CN114685337B - Preparation method of idecalcitol - Google Patents

Preparation method of idecalcitol Download PDF

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CN114685337B
CN114685337B CN202210434267.6A CN202210434267A CN114685337B CN 114685337 B CN114685337 B CN 114685337B CN 202210434267 A CN202210434267 A CN 202210434267A CN 114685337 B CN114685337 B CN 114685337B
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compound
solvent
reaction
idecalcitol
preparation
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CN114685337A (en
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方礼貌
单伟达
王丽虹
蔺翔
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Zhejiang Garden Biopharmaceutical Co.,Ltd.
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ZHEJIANG GARDEN BIOCHEMICAL HIGH-TECH CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The application relates to a method for synthesizing a medicine, in particular to a method for preparing idecalcitol, which takes 25-hydroxy cholesterol as a starting material, prepares idecalcitol through oxidation, dehydrogenation, isomerization, reduction, acetylation protection, dehydrogenation treatment, diene protection, epoxidation, deprotection, addition and illumination reaction, has simple operation and high yield, and is suitable for industrial production.

Description

Preparation method of idecalcitol
Technical Field
The application relates to a method for synthesizing a medicine, in particular to a method for preparing idecalcitol.
Background
Idecalcitol, the english name elecalcitol, is a white crystalline powder that is sensitive to light and air. Slightly soluble in methanol, ethanol and ethyl acetate. It is one of the most important metabolic active products of vitamin D3 in human body, and has the functions of promoting the small intestine to absorb calcium, regulating the transportation of inorganic salts in bone, and the like; mainly used for osteoporosis; renal osteodystrophy in patients with chronic renal failure, particularly in patients requiring long-term hemodialysis; spontaneous and pseudo parathyroid machine subsides after surgery; vitamin D3 dependent rickets and hypophosphite hypovitamin D resistant rickets; skin diseases such as psoriasis; and other vitamin D deficiency.
The idecalcitol is used as a novel active vitamin D analogue, and has lasting effect and high utilization rate compared with the traditional vitamin D. The idecalcitol has a particularly remarkable effect in increasing bone density, and is therefore used as a medicament for treating osteoporosis. Although idecalcitol has been of great interest as a drug for the treatment of smart osteoporosis.
The Chinese patent with application number 201710377709.7 discloses a preparation method of idecalcitol, which comprises the steps of coupling an A ring segment with a structure shown in a formula (I) and a CD ring segment with a structure shown in a formula (II) under the action of a catalyst, extracting and drying after the reaction is finished, and separating and purifying by column chromatography to obtain an intermediate with a structure shown in a formula (III); dissolving the obtained intermediate in tetrahydrofuran solution, adding hydrogen fluoride pyridine to remove silyl ether protecting groups, purifying and crystallizing to obtain the finished product of idecalcitol, and obtaining higher yield.
The Chinese patent with application number 202010325584.5 discloses a synthesis method of idecalcitol, which is prepared from lithocholic acid, N-bromosuccinimide, methanol, hydrochloric acid, methyl magnesium bromide and a crystallizing agent as raw materials, so that the conversion rate of the raw materials is greatly improved, more idecalcitol can be produced from the same amount of raw materials, and the input cost of a producer is reduced.
Disclosure of Invention
In order to solve the problems, the preparation method of the idecalcitol provided by the application can be used for efficiently completing the total synthesis of the idecalcitol, and is simple in process and high in yield.
The technical scheme adopted by the application for achieving the purpose is as follows:
a preparation method of idecalcitol comprises the following steps:
s1, oxidizing secondary alcohol into ketone by taking 25-hydroxycholesterol as a raw material in cyclohexanone solvent and taking aluminum isopropoxide as a catalyst, and performing aftertreatment to obtain intermediate ketone, namely a compound 1;
s2, mixing the compound 1 with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, performing dehydrogenation reaction, extracting, washing, concentrating, extracting, and crystallizing in acetonitrile solvent to obtain a dehydrogenated substance, namely the compound 2;
s3, ethanol is taken as a solvent, a compound 2, sodium ethoxide and potassium tert-butoxide are added into the solvent, after the rearrangement reaction of the compound 2 under the action of the potassium tert-butoxide, an isomer is obtained through extraction, washing and concentration, and the isomer is marked as a compound 3;
s4, dissolving the compound 3 in a pyridine solvent, adding sodium borohydride, reacting with 4-dimethylaminopyridine as a catalyst, selectively reducing ketocarbonyl to generate alcohol by the compound 3 under the action of the sodium borohydride, quenching, extracting, washing and concentrating to obtain a reduction product;
s5, adding acetic anhydride into the reduction product obtained in the step S4, acylating the reduction product by the acetic anhydride, extracting, washing, concentrating and crystallizing to obtain product ester, and marking the product ester as a compound 4;
s6, mixing the compound 4 with N-bromosuccinimide by taking normal hexane as a solvent, adding azodiisobutyronitrile, and carrying out bromination reaction to obtain 1-acetate-25-hydroxy-7-bromocholesterol-1-ene; then adding 2,4, 6-trimethylpyridine into the mixture to perform dehydrobromination reaction to obtain 1-acetate-25-hydroxy-cholesterol-1, 7-diene, and after the reaction is completed, adding potassium hydroxide into the mixture by taking methanol as a solvent to perform saponification reaction to obtain a compound 5;
s7, the compound 5 is treated by 4-phenyl-1, 2, 4-triazoline-3, 5-dione to protect diene, N-dimethylformamide is taken as a solvent, dimethyl tertiary butyl chlorosilane and imidazole are added to react, and hydroxyl is protected, so that 4-phenyl-1, 2, 4-triazoline-3, 5-dione protected conjugated diene ester is obtained, namely the compound 6;
s8, treating the obtained compound 6 with m-chloroperoxybenzoic acid to oxidize unprotected olefin to obtain 4-phenyl-1, 2, 4-triazolin-3, 5-dione protected epoxide, which is marked as a compound 7;
s9, treating the compound 7 by using tetrahydrofuran as a solvent, adding tetrabutylammonium fluoride, removing a TBS hydroxyl protecting group by reaction, and then removing a 4-phenyl-1, 2, 4-triazolin-3, 5-dione protecting group by adding 1, 3-dimethyl-2-imidazolone to obtain an epoxide, namely the compound 8;
s10, adding a compound 8 and potassium tert-butoxide into propylene glycol serving as a solvent, and ring-opening epoxy to obtain a hydroxy propoxy dehydrocompound, namely a compound 9;
s11, performing photochemical ring opening on the compound 9, and separating and purifying to obtain a product idecalcitol crystal.
Further, a capsule of idecalcitol consisting of a content consisting of idecalcitol, lecithin and chain triglycerides and a capsule shell; the capsule shell consists of modified polypropylene resin, sodium octoate, ethanol, glyceryl triacetate and titanium dioxide;
the preparation method of the modified polypropylene resin comprises the following steps: taking ethanol as a solvent, adding polypropylene resin and copper sulfate, heating and stirring, slowly dripping glycerol into the solvent, continuously stirring after dripping, and heating and refluxing to obtain an intermediate I; mixing the intermediate I with phosphoric acid, adding p-toluenesulfonic acid, heating and stirring, and distilling under reduced pressure after the reaction is completed to obtain the modified polypropylene resin.
The application has the following beneficial effects:
1. 25-hydroxycholesterol is used as a starting material, and is subjected to oxidation, dehydrogenation, isomerization, reduction, acetylation protection, dehydrogenation treatment, diene protection, epoxidation, deprotection, addition and illumination reaction to prepare idecalcitol, so that the preparation method is simple in operation, high in yield and suitable for industrial production;
2. the polypropylene resin is modified by using the glycerol, the glycerol has certain lubricating property to prevent the capsule from being adhered to the esophagus in the swallowing process, and the glycerol has mild property and can not cause damage to the esophagus; on the basis of modifying the polypropylene resin by glycerol, phosphoric acid is grafted to the glycerol modified polypropylene resin to form phosphate groups, so that the dissolution of the medicine is promoted, and the action effect of the medicine is improved.
Drawings
FIG. 1 is a flow chart of a process for preparing idecalcitol according to the present application.
Detailed Description
The technical solutions of the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application, and it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Example 1
The preparation method of the idecalcitol comprises the following specific processes as shown in figure 1:
s1, oppenauer oxidation: 40g of 25-hydroxycholesterol is taken as a raw material, 15.2g of aluminum isopropoxide is taken as a catalyst in 200mL of cyclohexanone solvent, the mixture is heated to 75 ℃ for 4 hours of reaction, and 38.2g of intermediate ketone 25-hydroxycholesterol-4-alkene-3-ketone is obtained after oxidation of secondary alcohol into ketone, namely the compound 1; the reaction process is as follows:
C 27 H 46 O 2 +C 6 H 10 O------C 27 H 44 O 2 +C 6 H 12 O；
s2, dehydrogenation reaction: 38g of compound 1 and 20g of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone are mixed, dehydrogenation reaction is carried out for 4 hours, extraction is carried out by ethyl acetate, washing is carried out by saturated sodium chloride for three times, concentration and extraction are carried out, and 36.8g of dehydrogenated substance 25-hydroxycholesterol-1, 4-diene-3-ketone is obtained by crystallization in acetonitrile solvent, namely compound 2; the reaction process is as follows:
C 27 H 44 O 2 +C 8 Cl 2 N 2 O----C 27 H 42 O 2 +C 8 H 2 Cl 2 N 2 O；
s3, isomerism reaction: adding 36g of compound 2, 15.2g of sodium ethoxide and 13.8g of potassium tert-butoxide into 200mL of ethanol serving as a solvent, reacting for 2 hours, carrying out rearrangement reaction on the compound 2 under the action of the potassium tert-butoxide, extracting with ethyl acetate, washing with saturated sodium chloride, and concentrating to obtain 34g of isomer 25-hydroxycholesteryl-1, 5-diene-3-ketone, which is marked as compound 3; the reaction process is as follows:
C 27 H 42 O 2 ------C 27 H 42 O 2 ；
s4, reduction reaction: 33.5g of compound 3 is dissolved in 250mL of pyridine solvent, 5.8g of sodium borohydride is added, 3.5g of 4-dimethylaminopyridine is used as a catalyst, the reaction is carried out for 4 hours in an ice bath, ketocarbonyl is selectively reduced by the compound 3 under the action of sodium borohydride to generate alcohol, after quenching, 32g of reduction product 25-hydroxycholesterol-1-alkene is obtained after extraction, washing and concentration, and the reaction process is as follows:
4C 27 H 42 O 2 +BH 4 Na+2H 2 O--4C 27 H 44 O+BNaO 2 ；
s5, acetylation protection: adding 10mL of acetic anhydride into 32g of the reduction product obtained in the step S4, refluxing for 3 hours, acylating the reduction product by the acetic anhydride, extracting by ethyl acetate, washing by saturated sodium chloride, concentrating, crystallizing to obtain 30.2g of product ester, and marking the 1-acetate-25-hydroxycholesterol-1-alkene as a compound 4; the reaction process is as follows:
C 27 H 44 O 2 +C 4 H 6 O 3 ----C 29 H 46 O 3 +C 2 H 4 O 2 ；
s6, dehydrogenation treatment:
bromination reaction: 30g of compound 4 and 150mL of N-bromosuccinimide are mixed by taking 300mL of normal hexane as a solvent, 15g of azodiisobutyronitrile is added for bromination reaction, 45 ℃ is kept, and the reaction is carried out for 4 hours, so that 29.5g of 1-acetate-25-hydroxy-7-bromocholesterol-1-ene is obtained; the reaction process is as follows:
C 29 H 46 O 3 +C 4 H 4 BrNO 2 -----C 29 H 45 BrO 3 +C 4 H 5 NO 2 ；
dehydrobromination reaction: then 4.5g of 2,4, 6-trimethylpyridine is added into the mixture, dehydrobromination reaction is carried out at 55 ℃ to obtain 22.3g of 1-acetate-25-hydroxy-cholesterol-1, 7-diene, and the reaction process is as follows:
C 29 H 45 BrO 3 +C 8 H 11 N---C 29 H 44 O 3 +C 8 H 12 NBr；
saponification reaction: after the reaction is completed, 200mL of methanol is taken as a solvent, 4g of potassium hydroxide is added for saponification reaction for 6 hours, 18.2g of compound 5, namely 25-hydroxycholesterol-1, 7-diene is obtained, and the reaction process is as follows:
C 29 H 44 O 3 +KOH---C 27 H 42 O 2 +C 2 H 3 O 2 K；
s7, protection:
conjugate addition: 18g of compound 5 are treated with 6g of 4-phenyl-1, 2, 4-triazolin-3, 5-dione to protect the diene, the reaction process is:
C 27 H 42 O 2 +C 8 H 5 N 3 O 2 ---C 35 H 47 N 3 O 2 ；
3-hydroxy protection: after the reaction is finished, 250mL of N, N-dimethylformamide is taken as a solvent, 5g of dimethyl tertiary butyl chlorosilane and 4.8g of imidazole are added for reaction, and hydroxyl groups are protected, so that 18.9g of 4-phenyl-1, 2, 4-triazolin-3, 5-dione protected conjugated diene ester is obtained, namely the compound 6, and the reaction process is as follows:
C 35 H 47 N 3 O 2 +C 6 H 15 ClSi+C 3 H 4 N 2 ---C 41 H 61 N 3 O 2 Si+C 3 H 5 N 2 Cl。
s8, epoxidation: the resulting 18.9g of compound 6 was treated with 15mL of m-chloroperoxybenzoic acid at 15℃for 2h to oxidize the unprotected olefin to give 16.34g of 4-phenyl-1, 2, 4-triazolin-3, 5-dione protected epoxide, designated compound 7, as follows:
C 41 H 61 N 3 O 2 Si+C 7 H 5 ClO 3 ----C 41 H 61 N 3 O 3 Si+C 7 H 5 ClO 2 ；
s9, deprotection: 200mL of tetrahydrofuran is taken as a solvent, 4.5g of tetrabutylammonium fluoride is added to treat the compound 7 at 15 ℃ for 4 hours, TBS hydroxyl protecting groups are removed by reaction, and the reaction process is as follows:
C 41 H 61 N 3 O 3 Si+C 16 H 36 FN+H 2 O-----C 16 H 37 O+C 6 H 15 FSi+C 35 H 47 N 3 O 5 。
after the reaction is completed, 4.2g of 1, 3-dimethyl-2-imidazolone is added to react for 1.5 hours at 50 ℃, 4-phenyl-1, 2, 4-triazolin-3, 5-dione protecting group is removed, and finally 8.4g of epoxide is obtained, namely the compound 8, wherein the reaction process is as follows:
C 35 H 47 N 3 O 5 +C 5 H 10 N 2 O---C 27 H 42 O 3 +C 13 H 15 N 5 O 3 ；
s10, addition reaction: 150mL of propylene glycol is taken as a solvent, 6g of compound 8 and 3g of potassium tert-butoxide are added for reaction for 4 hours, and epoxy ring opening is carried out to obtain 9.6g of hydroxy propoxy dehydro compound, namely 1a, 25-dihydroxy-2 beta- (3-hydroxy propoxy) cholesterol-7-alkene, which is marked as compound 9, and the reaction process is as follows:
C 27 H 42 O 3 +C 3 H 8 O 2 ----C 30 H 50 O 5 ；
s11, photochemical ring opening: 9.6g of compound 9 is subjected to photochemical ring opening (the light reaction condition is that the XPA light reaction instrument is used for carrying out the light reaction for 10-60 min)), 8.6g of product idecalcitol crystal is obtained after separation and purification, the total yield is 17.6%, and the reaction process is as follows:
C 30 H 50 O 5 ----C 30 H 50 O 5 。
example 2
The preparation method of the idecalcitol comprises the following specific processes as shown in figure 1:
s1, oppenauer oxidation: 80g of 25-hydroxycholesterol is taken as a raw material, 30g of aluminum isopropoxide is taken as a catalyst in 400mL of cyclohexanone solvent, the mixture is heated to 85 ℃ for reaction for 6 hours, and 72.4g of intermediate ketone 25-hydroxycholesterol-4-alkene-3-ketone is obtained after oxidation of secondary alcohol into ketone, namely the compound 1;
s2, dehydrogenation reaction: 71g of compound 1 and 42g of 2, 3-dichloro-5, 6-dicyano-p-benzoquinone are mixed, dehydrogenation reaction is carried out for 6 hours, extraction is carried out by ethyl acetate, washing is carried out by saturated sodium chloride for three times, concentration and extraction are carried out, and 58g of dehydrogenated substance 25-hydroxycholesteryl-1, 4-diene-3-ketone is obtained by crystallization in acetonitrile solvent, namely compound 2;
s3, isomerism reaction: taking 350mL of ethanol as a solvent, adding 58g of compound 2, 32g of sodium ethoxide and 26.8g of potassium tert-butoxide into the solvent, reacting for 4 hours, carrying out rearrangement reaction on the compound 2 under the action of the potassium tert-butoxide, extracting with ethyl acetate, washing with saturated sodium chloride for three times, and concentrating to obtain 51g of isomer 25-hydroxycholesteryl-1, 5-diene-3-ketone, which is marked as compound 3;
s4, reduction reaction: 51g of compound 3 is dissolved in 350mL of pyridine solvent, 12g of sodium borohydride is added, 8.5g of 4-dimethylaminopyridine is used as a catalyst, the reaction is carried out for 6h in an ice bath, ketocarbonyl is selectively reduced by the compound 3 under the action of sodium borohydride to generate alcohol, after quenching, 42g of reduction product 25-hydroxycholesterol-1-alkene is obtained after extraction, washing and concentration;
s5, acetylation protection: adding 25mL of acetic anhydride into 42g of the reduction product obtained in the step S4, refluxing for 5 hours, acylating the reduction product by the acetic anhydride, extracting by ethyl acetate, washing by saturated sodium chloride, concentrating, crystallizing to obtain 28.8g of product ester, and marking 1-acetate-25-hydroxycholesterol-1-alkene as a compound 4;
s6, dehydrogenation treatment:
bromination reaction: taking 450mL of normal hexane as a solvent, mixing 28g of compound 4 with 250mL of N-bromosuccinimide, adding 25g of azodiisobutyronitrile, carrying out bromination reaction, keeping the temperature of 50 ℃ and reacting for 4 hours to obtain 23g of 1-acetate-25-hydroxy-7-bromocholesterol-1-ene;
dehydrobromination reaction: then 11g of 2,4, 6-trimethylpyridine is added into the mixture to carry out dehydrobromination reaction at 60 ℃ to obtain 22.3g of 1-acetate-25-hydroxy-cholesterol-1, 7-diene;
saponification reaction: after the reaction is completed, adding 8g of potassium hydroxide into 400mL of methanol serving as a solvent to perform saponification reaction for 6 hours to obtain 18.2g of compound 5, namely 25-hydroxycholesterol-1, 7-diene;
s7, protection:
conjugate addition: 18g of Compound 5 were treated with 14g of 4-phenyl-1, 2, 4-triazolin-3, 5-dione to protect the diene;
3-hydroxy protection: after the reaction is finished, 450mL of N, N-dimethylformamide is taken as a solvent, 12g of dimethyl tertiary butyl chlorosilane and 12.2g of imidazole are added for reaction, and hydroxyl is protected, so 16g of 4-phenyl-1, 2, 4-triazolin-3, 5-dione protected conjugated diene ester is obtained, namely the compound 6;
s8, epoxidation: the resulting 16g of compound 6 was treated with 30mL of m-chloroperoxybenzoic acid at 12℃for 4 hours to oxidize the unprotected olefin to give 15.6g of 4-phenyl-1, 2, 4-triazolin-3, 5-dione-protected epoxide, designated compound 7;
s9, deprotection: using 450mL tetrahydrofuran as a solvent, adding 11g tetrabutylammonium fluoride to treat the compound 7 at 12 ℃ for 6 hours, and removing a TBS hydroxyl protecting group by reaction;
after the reaction is completed, adding 9.5g of 1, 3-dimethyl-2-imidazolone to react for 2 hours at 55 ℃, removing the 4-phenyl-1, 2, 4-triazolin-3, 5-dione protecting group, and finally obtaining 13.2g of epoxide, namely the compound 8;
s10, addition reaction: taking 300mL of propylene glycol as a solvent, adding 13g of compound 8 and 6g of potassium tert-butoxide, reacting for 6 hours, and opening epoxy ring to obtain 12.2g of hydroxy propoxy dehydro compound, namely 1a, 25-dihydroxy-2 beta- (3-hydroxy propoxy) cholesterol-7-alkene, which is marked as compound 9;
s11, photochemical ring opening: 12.2g of compound 9 is subjected to photochemical ring opening (the photoreaction condition: XPA photoreaction instrument, and the photoreaction is carried out for 40 min), and 10.5g of product idecalcitol crystal is obtained after separation and purification, and the total yield is 10.8%.
Example 3
A capsule of idecalcitol comprises a content and a capsule shell, wherein the content comprises 0.0001g of idecalcitol, 0.003g of lecithin and 0.015 chain triglyceride; the capsule shell consists of 50g of modified polypropylene resin, 2g of sodium octoate, 25g of ethanol, 2g of glycerol triacetate and 2g of titanium dioxide (800 capsules);
the preparation method of the modified polypropylene resin comprises the following steps: with 80g of ethanol as a solvent, 65g of polypropylene resin (Eudragit L100-55 (EL)) and 5g of copper sulfate are added, heated to 120 ℃ and stirred, 35g of glycerol is slowly added dropwise thereto, stirring is continued after the dropwise addition is completed, and the reaction process is as follows:
mixing the intermediate I with 35g of phosphoric acid, adding 5g of toluenesulfonic acid, heating to 110 ℃, stirring for 4 hours, and performing reduced pressure distillation after the reaction is finished to obtain modified polypropylene resin, wherein the reaction process is as follows:
the preparation method of the capsules of the idecalcitol comprises the following steps (the materials are weighed according to the weight ratio):
t1, mixing idecalcitol, lecithin and chain triglyceride, heating to 55 ℃, slowly and uniformly stirring, heating for 1h, stopping heating, and naturally cooling to room temperature to obtain a content;
t2, dissolving the modified polypropylene resin, sodium octoate, glyceryl triacetate and titanium dioxide in an ethanol solvent, heating to 45 ℃ and uniformly stirring, stopping heating after heating and stirring for 1.5h, and carrying out vacuum degassing and low-temperature refrigeration to obtain a capsule shell;
and T3, placing the content prepared in the step T1 and the capsule shell prepared in the step T2 into capsules, and performing pelleting, drying, inspection and packaging to obtain the finished product.
Comparative example 1
In the present comparative example, the preparation of the capsules of idecalcitol was carried out directly with commercially available polypropylene resin (Eudragit L100-55 (EL)) without modifying the polypropylene resin, and the conditions were unchanged, as compared with example 3, and the specific operation was described in example 3.
Comparative example 2
In the preparation of the capsule of the present comparative example, the modified polypropylene resin was replaced with the intermediate I to prepare the capsule shell, and the conditions were not changed, compared with example 3, and the specific operation was described in example 3.
Comparative example 3
In the preparation of the capsule of the present comparative example, the capsule shell was prepared by replacing the modified polypropylene resin with gelatin, as compared with example 3, and the conditions were unchanged, and the specific operation was described in example 3.
Comparative example 4
In the preparation of the capsules of the comparative example, the sodium octoate was not added in the preparation of the capsule shell, and the remaining conditions were unchanged, compared with example 3, and the specific operation was described in example 3.
Correlation test:
test grouping: 160 female SD rats of 200-220g in 4 months of age are selected and randomly divided into 8 groups of 20 rats each, which are respectively:
(1) A blank control group, wherein distilled water is used for replacing medicines in the experimental process;
(2) A negative control group, wherein distilled water is used for replacing the medicine in the experimental process;
(3) A positive control group, wherein the dosage of the nieiestrol is 1mg/kg in the experimental process;
(4) Example 1 group, capsule of example 1 was dosed at 5 μg/kg during the experiment;
(5) Comparative example 1 group, capsule of comparative example 1 was given during the experiment at a dose of 5 μg/kg;
(6) Comparative example 2 group, capsule of comparative example 2 was given during the experiment at a dose of 5 μg/kg;
(7) Comparative example 3 group, capsule of comparative example 3 was given during the experiment at a dose of 5 μg/kg;
(8) Comparative example 4 group, capsule of comparative example 4 was given during the experiment at a dose of 5 μg/kg;
wherein, the ovaries are reserved in the blank control group, and the ovaries are removed from the other groups.
The experimental method comprises the following steps: animals of each group were orally administered 1 time a day for 1 month, rats were anesthetized with 10% chloral hydrate, the skin and muscle were cut open at the abdomen, the abdominal cavity was exposed, the abdominal artery was bled, serum was isolated, the uterus was rapidly stripped, and the weight was weighed. The right tibia was removed, the attached muscles and other tissues were removed, and stored in 70% ethanol for bone density determination.
Bone density and solid content determination:
the test results are shown in table 1:
TABLE 1
From the above results, it can be seen that the total bone density, bone trabecular bone density and cortical bone density of the negative control group were lower than those of the blank control group, the total bone density, bone trabecular bone density and cortical bone density of the positive control group were higher than those of the blank control group, the total bone density, bone trabecular bone density and cortical bone density of the example 1 group were comparable to those of the positive control group, the total bone density, bone trabecular bone density and cortical bone density of the comparative examples 1 to 4 groups were lower than those of the example 3, the above indicated that the capsule shell prepared using the modified polypropylene resin was capable of improving the absorption of the drug, and the test data of the comparative examples 3 and 4 revealed that there was a synergistic effect between sodium octoate and the modified polypropylene resin.
The results of the determination of bone content in ovariectomized osteoporosis rats are shown in Table 2.
TABLE 2
From the above results, the total bone content, bone trabecular bone content and cortical bone content of the negative control group were lower than those of the blank control group, and the total bone content, bone trabecular bone content and cortical bone content of the positive control group were higher than those of the blank control group, and the total bone content, bone trabecular bone content and cortical bone content of the example 1 group were equivalent to those of the positive control group and were higher than those of the comparative examples 1 to 4.
The results of the measurement of the bone calcium content of the rat with the ovarian osteoporosis are shown in table 3.
TABLE 3 Table 3
From the above results, it was found that each of the preoperative groups had equivalent osteocalcin, the serum osteocalcin content of the negative control group was decreased three months after the operation, the serum osteocalcin content of the example 3 and the control groups 1 to 4 was increased, and the increase in the example 3 was large.
Compared with the prior art, the modified polypropylene resin is used for replacing the commonly used gelatin in the preparation process of the capsule shell, so that the problems that the capsule shell prepared by the prior art is poor in protection on moisture and oxygen sensitive drugs, easy to adhere to esophagus, slow in disintegration and low in drug dissolution in the storage process are effectively solved. In order to enable the medicine to be better dissolved out, the polypropylene resin is modified by utilizing the glycerol, the glycerol has certain lubricating property to prevent the capsule from being adhered to the esophagus in the swallowing process, and the glycerol is mild in property and cannot cause damage to the esophagus; in addition, in order to promote the absorption of medicine by intestinal canal, phosphoric acid is grafted onto glycerin modified polypropylene resin to form phosphate radical, and the membrane is mainly elastic semipermeable membrane comprising phospholipid, so that the capsule shell prepared with the modified polypropylene resin has interaction with the membrane easily and the capsule shell is preparedSodium octoate is also added in the preparation process, and the substance can increase intracellular calcium concentration by interacting with cell membrane to cause Ca 2+ The actin microfilaments dependent on the calmodulin shrink to temporarily open the epithelial tight connection, so that the dissolution of the medicine can be further promoted and the action effect of the medicine can be improved.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present application have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the application, the scope of which is defined in the appended claims and their equivalents.

Claims (4)

1. Use of idecalcitol in the preparation of a capsule, characterized in that the capsule consists of a content and a capsule shell, the content consisting of idecalcitol, lecithin and chain triglycerides; the capsule shell consists of modified polypropylene resin, sodium octoate, ethanol, glyceryl triacetate and titanium dioxide;
the preparation method of the modified polypropylene resin comprises the following steps: taking ethanol as a solvent, adding polypropylene resin and copper sulfate, heating and stirring, slowly dripping glycerol into the solvent, continuously stirring after dripping, and heating and refluxing to obtain an intermediate I; mixing the intermediate I with phosphoric acid, adding p-toluenesulfonic acid, heating and stirring, and distilling under reduced pressure after the reaction is completed to obtain modified polypropylene resin;
the preparation method of the idecalcitol comprises the following steps:
s1, oxidizing secondary alcohol into ketone by taking 25-hydroxycholesterol as a raw material in cyclohexanone solvent and taking aluminum isopropoxide as a catalyst, and performing aftertreatment to obtain intermediate ketone, namely a compound 1;
s2, mixing the compound 1 with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, performing dehydrogenation reaction, extracting, washing, concentrating, extracting, and crystallizing in acetonitrile solvent to obtain a dehydrogenated substance, namely the compound 2;
s3, ethanol is taken as a solvent, a compound 2, sodium ethoxide and potassium tert-butoxide are added into the solvent, after the rearrangement reaction of the compound 2 under the action of the potassium tert-butoxide, an isomer is obtained through extraction, washing and concentration, and the isomer is marked as a compound 3;
s4, dissolving the compound 3 in a pyridine solvent, adding sodium borohydride, reacting with 4-dimethylaminopyridine as a catalyst, selectively reducing ketocarbonyl to generate alcohol by the compound 3 under the action of the sodium borohydride, quenching, extracting, washing and concentrating to obtain a reduction product;
s5, adding acetic anhydride into the reduction product obtained in the step S4, acylating the reduction product by the acetic anhydride, extracting, washing, concentrating and crystallizing to obtain product ester, and marking the product ester as a compound 4;
s6, mixing the compound 4 with N-bromosuccinimide by taking normal hexane as a solvent, and adding azodiisobutyronitrile to carry out bromination reaction under the condition of: temperature: 45-50 ℃ to obtain 1-acetate-25-hydroxy-7-bromo-cholesterol-1-ene; then adding 2,4, 6-trimethylpyridine into the mixture to perform dehydrobromination reaction, wherein the dehydrobromination reaction conditions are as follows: temperature: obtaining 1-acetate-25-hydroxy-cholesterol-1, 7-diene at 55-60 ℃, after the reaction is completed, adding potassium hydroxide into methanol serving as a solvent to carry out saponification reaction to obtain a compound 5;
s7, the compound 5 is treated by 4-phenyl-1, 2, 4-triazoline-3, 5-dione to protect diene, N-dimethylformamide is taken as a solvent, dimethyl tertiary butyl chlorosilane and imidazole are added to react, and hydroxyl is protected, so that 4-phenyl-1, 2, 4-triazoline-3, 5-dione protected conjugated diene ester is obtained, namely the compound 6;
s8, treating the obtained compound 6 with m-chloroperoxybenzoic acid to oxidize unprotected olefin to obtain 4-phenyl-1, 2, 4-triazolin-3, 5-dione protected epoxide, which is marked as a compound 7;
s9, treating the compound 7 by using tetrahydrofuran as a solvent, adding tetrabutylammonium fluoride, removing a TBS hydroxyl protecting group by reaction, and then removing a 4-phenyl-1, 2, 4-triazolin-3, 5-dione protecting group by adding 1, 3-dimethyl-2-imidazolone to obtain an epoxide, namely the compound 8;
s10, adding a compound 8 and potassium tert-butoxide into propylene glycol serving as a solvent, and ring-opening epoxy to obtain a hydroxy propoxy dehydrocompound, namely a compound 9;
s11, performing photochemical ring opening on the compound 9, and separating and purifying to obtain a product idecalcitol crystal;
the model of the polypropylene resin is Eudragit L100-55.
2. Use of idecalcitol according to claim 1 in the preparation of capsules, characterized in that in step S2, extraction with ethyl acetate, washing with saturated sodium chloride.
3. The use of idecalcitol according to claim 1 in the preparation of capsules, characterized in that in step S4 the reaction takes place in an ice bath for a period of 4-6 hours.
4. Use of idecalcitol according to claim 1 in the preparation of capsules, characterized in that the preparation process of the capsules is as follows:
t1, mixing idecalcitol, lecithin and chain triglyceride, heating, slowly stirring uniformly, and naturally cooling to room temperature to obtain a content;
t2, dissolving the modified polypropylene resin, sodium octoate, glyceryl triacetate and titanium dioxide in an ethanol solvent, heating and stirring uniformly, vacuum degassing, and refrigerating at low temperature to obtain a capsule shell;
and T3, placing the content prepared in the step T1 and the capsule shell prepared in the step T2 into capsules, and performing pelleting, drying, inspection and packaging to obtain the finished product.
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