuo, and distillation was performed in vacuo at an external temperature of 120 ℃ to obtain pure (3R,4R) -4- (4-methoxybenzyloxy) hexa-1, 5-dien-3-ol 4(127g, 35%).
1H NMR(300MHz,CDCl3):δ7.27-7.24(2H,d,J＝8.7Hz),6.90-6.87(2H,dd,J＝1.9,6.7Hz),5.86-5.67(2H,m),5.99-5.35(2H,m),5.32-5.28(1H,m),5.22-5.17(1H,dt,J＝1.5,10.5Hz),4.61-4.29(2H,dd,J＝11.1,86.1Hz),4.07-4.01(1H,m),3.80(3H,s),3.67-3.62(1H,t,J＝7.5Hz),2.77-2.76(1H,d,J＝3.0Hz)。
Example 3: preparation of the Compound of chemical formula 5
To 960ml of methylene chloride was added 80g of molecular sieve (molecular sieve)
245ml of isopropyl titanate and 203ml of (+) -diisopropyl tartrate are stirred at room temperature for about 20 minutes. 162g of (3R,4R) -4- (4-methoxybenzyloxy) hexa-1, 5-dien-3-ol 4 are diluted and added dropwise to 640ml of dichloromethane and stirred at room temperature for about 20 minutes. 248ml of t-butyl hydroperoxide was added dropwise while maintaining at 20 ℃ or lower and stirred at room temperature for about 5 hours, and the progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 2: 1). After the reaction was completed, undissolved solids were filtered and removed using celite, and 230g of ferrous sulfate heptahydrate and 79.5g of citric acid were dissolved in 2400ml of water and added to the filtrate. The reaction mixture was stirred at room temperature for 1 hour, and the organic layer of the filtrate was separated by filtration and removal of undissolved solids using celite. 115g of sodium hydroxide was dissolved in 1615ml of 20% saline, and added to the separated organic layer and stirred at room temperature for about 30 minutes. The progress of the reaction to remove the (+) -diisopropyl tartrate used in the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 2: 1). The organic layer was separated, 500ml of a 1N aqueous hydrochloric acid solution was added thereto, and the mixture was stirred for about 10 minutes. The organic layer was separated, 1600ml of a 5% aqueous sodium bicarbonate solution was added, and the mixture was stirred for about 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture, and the external temperature was 140 deg.CDistillation was performed in vacuo to afford pure (1S,2R) -2- (4-methoxybenzyloxy) -1- ((R) -oxiran-2-yl) but-3-en-1-ol 5(160g, 93%).
1H NMR(300MHz,CDCl3):δ7.27-7.24(2H,d,J＝8.4Hz),6.90-6.87(2H,d,J＝8.7Hz),5.92-5.80(1H,m),5.42(1H,s),5.39-5.37(1H,d,J＝8.4Hz),4.64-4.33(1H,dd,J＝11.4,81.9Hz),3.93-3.89(1H,m),3.81(3H,s),3.50-3.46(1H,t,J＝Hz),3.66-3.61(1H,t,J＝5.1Hz),3.05-3.01(1H,m),2.75-2.77(2H,d,J＝3.3Hz)。
Example 4: preparation of the compound of chemical formula 6
75.6g of 1, 3-propanediol are diluted in 1130ml of dichloromethane and 139ml of triethylamine are added and stirred. The temperature of the reaction mass was cooled to 0 ℃ and 258ml of tert-butyldiphenylchlorosilane were added dropwise. The temperature of the reaction was raised to room temperature and stirred for 24 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate 4: 1). After the reaction was completed, 1130ml of water was added and stirred for about 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture, and distillation was performed in vacuo at an external temperature of 150 ℃ to obtain pure 3- (t-butyldiphenylsiloxy) propan-1-ol (284g, 91%). 284g of the 3- (tert-butyldiphenylsiloxy) propan-1-ol obtained were dissolved in 2840ml of n-heptane, and 165ml of diisopropylethylamine was added. The temperature of the reaction was cooled to about 10 ℃ and 152ml of anhydrous trifluoromethanesulfonic acid was added dropwise. The temperature of the reaction was maintained at about 10 ℃ while stirring for 30 minutes. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate 4: 1). After the reaction was completed, 1420ml of water was added and stirred for about 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give 3- (tert-butyldiphenylsiloxy) propyl trifluoromethanesulfonate 6(395g, 98%).
1H NMR(300MHz,CDCl3):δ7.66-7.63(4H,m),7.47-7.35(6H,m),4.76-4.72(2H,t,J＝6.2Hz),3.79-3.75(2H,t,J＝5.7Hz),2.05-1.97(1H,m),1.07-1.04(9H,m)。
Example 5: preparation of the Compound of chemical formula 7
35.4g of 60% sodium hydride was slowly added to and suspended in 990ml of acetonitrile, and the temperature of the reaction was cooled to-5 ℃. 142.9g of (1S,2R) -2- (4-methoxybenzyloxy) -1- ((R) -oxiran-2-yl) but-3-en-1-ol 5 were diluted in 425ml of acetonitrile and slowly added dropwise while maintaining 0 ℃ or lower. 420g of 3- (tert-butyldiphenylsiloxy) propyl trifluoromethanesulfonate 6 was diluted in 285ml of acetonitrile, slowly added dropwise while maintaining the temperature at 0 ℃ or lower, and then slowly warmed to room temperature and stirred for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate 4: 1). After the reaction was completed, 46ml of methanol was added and the reaction was completed, and 1400ml of water and 1400ml of ethyl acetate were added and stirred for about 10 minutes. After separating the organic layer and adding 1400ml of water, stirring was carried out for about 10 minutes, and then the organic layer was separated and dried over anhydrous sodium sulfate. After filtering anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture, and purified by column chromatography using silica gel (hexane: ethyl acetate ═ 10:1) to obtain pure (3R,4S) -1- (4-methoxyphenyl) -11, 11-dimethyl-4- ((R) -oxiran-2-yl) -10, 10-diphenyl-3-vinyl-2, 5, 9-trioxa-10-siladodecane 7(262g, 84%).
1H NMR(300MHz,CDCl3):δ7.67-7.61(4H,m),7.44-7.33(6H,m),7.25-7.22(2H,m),6.86-6.83(2H,m),5.91-5.81(1H,m),5.31-5.24(2H,m),4.62-4.58(1H,d,J＝12.0Hz),4.36-4.32(1H,d,J＝11.7Hz),3.93-3.90(1H,q,J＝3.9Hz),3.78(3H,s),3.76-3.68(3H,m),3.64-3.56(1H,m),3.23-3.20(1H,t,J＝4.5Hz),3.10-3.06(1H,m),2.76-2.72(2H,m),1.83-1.74(2H,m),1.03(9H,s)。
Example 6: preparation of the Compound of chemical formula 9
75g of 2- (prop-2-ynyloxy) tetrahydro-2H-pyran 8 are diluted in 750ml of tetrahydrofuran and the temperature of the reaction is cooled to below-65 ℃. N-butyllithium (200 ml in n-hexane, 2.5M) was added dropwise while maintaining the temperature at-60 ℃ or lower. The reaction was stirred at the same temperature for 30 minutes, and 98g of (3R,4S) -1- (4-methoxyphenyl) -11, 11-dimethyl-4- ((R) -oxiran-2-yl) -10, 10-diphenyl-3-vinyl-2, 5, 9-trioxa-10-siladodecane 7 was added dropwise while diluting in 250ml of tetrahydrofuran and maintaining at-60 ℃ or lower. 24.3ml of boron trifluoride diethyl ether (BF)3·OEt2) The dropwise addition was carried out while maintaining-60 ℃ or lower, and the temperature of the reaction mixture was slowly raised to room temperature and then stirred for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5: 1). After the reaction was completed, 980ml of 10% ammonium chloride was added to complete the reaction, and 1500ml of ethyl acetate was added and stirred for about 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give (3R,4R,5R) -4- (3- (tert-butyldiphenylsiloxy) propoxy) -3- (4-methoxybenzyloxy) -9- (tetrahydro-2H-pyran-2-yloxy) non-1-en-7-yn-5-ol 9 containing impurities. The reaction of the next step was carried out without further purification process.
1H NMR(300MHz,CDCl3):δ7.66-7.63(4H,m),7.45-7.34(6H,m),7.25-7.21(2H,m),6.88-6.83(1H,dt,J＝2.5,9.2Hz),5.98-5.86(1H,m),5.35-5.29(2H,m),4.80-4.78(1H,t,J＝3.3Hz),4.61-4.57(1H,d,J＝11.7Hz),4.32-4.28(1H,d,J＝11.7Hz),4.27-4.23(2H,m),4.11-4.07(1H,m),3.87-3.82(2H,m),3.79(3H,s),3.75-3.65(4H,m),3.55-3.46(1H,m),3.37-3.34(1H,m),3.00-2.98(1H,d,J＝4.8Hz),2.56-2.40(2H,m),1.82-1.49(8H,m),1.04(9H,s)。
Example 7: preparation of the Compound of chemical formula 10
123g (theoretical yield) of (3R,4R,5R) -4- (3- (tert-butyldiphenylsiloxy) propoxy) -3- (4-methoxybenzyloxy) -9- (tetrahydro-2H-pyran-2-yloxy) non-1-en-7-yn-5-ol 9 containing impurities were diluted in 1230ml of dimethylformamide and 3.1g of imidazole and 60.7g of tert-butyldimethylchlorosilane were added. The temperature of the reaction was raised to about 60 to 70 ℃ and stirred for more than 12 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5: 1). After the reaction was completed, 1000ml of 5% ammonium chloride was added to complete the reaction, and 1000ml of ethyl acetate was added and stirred for 10 minutes. The organic layer was separated and 1000ml of water was added thereto, followed by stirring for 10 minutes, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to give (5R,6S) -6- ((R) -1- (4-methoxybenzyloxy) allyl) -2,2,3,3,13, 13-hexamethyl-12, 12-diphenyl-5- (4- (tetrahydro-2H-pyran-2-yloxy) but-2-ynyl) -4,7, 11-trioxa-3, 12-disilatetradecane 10 containing impurities. The reaction of the next step was carried out without further purification process.
1H NMR(300MHz,CDCl3):δ7.68-7.64(4H,m),7.43-7.33(6H,m),7.23-7.20(2H,m),6.84-6.79(1H,dt,J＝2.5,9.2Hz),5.93-5.81(1H,m),5.31-5.28(1H,m),5.25(1H,s),4.30-4.21(3H,m),3.97-3.74(10H,m),3.53-3.47(1H,m),3.38-3.34(1H,m),2.51-2.49(1H,m),1.89-1.48(8H,m),1.04(9H,s),0.86(9H,s),0.07(3H,s),0.01(3H,s)。
Example 8: preparation of the compound of chemical formula 11
(5R,6S) -6- ((R) -1- (4-methoxybenzyloxy) allyl) -2,2,3,3,13, 13-hexamethyl-12, 12-diphenyl-5- (4- (tetrahydro-2H-pyran-2-yloxy) but-2-ynyl) -4,7, 11-trioxa-3, 12-disilatetradecane 10(143.6g, theoretical yield), which contains impurities, was diluted in 1430ml of dichloromethane and 70.2ml of water was added. 40.7g of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) was added to the reaction solution, and stirred at room temperature for about 1 to 1.5 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5: 1). After the reaction was completed, 10.8g of sodium hydroxide was dissolved and added to 1500ml of water and stirred for 10 minutes. The organic layer was separated, 280g of sodium hydrogen sulfite and 1000ml of water were added thereto, followed by stirring for 10 minutes, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain (3R,4S,5R) -5- (tert-butyldimethylsilyloxy) -4- (3- (tert-butyldiphenylsiloxy) propoxy) -9- (tetrahydro-2H-pyran-2-yloxy) non-1-en-7-yn-3-ol 11 containing impurities. The reaction of the next step was carried out without further purification process.
1H NMR(300MHz,CDCl3):δ7.67-7.64(4H,m),7.45-7.35(6H,m),5.99-5.88(1H,m),5.38-5.31(1H,dt,J＝1.7,17.2Hz),5.20-5.16(1H,dt,J＝1.5,10.5Hz),4.81-4.79(1H,t,J＝3.1Hz),4.31-4.22(3H,m),3.93-3.79(3H,m),3.75-3.64(3H,m),3.54-3.47(1H,m),3.35-3.31(1H,dd,J＝3.9,5.7Hz),2.67-2.65(1H,d,J＝6.3Hz),2.58-2.43(2H,m),1.87-1.65(4H,m),1.61-1.50(4H,m),1.04(9H,s),0.90(9H,s),0.11(3H,s),0.09(3H,s)。
Example 9: preparation of the Compound of chemical formula 12
(3R,4S,5R) -5- (tert-butyldimethylsilyloxy) -4- (3- (tert-butyldiphenylsiloxy) propoxy) -9- (tetrahydro-2H-pyran-2-yloxy) non-1-en-7-yn-3-ol 11(122.1g, theoretical yield), containing impurities, was diluted in 1220ml of dimethylformamide and 19.5g of imidazole and 40.5g of tert-butyldimethylsilyl chloride were added. The temperature of the reaction was raised to about 50 to 60 ℃ and stirred for about 4 to 5 hours or more. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5:1,10: 1). After the reaction was completed, 1000ml of 5% ammonium chloride was added to complete the reaction, and 1000ml of ethyl acetate was added and stirred for about 10 minutes. The organic layer was separated and 1000ml of water was added thereto, followed by stirring for 10 minutes, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtering anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture, and purified by column chromatography using silica gel (hexane: ethyl acetate ═ 30:1) to obtain pure (5R,6R) -6- ((1R) -1- (tert-butyldimethylsilyloxy) -5- (tetrahydro-2H-pyran-2-yloxy) pent-3-ynyl) -2,2,3,3,13, 13-hexamethyl-12, 12-diphenyl-5-vinyl-4, 7, 11-trioxa-3, 12-disilatetradecane 12(89g, 62%).
1H NMR(300MHz,CDCl3):δ7.68-7.64(4H,m),7.44-7.34(6H,m),5.93-5.81(1H,m),5.27-5.20(1H,dt,J＝1.5,17.4Hz),5.14-5.10(1H,m),4.79-4.78(1H,m),4.30-4.25(1H,m),4.20-4.13(2H,m),3.98-3.94(1H,m),3.86-3.67(5H,m),3.54-3.47(1H,m),3.27-3.25(1H,dd,J＝1.5,6.6Hz),2.51-2.33(2H,m),1.86-1.47(8H,m),1.04(9H,s),0.89(9H,s),0.87(9H,s),0.08(3H,s),0.06(3H,s),0.04(3H,s),0.02(3H,s)。
Example 10: preparation of the Compound of chemical formula 13
80g of (5R,6R) -6- ((1R) -1- (tert-butyldimethylsilyloxy) -5- (tetrahydro-2H-pyran-2-yloxy) pent-3-ynyl) -2,2,3,3,13, 13-hexamethyl-12, 12-diphenyl-5-vinyl-4, 7, 11-trioxa-3, 12-disilatetradecane 12 are diluted in 800ml of dichloromethane and the temperature of the reaction is cooled to 0 ℃. Dimethylaluminum chloride (201.2ml, 0.9M in heptane) was added dropwise and stirred for about 5 to 6 hours after warming to room temperature. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5:1,10: 1). After the reaction was completed, the temperature of the reaction mass was cooled to 0 ℃, and 12.3ml of methanol was added dropwise and stirred for 10 minutes to complete the reaction. 28.2g of sodium hydroxide was dissolved in 800ml of water and added dropwise to the reaction mixture, followed by stirring for 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture, and purified by column chromatography using silica gel (hexane: ethyl acetate ═ 10:1) to obtain pure (5R,6R,7R) -5, 7-bis (tert-butyldimethylsilyloxy) -6- (3- (tert-butyldiphenylsiloxy) propoxy) non-8-en-2-yn-1-ol 13(72g, 74%).
1H NMR(300MHz,CDCl3):δ7.68-7.64(4H,m),7.44-7.34(6H,m),5.93-5.81(1H,m),5.27-5.20(1H,dt,J＝1.6,17.3Hz),5.15-5.10(1H,dt,J＝1.5,10.5Hz),4.29-4.21(2H,m),4.18-4.13(1H,m),3.98-3.93(1H,m),3.87-3.67(4H,m),3.28-3.25(1H,dd,J＝1.8,6.6Hz),2.49-2.34(2H,m),1.87-1.78(2H,m),1.39-1.35(1H,t,J＝6.0Hz),1.04(9H,s),0.89(9H,s),0.88(9H,s),0.09(3H,s),0.06(3H,s),0.05(3H,s),0.02(3H,s)。
Example 11: preparation of the Compound of chemical formula 14
75g of (5R,6R,7R) -5, 7-bis (tert-butyldimethylsilyloxy) -6- (3- (tert-butyldiphenylsiloxy) propoxy) non-8-en-2-yn-1-ol 13 are diluted in 1120ml of diethyl ether and the temperature of the reaction mass is cooled to 0 ℃. Sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) (82.3ml, 60% in toluene) was added dropwise, and stirred after warming to room temperature for about 4 to 5 hours. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5: 1). After the reaction was completed, 10.3ml of ethyl acetate was added, and stirred at room temperature for about 30 minutes. The temperature of the reaction mass was cooled to about-65 to-60 ℃, and 53.5g of iodine was dissolved in 150ml of tetrahydrofuran and then added dropwise while maintaining the temperature below-60 ℃. After stirring the reaction for 30 minutes at about-65 to-60 ℃, the reaction was completed by slowly warming to room temperature. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5: 1). After the reaction was completed, 750ml of a 10% ammonium chloride aqueous solution was added and stirred for 10 minutes. The organic layer was separated, 750ml of a 10% aqueous solution of sodium thiosulfate was added thereto, and the mixture was stirred for 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration of anhydrous sodium sulfate, the filtrate was concentrated in vacuo to obtain a mixture, and purified by column chromatography using silica gel (hexane: ethyl acetate ═ 7:1) to obtain pure (5R,6R,7R, Z) -5, 7-bis (tert-butyldimethylsiloxy) -6- (3- (tert-butyldiphenyloxy) propoxy) -3-iodonona-2, 8-dien-1-ol 14(62g, 70%).
1H NMR(300MHz,CDCl3):δ7.69-7.62(4H,m),7.45-7.34(6H,m),5.93-5.76 21H,m),5.34-5.27(1H,dt,J＝1.5,17.3Hz),5.20-5.16(1H,dt,J＝1.4,10.5Hz),4.20-4.01(4H,m),3.89-3.69(4H,m),3.29-3.26(1H,dd,J＝0.9,7.5Hz),2.74-2.67(1H,m),2.61-2.56(1H,m),1.89-1.80(2H,m),1.41-1.37(1H,t,J＝6.0Hz),1.05(9H,s),0.90(9H,s),0.84(9H,s),0.06(3H,s),0.05(3H,s),0.02(3H,s)。
Example 12: preparation of the Compound of chemical formula 15
62g of (5R,6R,7R, Z) -5, 7-bis (tert-butyldimethylsilyloxy) -6- (3- (tert-butyldiphenylsiloxy) propoxy) -3-iodonona-2, 8-dien-1-ol 14 are diluted in 1860ml of acetonitrile. After 4.3g of tetrakis (triphenylphosphine) palladium (0) and 11.1ml of triethylamine (11.1ml) were added, the mixture was stirred under reflux for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 5: 1). After the reaction was completed, the reaction was cooled to room temperature and concentrated in vacuo to obtain a mixture, and purified by column chromatography using silica gel (hexane: ethyl acetate ═ 7:1) to obtain pure (Z) -2- ((3R,4R,5R) -3, 5-bis- (tert-butyldimethylsilyloxy) -4-3- (tert-butyldiphenylsiloxy) propoxy) -2-methylenecyclohexylidene) ethanol 15(49g, 93%).
1H NMR(300MHz,CDCl3):δ7.67-7.64(4H,m),7.44-7.33(6H,m),5.54-5.50(1H,t,J＝6.7Hz),5.23(1H,s),4.84-4.82(1H,m),4.25-4.09(4H,m),3.80-3.62(4H,m),3.19-3.16(1H,dd,J＝2.1,6.9Hz),2.43-2.36(1H,m),2.26-2.17(1H,m),1.88-1.79(2H,m),1.04(9H,s),0.89(9H,s),0.86(9H,s),0.06(3H,s),0.04-0.03(9H,m)。
Example 13: preparation of the Compound of example 16
15.5g of N-chlorosuccinimide were diluted in 375ml of dichloromethane, and the temperature of the reaction liquid was cooled to 0 ℃. 9.14ml of dimethyl sulfide are added dropwise and stirred for 30 minutes at about 0 ℃. The temperature of the reaction solution was cooled to-20 ℃ and 40g of (Z) -2- ((3R,4R,5R) -3, 5-bis- (tert-butyldimethylsilyloxy) -4-3- (tert-butyldiphenylsiloxy) propoxy) -2-methylenecyclohexylidene) ethanol 15 was diluted and added dropwise to 229ml of dichloromethane. After the end of the dropwise addition, stirring was carried out at the same temperature for about 10 to 20 minutes, and the temperature was slowly raised to room temperature. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 10: 1). After the reaction was completed, 375ml of water was added to the reaction, followed by stirring for 10 minutes, and the organic layer was separated and dried over anhydrous sodium sulfate. Concentration was performed in vacuo to obtain a mixture, and purification was performed by column chromatography using silica gel (hexane: ethyl acetate: triethylamine: 10:1) to obtain pure ((1R,2R,3R, Z) -2- (3- (tert-butyldiphenylsiloxy) propoxy) -5- (2-chloroethylene) -4-methylenecyclohexane-1, 3-diyl) bis (oxy) bis (tert-butyldimethylsilane) 16(40g, 98%).
1H NMR(300MHz,CDCl3):δ7.67-7.63(4H,m),7.44-7.34(6H,m),5.54-5.49(1H,t,J＝7.8Hz),5.29(1H,s),5.04-5.03(1H,m),4.26-4.23(1H,d,J＝7.2Hz),4.19-4.09(3H,m),3.79-3.62(4H,m),3.17-3.15(1H,m),2.42-2.36(1H,dd,J＝6.9,13.5Hz),2.23-2.17(1H,m),1.88-1.79(2H,m),1.04(9H,s),0.89(9H,s),0.85(9H,s),0.06(3H,s),0.04(3H,s),0.03(3H,s),0.02(3H,s)。
Example 14: preparation of the Compound of chemical formula 17
14.52ml of diphenylphosphine were diluted in 500ml of tetrahydrofuran and the temperature of the reaction was cooled to 0 ℃. N-butyllithium (33.4ml, 2.0M in hexane) was added dropwise and stirred at 0 ℃ for about 30 minutes. In a further reactor, 40.6g of ((1R,2R,3R, Z) -2- (3- (tert-butyldiphenylsiloxy) propoxy) -5- (2-chloroethylene) -4-methylenecyclohexane-1, 3-diyl) bis (oxy) bis (tert-butyldimethylsilane) 16 are diluted in 500ml of tetrahydrofuran. The temperature of the reaction mass was cooled to below-65 ℃ and the prepared lithium diphenylphosphine solution was added dropwise. The reaction was stirred for about 1 hour while maintaining below-65 ℃. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 10: 1). After the reaction was completed, 5.5ml of water was added dropwise and stirred for 10 minutes to complete the reaction. After warming to room temperature, concentration was performed in vacuo to obtain a mixture, and the concentrated residue was dissolved in 715ml of chloroform and 340ml of 5% hydrogen peroxide was added thereto and stirred for about 1 hour. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 1: 1). After the reaction was completed, the organic layer was separated, 400ml of a 10% aqueous solution of sodium thiosulfate was added thereto, and the mixture was stirred for about 1 hour. The organic layer was separated and dried over anhydrous sodium sulfate. Concentration was performed in vacuo to obtain a mixture, and purification was performed by column chromatography using silica gel (hexane: ethyl acetate: triethylamine ═ 1:1:0.1) to obtain pure (Z) - [2- { (3R,4R,5R) -3, 5-bis (tert-butyldimethylsilyloxy) -2-methylene-4- (3- (tert-butyldiphenylsilanyloxy) propoxy) cyclohexylidene } diphenylphosphine oxide 17(41.3g, 83%).
1H NMR(300MHz,CDCl3):δ7.78-7.71(4H,m),7.70-7.66(4H,m),7.59-7.37(12H,m),5.39-5.32(1H,dd,J＝7.2,14.4Hz),5.26(1H,s),4.84-4.83(1H,t,J＝1.8Hz),4.28-4.25(1H,d,J＝7.5Hz),4.15-4.11(1H,m),3.79-3.64(4H,m),3.43-3.31(1H,m),3.28-3.15(1H,m),3.13-3.10(1H,dd,J＝2.0,7.7Hz),2.38-2.33(1H,m),2.23-215(1H,m),1.91-1.82(2H,m),1.07(9H,s),0.93(9H,s),0.83(3H,s),0.10(3H,s),0.05-0.03(9H,m)。
Example 15: preparation of the Compound of chemical formula 19
5.1g of (Z) - [2- { (3R,4R,5R) -3, 5-bis (tert-butyldimethylsilyloxy) -2-methylene-4- (3- (tert-butyldiphenylsilanyloxy) propoxy) cyclohexylidene } diphenylphosphine oxide 17 were diluted in 50ml of tetrahydrofuran, and the temperature of the reaction was cooled to-65 ℃ or below. N-butyllithium (2.3ml, 2.5M in hexane) was added dropwise at-65 ℃ or less, and stirred under the same for about 1 hour. 10g of (1R,3aR,7aR) -7 a-methyl-1- ((R) -6-methyl-6- (trimethylsiloxy) heptan-2-yl) hexahydro-1H-inden-4 (2H) -one 18 are diluted and added dropwise to 10ml of tetrahydrofuran and the temperature is slowly raised to room temperature. The progress of the reaction was observed by thin layer chromatography (hexane: ethyl acetate ═ 10: 1). After the reaction was completed, 50ml of a 5% ammonium chloride aqueous solution and 50ml of ethyl acetate were added and stirred for 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a mixture. Purification was performed by column chromatography using silica gel (hexane: ethyl acetate ═ 30:1 to 20:1) to obtain pure ((1R,2R,3R, Z) -2- (3- (tert-butyldiphenylsiloxy) propoxy) -5- ((E) -2- ((1R,3aS,7aR) -7 a-methyl-1- ((R) -6-methyl-6- (trimethylsiloxy) heptan-2-yl) dihydro-1H-indene-4 (2H,5H,6H, 7aH) -ylidene) ethylene) -4-methylenecyclohexane-1, 3-diyl) di (oxy) di (tert-butyldimethylsilane) 19(2.3g, 86%).
1H NMR(300MHz,CDCl3):δ7.666-7.637(4H,m),7.437-7.329(6H,m),6.223(1H,d,J＝11.4Hz),5.994(1H,d,J＝11.1Hz),5.240-5.236(1H,m),4.958(1H,d,J＝2.1Hz),4.183-4.085(2H,m),3.800-3.644(4H,m),3.230-3.202(1H,m),2.831-2.795(1H,m),2.480-2.410(1H,m),2.235-2.133(1H,m),2.043-1.214(14H,m),1.185(6H,s),1.039(12H,s),0.971-0.848(27H,m),0.600-0.523(9H,m),0.062-0.036(12H,m)。
Example 16: preparation of Adelcitol
2.3g of ((1R,2R,3R, Z) -2- (3- (tert-butyldiphenylsiloxy) propoxy) -5- ((E) -2- ((1R,3aS,7aR) -7 a-methyl-1- ((R) -6-methyl-6- (trimethylsiloxy) heptan-2-yl) dihydro-1H-indene-4 (2H,5H,6H,7H,7aH) -ylidene) ethylene) -4-methylenecyclohexane-1, 3-diyl) di (oxy) di (tert-butyldimethylsilane) 19 are diluted in dichloromethane: to a mixed solution of methanol (1:1,34.5ml), and after adding 0.4g of p-toluenesulfonic acid, stirred for about 5 to 6 hours. The progress of the reaction was observed by thin layer chromatography (dichloromethane: methanol ═ 10: 1). After the reaction was completed, 30ml of a saturated aqueous sodium bicarbonate solution was added to complete the reaction, and 40ml of dichloromethane was added and stirred for 10 minutes. The organic layer was separated and dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a mixture. Purification was performed by column chromatography using silica gel (dichloromethane: methanol ═ 10:1) to obtain idicalciferol 1(1.0g, 88%) with a purity of 98% or more.
1H NMR(300MHz,CDCl3):δ6.353(1H,d,J＝11.07Hz),6.043(1H,d,J＝11.07Hz),5.496(1H,t,1.98Hz),5.076(1H,t,J＝1.98Hz),4.313(1H,d,J＝8.16Hz),4.254(1H,s),3.949-3.880(1H,m),3.8314(2H,s),3.752-3.682(1H,m),3.273-3.234(1H,dd,J＝9.06Hz,J＝2.8Hz),2.828-2.2782(1H,m),2.538(1H,dd,J＝14.49Hz,J＝3.96Hz),2.435-2.387(1H,m),2.007-1.259(16H,m),1.212(6H,s),1.130-1.002(1H,m),0.935(3H,d,J＝6.27Hz),0.547(3H,s)。
Claims (19)
1. A method for preparing an eldecalcitol of the following chemical formula 1, comprising:
step i: reacting a compound of the following chemical formula 2 with p-anisaldehyde in the presence of an acid catalyst to obtain a compound of the following chemical formula 3;
step ii: subjecting acetyl group of the compound of the following chemical formula 3 to a reduction reaction to obtain a compound of the following chemical formula 4;
step iii: subjecting an allyl alcohol group of a compound of the following chemical formula 4 to an asymmetric epoxidation reaction to obtain a compound of the following chemical formula 5;
step iv: reacting a compound of the following chemical formula 5 with a compound of the following chemical formula 6 in the presence of a base to obtain a compound of the following chemical formula 7;
step v: reacting a compound of the following chemical formula 7 with a compound of the following chemical formula 8 to obtain a compound of the following chemical formula 9;
step vi: obtaining a compound of the following chemical formula 10 by protecting a secondary hydroxyl group of the compound of the following chemical formula 9;
step vii: selectively deprotecting a PMB group of a compound of the following chemical formula 10 to obtain a compound of the following chemical formula 11;
step viii: obtaining a compound of the following chemical formula 12 by protecting a secondary hydroxyl group of the compound of the following chemical formula 11;
step ix: selectively subjecting the THP group of the compound of the following chemical formula 12 to deprotection reaction to obtain a compound of the following chemical formula 13;
step x: obtaining a compound of the following chemical formula 14 by subjecting an ethynyl group of the compound of the following chemical formula 13 to a reduction reaction and reacting with iodine;
step xi: subjecting a compound of the following chemical formula 14 to a cyclization reaction to obtain a compound of the following chemical formula 15;
step xii: obtaining a compound of the following chemical formula 16 by subjecting a compound of the following chemical formula 15 to a halogenation reaction;
step xiii: reacting a compound of the following chemical formula 16 with diphenylphosphine and performing an oxidation reaction to obtain a compound of the following chemical formula 17;
step xiv: subjecting a compound of the following chemical formula 17 to wittig-horner reaction with a compound of the following chemical formula 18 to obtain a compound of the following chemical formula 19; and
step xv: a deprotection reaction of a compound of the following chemical formula 19 is performed,
[ chemical formula 2]
[ chemical formula 3]
[ chemical formula 4]
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
[ chemical formula 8]
[ chemical formula 9]
[ chemical formula 10]
[ chemical formula 11]
[ chemical formula 12]
[ chemical formula 13]
[ chemical formula 14]
[ chemical formula 15]
[ chemical formula 16]
[ chemical formula 17]
[ chemical formula 18]
[ chemical formula 19]
[ chemical formula 1]
In the above-mentioned formula, the compound of formula,
PMP is p-methoxyphenyl and PMP is p-methoxyphenyl,
PMB is a p-methoxybenzyl group,
TBDPS is tert-butyl diphenyl silicon base,
TfO is a trifluoromethyl sulfonic acid group,
THP is tetrahydro-2H-pyran-2-yl,
TBS is tert-butyl dimethyl silicon base,
TMS is trimethylsilyl.
2. The production method according to claim 1,
in step i, the acid catalyst is p-toluenesulfonic acid.
3. The production method according to claim 1,
in step ii, the reduction reaction is carried out in the presence of diisobutylaluminum hydride.
4. The production method according to claim 1,
in step iii, the asymmetric epoxidation reaction is performed in the presence of isopropyl titanate, (+) -diisopropyl tartrate and tert-butyl hydroperoxide.
5. The production method according to claim 1,
in step iii, the temperature of the asymmetric epoxidation reaction is from 0 to 30 ℃.
6. The production method according to claim 1,
in step iv, the base is sodium hydride.
7. The production method according to claim 1,
in step v, the reaction was carried out in the presence of n-butyllithium and boron trifluoride diethyl ether.
8. The production method according to claim 1,
in step vi, the protection reaction is performed by reacting the compound of formula 9 with t-butyldimethylsilyl chloride in the presence of a base.
9. The production method according to claim 1,
in step vii, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone is used to perform the deprotection reaction.
10. The production method according to claim 1,
in step viii, the protection reaction is performed by reacting the compound of chemical formula 11 with t-butyldimethylsilyl chloride in the presence of a base.
11. The production method according to claim 1,
in step ix, the deprotection reaction is performed in the presence of dimethylaluminum chloride.
12. The production method according to claim 1,
in step x, the reduction reaction is carried out in the presence of sodium bis (2-methoxyethoxy) aluminum hydride.
13. The production method according to claim 1,
in step xi, the cyclization reaction is performed in the presence of a base and a palladium catalyst.
14. The production method according to claim 1,
in step xii, the halogenation reaction is performed using N-chlorosuccinimide and dimethyl sulfide.
15. The production method according to claim 1,
in step xiii, the reaction with diphenylphosphine is performed in the presence of a base, and the oxidation reaction is performed using hydrogen peroxide.
16. The production method according to claim 1,
in step xiv, the wittig-horner reaction is performed in the presence of a base.
17. The production method according to claim 1,
in step xv, a deprotection reaction is performed in the presence of p-toluenesulfonic acid.
18. A compound of the following chemical formula 5,
[ chemical formula 5]
In the above-mentioned formula, the compound of formula,
PMB is p-methoxybenzyl.
19. A method for preparing a compound of the following chemical formula 17, comprising:
step iv: reacting a compound of the following chemical formula 5 with a compound of the following chemical formula 6 in the presence of a base to obtain a compound of the following chemical formula 7;
step v: reacting a compound of the following chemical formula 7 with a compound of the following chemical formula 8 to obtain a compound of the following chemical formula 9;
step vi: obtaining a compound of the following chemical formula 10 by protecting a secondary hydroxyl group of the compound of the following chemical formula 9;
step vii: selectively deprotecting a PMB group of a compound of the following chemical formula 10 to obtain a compound of the following chemical formula 11;
step viii: obtaining a compound of the following chemical formula 12 by protecting a secondary hydroxyl group of the compound of the following chemical formula 11;
step ix: selectively subjecting the THP group of the compound of the following chemical formula 12 to deprotection reaction to obtain a compound of the following chemical formula 13;
step x: obtaining a compound of the following chemical formula 14 by subjecting an ethynyl group of the compound of the following chemical formula 13 to a reduction reaction and reacting with iodine;
step xi: subjecting a compound of the following chemical formula 14 to a cyclization reaction to obtain a compound of the following chemical formula 15;
step xii: obtaining a compound of the following chemical formula 16 by subjecting a compound of the following chemical formula 15 to a halogenation reaction; and
step xiii: a compound of the following chemical formula 16 is reacted with diphenylphosphine and subjected to an oxidation reaction,
[ chemical formula 5]
[ chemical formula 6]
[ chemical formula 7]
[ chemical formula 8]
[ chemical formula 9]
[ chemical formula 10]
[ chemical formula 11]
[ chemical formula 12]
[ chemical formula 13]
[ chemical formula 14]
[ chemical formula 15]
[ chemical formula 16]
[ chemical formula 17]
In the above-mentioned formula, the compound of formula,
PMB is a p-methoxybenzyl group,
TBDPS is tert-butyl diphenyl silicon base,
TfO is a trifluoromethyl sulfonic acid group,
THP is tetrahydro-2H-pyran-2-yl,
TBS is tert-butyl dimethyl silicon base.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2016-0155127 | 2016-11-21 | ||
| KR1020160155127A KR101884729B1 (en) | 2016-11-21 | 2016-11-21 | Process for Preparing Eldecalcitol and Intermediate Therefor |
| PCT/KR2017/013209 WO2018093223A2 (en) | 2016-11-21 | 2017-11-20 | Method for preparing eldecalcitol and intermediate therefor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109982992A CN109982992A (en) | 2019-07-05 |
| CN109982992B true CN109982992B (en) | 2022-05-17 |
Family
ID=62146692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780071892.6A Active CN109982992B (en) | 2016-11-21 | 2017-11-20 | Method for preparing eldecalcitol and intermediate for same |
Country Status (4)
| Country | Link |
|---|---|
| JP (2) | JP6775809B2 (en) |
| KR (1) | KR101884729B1 (en) |
| CN (1) | CN109982992B (en) |
| WO (1) | WO2018093223A2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11591280B2 (en) | 2019-05-13 | 2023-02-28 | Faes Farma, S.A. | Process and intermediates for the preparation of eldecalcitol |
| CN113105495A (en) * | 2020-01-09 | 2021-07-13 | 成都必凯科技有限公司 | Preparation method of elcalcitol A ring intermediate |
| CN112094291A (en) * | 2020-08-14 | 2020-12-18 | 甘肃皓天医药科技有限责任公司 | Synthesis method of adicalcitol A ring intermediate |
| CN113651845A (en) * | 2021-08-03 | 2021-11-16 | 甘肃皓天医药科技有限责任公司 | Preparation method of ossifying diol intermediate A ring |
| CN114656384A (en) * | 2022-04-20 | 2022-06-24 | 正大制药（青岛）有限公司 | Preparation method of eldecalcitol 20S isomer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334740A (en) * | 1991-03-13 | 1994-08-02 | Kurary Co., Ltd. | Cyclohexanetriol derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009013154A (en) * | 2006-09-29 | 2009-01-22 | Teijin Pharma Ltd | 2-substituted 14-epi-previtamin d3 derivative |
| US11116849B2 (en) | 2013-04-22 | 2021-09-14 | Ascendis Pharma A/S | Hydrogel-linked prodrugs releasing tagged drugs |
| US9585934B2 (en) | 2014-10-22 | 2017-03-07 | Extend Biosciences, Inc. | Therapeutic vitamin D conjugates |
-
2016
- 2016-11-21 KR KR1020160155127A patent/KR101884729B1/en active IP Right Grant
-
2017
- 2017-11-20 JP JP2019542342A patent/JP6775809B2/en active Active
- 2017-11-20 WO PCT/KR2017/013209 patent/WO2018093223A2/en active Application Filing
- 2017-11-20 CN CN201780071892.6A patent/CN109982992B/en active Active
-
2020
- 2020-07-28 JP JP2020127472A patent/JP7072273B2/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334740A (en) * | 1991-03-13 | 1994-08-02 | Kurary Co., Ltd. | Cyclohexanetriol derivatives |
Non-Patent Citations (4)
| Title |
|---|
| Convergent synthesis of lα,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D3(ED-71);Susumi Hatakeyama等;《Bioorganic & Medicinal Chemistry Letters》;19971231;第7卷(第22期);第2872-2873页、图3和图4 * |
| Search for and Development of Active Vitamin D3 Analogues;KUBODERA,N.等;《Journal of Synthetic Organic Chemistry》;20051231;第63卷(第7期);摘要、图7和图18 * |
| Structural revisions of the reported A-ring phosphine oxide synthon for ED-71 (Eldecalcitol) and a new synthesis;Guo-Dong Zhao等;《Tetrahedron》;20150824;第71卷;第8033-8040页 * |
| Synthesis and biological evaluation of a 3-positon epimer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71);Susumi Hatakeyama等;《Journal of Steroid Biochemistry & Molecular Biology》;20071231;第103卷;第222-226页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6775809B2 (en) | 2020-10-28 |
| JP2020189844A (en) | 2020-11-26 |
| WO2018093223A2 (en) | 2018-05-24 |
| CN109982992A (en) | 2019-07-05 |
| KR101884729B1 (en) | 2018-08-02 |
| JP2019536814A (en) | 2019-12-19 |
| KR20180057033A (en) | 2018-05-30 |
| JP7072273B2 (en) | 2022-05-20 |
| WO2018093223A3 (en) | 2018-07-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109982992B (en) | Method for preparing eldecalcitol and intermediate for same | |
| EP0078704B1 (en) | Intermediates in the synthesis of vitamin d derivatives | |
| Tadano et al. | Ortho ester Claisen rearrangements of three 3-C-(hydroxymethyl) methylene derivatives of hexofuranose: stereoselective introduction of a quaternary center on C-3 of D-ribo-, L-lyxo-, and D-arabino-hexofuranoses | |
| Fraser-Reid et al. | Dipyranoside precursors for ansamycins. Pyranosidic homologation. 5 | |
| CN108463457B (en) | The method for preparing beraprost | |
| KR101936375B1 (en) | Process for Preparing Eldecalcitol and Intermediate Therefor | |
| EP0143323B1 (en) | Process for an anthracycline derivative, and an anthracyclinone derivative useful for the process | |
| Kanemasa et al. | Diene-transmissive Diels-Alder Reaction Using 2-Ethoxy-3-methylene-1, 4-pentadiene and 2-(2-Bromo-1-ethoxyethyl) 1, 3-butadiene | |
| EP0180399B1 (en) | Anti-tumor 4-hydroxy-2-cyclopentenones | |
| EP1061070B1 (en) | Process for the preparation of ED-71 | |
| CN101830839A (en) | Method for synthesizing Seocalcitol | |
| US5136066A (en) | Process for preparing optically active cyclopentenone derivative | |
| EP0154185B1 (en) | Calciferol derivatives | |
| JP3773578B2 (en) | Taxol synthetic intermediate | |
| WO1998050353A1 (en) | Vitamin d3 derivatives and process for producing the same | |
| Yoshida et al. | Triterpenoid total synthesis. Part 6. 1 Synthesis of testudinariols A and B, triterpene metabolites of the marine mollusc Pleurobrancus testudinarius | |
| Gimazetdinov et al. | Synthetic Approaches to 15-Deoxy-Δ 12, 14-prostaglandin J 2. A New Key Building Block Based on (3a R, 6 R, 6a S)-6-Trimethylsilyl)-3, 3a, 6, 6a-tetrahydro-1 H-cyclopenta [c] furan-1-one | |
| KR102300311B1 (en) | Process for Preparing Tacalcitol and Intermediate Therefor | |
| US5180844A (en) | Optically active 2-methylenecyclopentanone derivative and process for preparing same | |
| Grzeszczyk et al. | Homologation of methyl 2-azido-and 2-acetamido-3, 4-di-O-benzyl-2-deoxy-d-hexopyranosides with allyloxymethylmagnesium chloride | |
| CN105152992B (en) | Cyclopiane tetracyclic diterpene analogue and synthesis method and application thereof | |
| US5216187A (en) | Optically active 2-methylenepentane derivative and process for preparing same | |
| US20130006003A1 (en) | New synthones for preparation of 19-nor vitamin d derivatives | |
| Otaka et al. | Synthesis of Sphingofungin D and Its Three Diastereomers | |
| JP2832356B2 (en) | Synthetic intermediates and production methods for hygromycins |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |