CN111320664A - Preparation method of 24-cholenenoic acid ethyl ester - Google Patents
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Abstract
The invention discloses a preparation method of 24-cholenenoic acid ethyl ester. The invention provides a preparation method of 24-cholenenoic acid ethyl ester shown as a formula 04, which comprises the following steps: the method comprises the following steps of (1) carrying out alkylation reaction on a compound shown as a formula 02 and ethyl acrylate in an organic solvent in the presence of zinc, a catalyst and an alkaline reagent to obtain a compound shown as a formula 03; and (2) in water and an organic solvent, in the presence of an acidic reagent, carrying out the reaction shown in the formula 03 in the step (1) to obtain a compound shown in a formula 04. The preparation method has the advantages of short reaction steps, high yield (the total yield of the two steps can reach 80-91%), mild reaction conditions, low reagent price and low requirement on experimental equipment, and is suitable for large-scale synthesis.
Description
Technical Field
The invention relates to a preparation method of 24-cholenenoic acid ethyl ester.
Background
The 25-hydroxycholesterol is vitamin D3The metabolite precursor of the compound, 24-cholenenoic acid ethyl ester, is used as a key intermediate for synthesizing 25-hydroxycholesterol, and the 25-hydroxycholesterol can be synthesized by only one step.
There are two main routes reported in the literature for synthesizing 24-cholenenoic acid ethyl ester. Route one:
the lithocholic acid is used as a starting material and is prepared by 11 steps of reactions, and the lithocholic acid has the defects of long route, low yield (the total yield is 11.13%), expensive experimental reagents and the like (steroids 121 (2017)) 22-31.
And a second route:
dehydroepiandrosterone is used as a raw material, and a product is obtained through 5 steps of reaction, wherein Wittig reaction is used twice, and anhydrous and anaerobic operation is needed; the three-step reaction needs to be carried out at-78 ℃, and reagents used in the multi-step reaction are expensive. Is not suitable for large-scale synthesis (Tetrahedron letters Vol.23, NO.20, PP 2077-2080, 1982).
In summary, neither route is suitable for larger scale synthesis.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the technical defects of long route, low yield, expensive reagent, or harsh operation condition and unsuitability for large-scale synthesis of the existing preparation method of 24-cholestene ethyl ester, and provides the preparation method of the 24-cholestene ethyl ester. The preparation method provided by the invention has the advantages of short reaction steps, high yield, mild reaction conditions, low reagent price and low requirement on experimental equipment, and is suitable for large-scale synthesis.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a preparation method of 24-cholenenoic acid ethyl ester shown as a formula 04, which comprises the following steps:
in an organic solvent, in the presence of zinc, a catalyst and an alkaline reagent, carrying out alkylation reaction on a compound shown as a formula 02 and ethyl acrylate as shown in the specification to obtain a compound shown as a formula 03;
step (2), in water and an organic solvent, in the presence of an acidic reagent, carrying out the reaction shown as the following on the compound shown as the formula 03 in the step (1) to obtain a compound shown as a formula 04;
in the step (1), the organic solvent may be an organic solvent conventional in the reaction in the field, such as a pyridine solvent (e.g., pyridine) and/or a cyclic ether solvent (e.g., tetrahydrofuran); preferably pyridine.
In the step (1), the catalyst may be a catalyst conventional in the art for such reactions, and in the present invention, nickel chloride hexahydrate is preferred.
In the step (1), the alkaline agent may be an alkaline agent conventional in the reaction of this type in the art, and in the present invention, an organic base (e.g., pyridine) is preferred.
In the step (1), the amount of the organic solvent is not particularly limited, so as not to affect the reaction; in the present invention, the mass-to-volume ratio of the compound represented by the formula 02 to the organic solvent is preferably 0.01g/mL to 1g/mL (for example, 0.25g/mL to 0.4 g/mL).
In the step (1), the zinc can be zinc which is conventional in the reactions of the type in the field, such as zinc powder; the molar ratio of the zinc to the compound represented by formula 02 may be 5:1 to 10:1, preferably 6:1 to 8:1 (e.g., 7.5: 1).
In the step (1), the molar ratio of the catalyst to the compound represented by the formula 02 is preferably 1:1 to 2:1 (for example, 1: 1).
In the step (1), the molar ratio of the alkaline agent to the compound represented by the formula 02 is preferably 7.5:1 to 25:1 (for example, 22: 1).
In the step (1), the molar ratio of the ethyl acrylate to the compound represented by the formula 02 may be 5:1 to 10:1, preferably 6:1 to 8:1 (for example, 7.5: 1).
In the step (1), the temperature of the alkylation reaction is preferably 0 ℃ to 80 ℃ (for example, 10 ℃ to 70 ℃, further for example, 10 ℃ to 30 ℃, 40 ℃ to 70 ℃).
In the step (1), the progress of the alkylation reaction can be monitored by a conventional monitoring method in the art (e.g., TLC or NMR), and is generally terminated when the compound represented by the formula 02 disappears or is no longer reacted.
In the step (1), the method can further comprise a post-treatment operation, wherein the post-treatment operation comprises the following steps of filtering, washing, concentrating and purifying by column chromatography to obtain the compound shown as the formula 03 after the alkylation reaction is finished; the washing, the concentration and the column chromatography purification can be conventional operations in the field; for example, the washing can be sequentially and respectively washing with sodium ethylene diamine tetracetate aqueous solution and saline; the column chromatography purification can be performed according to the conventional operation in the field, and for example, elution is performed by using n-hexane and ethyl acetate (volume ratio is 20: 1).
In the step (2), the organic solvent may be an organic solvent which is conventional in the reactions of this type in the art, and in the present invention, a cyclic ether solvent (such as dioxane and/or tetrahydrofuran) is preferred.
In the step (2), the acid may be an acid conventional in such reactions in the art, and in the present invention, p-toluenesulfonic acid and/or methanesulfonic acid is preferred.
In the step (2), the volume ratio of the water to the organic solvent is preferably 2:1 to 1:2 (e.g., 1: 1).
In the step (2), the amount of the organic solvent is not particularly limited, so as not to affect the reaction; in the present invention, the mass-to-volume ratio of the compound of formula 03 to the organic solvent is preferably 0.01g/mL to 0.5g/mL (for example, 0.09g/mL to 0.12 g/mL).
In the step (2), the molar ratio of the acid to the compound represented by the formula 03 is preferably 0.05:1 to 0.5:1 (for example, 0.08:1 to 0.1: 1).
In the step (2), the reaction temperature may be a temperature conventional in the reaction of this type in the art, and in the present invention, it is preferably 80 to 100 ℃.
In the step (2), the progress of the reaction can be monitored by a conventional monitoring method in the art (e.g., TLC or NMR), and the end point of the reaction is generally the disappearance or no longer reaction of the compound represented by the formula 03.
In the step (2), a post-treatment operation can be further included, wherein the post-treatment operation comprises the following steps of extracting, washing and concentrating a reaction system after the reaction is finished to obtain the compound shown as the formula 04; the extraction, washing and concentration can be conventional operations in the field; for example, the extraction may be performed with ethyl acetate.
The preparation method can also comprise the following steps of carrying out iodination reaction on the compound shown as the formula 01 and iodine in an organic solvent in the presence of an alkaline reagent and a ligand to obtain the compound shown as the formula 02;
in the iodination reaction, the organic solvent may be an organic solvent conventional in such reactions in the art, such as a halogenated alkane solvent (e.g., dichloromethane).
In the iodination reaction, the ligand may be a ligand conventional in such reactions in the art, such as a phosphine ligand, and in the present invention triphenylphosphine is preferred.
In the iodination, the basic agent may be one conventional in the art, and in the present invention, an organic base (e.g., imidazole) is preferred.
In the iodination reaction, the amount of the organic solvent may not be particularly limited so as not to affect the reaction; in the present invention, the mass-to-volume ratio of the compound represented by the formula 01 to the organic solvent is preferably 0.01g/mL to 0.2g/mL (for example, 0.07g/mL to 0.09 g/mL).
In the iodination, the molar ratio of iodine to the compound represented by formula 01 may be 2.3:1 to 1.5:1, and in the present invention, the molar ratio is preferably 2.3:1 to 2: 1.
In the iodination reaction, the molar ratio of the ligand to the compound represented by formula 01 may be 2.3:1 to 1.5:1, and in the present invention, the molar ratio is preferably 2.3:1 to 2: 1.
In the iodination reaction, the molar ratio of the alkaline reagent to the compound represented by formula 01 may be 3:1 to 6:1, and in the present invention, is preferably 4:1 to 6: 1.
The temperature of the iodination is preferably room temperature (e.g., 10 ℃ C. to 30 ℃ C.).
The progress of the iodination reaction can be monitored by a monitoring method (e.g., TLC or NMR) conventionally used in the art, and is generally at the end of the reaction when the compound represented by the formula 01 disappears or does not react any more.
The preparation method of the compound shown as the formula 02 can also comprise a post-treatment operation, wherein the post-treatment operation comprises the following steps of washing, concentrating and pulping a reaction system after the iodination reaction is finished to obtain the compound shown as the formula 02; the washing, concentration and pulping can be the conventional operation in the field; for example, the washing may be sequentially with Na2S2O4Washing with water solution, pure water and saline water respectively; the beating may be conventional in the art to remove insoluble materials such as ligands; in the beating, the organic solvent may be an organic solvent conventionally used in such procedures in the art, preferably a halogenated alkane solvent (e.g., methylene chloride) and/or an ether solvent (e.g., diethyl ether and/or methyl tert-butylEther).
The preparation method of the compound shown as the formula 02 can also comprise the following step of directly using the compound shown as the formula 02 in the alkylation reaction to prepare the compound 03 after the post-treatment operation, preferably without purification.
The compound represented by the formula 01 can be referred to in the literature, "Vitamin D3Metabolites I.Synthesisof 25 Hydroxycholestolesterol John J.Partridge Stephanie Faber Milan R.
Preparing the Chinese medicinal preparation.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method provided by the invention has the advantages of short reaction steps, high yield (the total yield of the two steps can reach 80-91%), mild reaction conditions, cheap reagents and low requirement on experimental equipment, and is suitable for large-scale synthesis.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, HPLC methods:
a chromatographic column: thermo C184.6 x 150mm
Sample introduction amount: 15 μ L
Wavelength: 205nm
Column temperature: 30 deg.C
Flow rate: 1mL/min
Mobile phase: a is methanol; b, 10% methanol water solution; and A, B, 87: 13.
Preparation of Compound 02
Example 1
36.17g of triphenylphosphine and 24.51g of imidazole were dissolved in 300ml of dichloromethane, 35.03g of iodine was added, and after a reaction time, a dichloromethane solution of Compound 01 (0120.78 g of Compound, 150ml of dichloromethane) was added dropwise and the mixture was reacted at room temperature. TLC plate showed complete reaction and essentially complete conversion of starting material to compound 02; na for reaction solution2S2O4The aqueous solution, pure water and brine are respectively washed, dried, filtered and dried to obtain a white solid, the solid is pulped by 150ml of n-hexane, and the filtrate is dried to obtain 29.9g of a crude compound 02, (the crude compound 01: triphenylphosphine: imidazole: iodine: 1: 2.3: 6: 2.3; and the crude product contains triphenylphosphine, so that the material yield is 109.22%), and the crude compound is directly put into a further reaction without further purification.
Example 2
131.05g of triphenylphosphine and 68.08g of imidazole were dissolved in 1000ml of dichloromethane, 126.9g of iodine was added, and after a reaction time, a dichloromethane solution of Compound 01 (0186.67 g of Compound, 500ml of dichloromethane) was added dropwise and the mixture was reacted at room temperature. TLC plate showed complete reaction and essentially complete conversion of starting material to compound 02; na for reaction solution2S2O4The aqueous solution, pure water and brine are respectively washed, dried, filtered and dried to obtain a white solid, the solid is pulped by 500ml of n-hexane, and the filtrate is dried to obtain 125.6g of a crude compound 02 (the crude compound 01: triphenylphosphine: imidazole: iodine: 1: 2: 4: 2; and the material yield is 110.0 percent because the crude product contains triphenylphosphine), and the crude compound is directly put into further reaction without further purification.
Example 3
Triphenylphosphine (23.59 g) and imidazole (12.25 g) were dissolved in 300ml dichloromethane, iodine (22.84 g) was added, and after a reaction time, a dichloromethane solution of Compound 01 (0120.78 g, dichloromethane (150 ml)) was added dropwise, and the reaction was carried out at room temperature. TLC plate showed residual material, reaction solution was Na2S2O4Washing the water solution, pure water and saline water respectively, drying, filtering, spin-drying to obtain white-like solid, pulping the solid with 150ml n-hexane, and spin-drying the filtrate to obtain the compound27.3g of crude 02 product. (Compound 01: triphenylphosphine: imidazole: iodine ═ 1: 1.5: 3: 1.5; triphenylphosphine was contained in the crude product, yield 99.73%), and the reaction was carried out without further purification.
Preparation of Compound 03
Example 4
8.17g of zinc powder, 5.94g of nickel chloride hexahydrate and 13.31ml of ethyl acrylate were suspended in 30ml of pyridine, and the mixture was heated to initiate (40 ℃ C. to 70 ℃ C.), and the temperature was lowered to room temperature, and a pyridine solution (0212.54 g of compound (0211.4 g of compound obtained by the above step of 100%) of compound 02 (obtained in example 2) and 15ml of pyridine were added dropwise and stirred after completion of the addition. TLC plate showed more material remaining and a little impurity, the reaction solution was filtered, and the filtrate was extracted with 50ml of EDTA solution (EDTA:4g, NaHCO)3:4g，H250ml of O), washing with brine, drying, filtering, spin-drying and purifying by column chromatography to obtain about 8.47g of oily substance. (02: zinc powder: ethyl vinylate: nickel chloride hexahydrate ═ 1: 5: 5: 1; two-step yield 78.76%)
MS:453.34[M+Na]+，399.33[M-CH3O]+；1HNMR(400MHz,CD3Cl)δ:4.01(2H,q),3.41(3H,s),3.04(1H,t),2.35(2H,t),1.90(4H,m),1.60(8H,m),1.50(2H,m),1.38(6H,m),1.19(2H,m),1.07(7H,m),0.85(9H,m)。
Example 5
8.17g of zinc powder, 5.94g of nickel chloride hexahydrate and 13.31ml of ethyl acrylate were suspended in 15ml of pyridine +15ml of tetrahydrofuran, and the mixture was heated to initiate (40 ℃ C. to 70 ℃ C.), and the temperature was lowered to room temperature, and a mixed solution of compound 02 (obtained in example 2) (0212.54 g of compound (0211.4 g of compound obtained by the above step of 100%), 15ml of pyridine and 15ml of tetrahydrofuran) was added dropwise and stirred. TLC plate showed more raw material remained and impurity slightly more than example 4, reaction liquid was filtered, filtrate was washed with EDTA aqueous solution, brine, dried, filtered, dried by spinning, column chromatography was purified to obtain about 7.92g of oily substance. (02: zinc powder: ethyl vinylate: nickel chloride hexahydrate ═ 1: 5: 5: 1; two-step yield 73.65%)
Example 6
12.26g of zinc powder, 5.94g of nickel chloride hexahydrate and 13.31ml of ethyl acrylate were suspended in 30ml of pyridine, and the mixture was heated to initiate (40 ℃ C. to 70 ℃ C.), and the temperature was lowered to room temperature, a pyridine solution (0212.54 g of compound (0211.4 g of compound obtained by the above step of 100%) of compound 02 (obtained in example 2) and 15ml of pyridine were added dropwise, followed by stirring after completion of the addition. TLC plate showed small amount of remaining raw material and less impurities than example 4, reaction solution was filtered, filtrate was washed with EDTA aqueous solution, brine, dried, filtered, dried, and purified by column chromatography to obtain about 9.79g of oily substance. (02: zinc powder: ethyl vinylate: nickel chloride hexahydrate ═ 1: 7.5: 5: 1; two-step yield 91.04%)
Example 7
98.09g of zinc powder, 47.54g of nickel chloride hexahydrate and 159.69ml of ethyl acrylate were suspended in 300ml of pyridine, and the mixture was heated to initiate (40 ℃ C. -70 ℃ C.), and the temperature was lowered to room temperature, and a pyridine solution (compound 02100.36 g (compound 0291.24g, calculated as above 100%) of compound 02 (obtained in example 2) was added dropwise thereto (100 ml of pyridine), and the mixture was stirred after completion of dropwise addition. TLC plate shows that the raw material is basically reacted completely with only trace impurity, the reaction solution is filtered, the filtrate is washed by EDTA aqueous solution and brine, dried, filtered, dried by spinning, and purified by column chromatography to obtain about 86.13g of oily substance. (02: zinc powder: ethyl vinylate: nickel chloride hexahydrate ═ 1: 7.5: 7.5: 1; two-step yield 100.08%)
Example 8
24.52g of zinc powder, 11.88g of nickel chloride hexahydrate and 39.92ml of ethyl acrylate were suspended in 30ml of pyridine and 30ml of tetrahydrofuran, and the mixture was heated to initiate (40 ℃ C. -70 ℃ C.), and the temperature was lowered to room temperature, and a mixed solution of compound 02 (obtained in example 2) (0225.08 g of compound (0222.8 g, calculated as 100% in the above step), 15ml of pyridine and 15ml of tetrahydrofuran) was added dropwise and stirred. TLC plate shows that the raw material is basically reacted completely, the reaction solution is filtered, the filtrate is washed by EDTA aqueous solution and brine, dried, filtered, dried by spinning, and purified by column chromatography to obtain about 21.17g of oily matter. (02: zinc powder: ethyl vinylate: nickel chloride hexahydrate ═ 1: 7.5: 7.5: 1; two-step yield 98.45%)
Preparation of Compound 04
Example 9
About 8.47g of the oily compound 03 obtained in example 4 was dissolved in a mixed solvent of 80ml of 1, 4-dioxane and 80ml of water, and 0.34g of p-toluenesulfonic acid monohydrate was added to the mixture and reacted under heating and refluxing (80 ℃ C. to 100 ℃ C.). TLC plates showed complete reaction, extracted with EA, combined organic layers, washed with brine, dried, filtered, and spun-dried to give 7.29g of white solid in 89.0% yield (one step yield of 03 preparation 04) (compound 02, 100% theoretical yield, two step yield 70%; HPLC purity 96.5%).
Example 10
About 7.92g of the oily compound 03 obtained in example 5 was dissolved in a mixed solvent of 80ml of 1, 4-dioxane and 80ml of water, and 0.32g of p-toluenesulfonic acid monohydrate was added to the mixture and the mixture was heated under reflux. TLC plates showed complete reaction, extracted with EA, combined organic layers, washed with brine, dried, filtered, and spun-dried to give 6.73g of white solid in 87.86% yield (one step yield of 03 preparation 04) (65% yield over two steps with 100% theoretical yield of compound 02; 96.0% purity by HPLC).
Example 11
About 9.79g of the oily compound 03 obtained in example 6 was dissolved in a mixed solvent of 90ml of 1, 4-dioxane and 90ml of water, and 0.39g of p-toluenesulfonic acid monohydrate was added to the mixture and the mixture was heated under reflux. TLC plates showed complete reaction, extracted with EA, combined organic layers, washed with brine, dried, filtered, and spun-dried to give 8.57g of white solid in 90.48% yield (one step yield of 03 preparation 04) (82.4% yield in two steps with 100% theoretical yield of compound 02; 97.5% HPLC purity).
Example 12
About 86.13g of the oily compound 03 obtained in example 7 was dissolved in a mixed solvent of 800ml of 1, 4-dioxane and 800ml of water, and 3.46g of p-toluenesulfonic acid monohydrate was added to conduct a reflux reaction under heating. TLC plates showed complete reaction, extracted with EA, combined organic layers, washed with brine, dried, filtered, and spun-dried to give 75.74g of white solid in 90.9% yield (one step yield of 03 preparation 04) (two step yield 90.9% based on 100% theoretical yield of compound 02; HPLC purity 99.1%).
Example 13
About 21.17g of the oily compound 03 obtained in example 8 was dissolved in a mixed solvent of 180ml of 1, 4-dioxane and 180ml of water, and 0.83g of p-toluenesulfonic acid monohydrate was added to the mixture and the mixture was heated under reflux. TLC plates showed complete reaction, extracted with EA, combined organic layers, washed with brine, dried, filtered, and spun-dried to give 18.48g of a white solid in 90.21% yield (one step yield of 03 preparation 04) (88.8% yield in two steps with 100% theoretical yield of compound 02; 98.7% HPLC purity).
Claims (10)
1. A preparation method of 24-cholenenoic acid ethyl ester shown as a formula 04 is characterized by comprising the following steps:
the method comprises the following steps of (1) carrying out alkylation reaction on a compound shown as a formula 02 and ethyl acrylate in an organic solvent in the presence of zinc, a catalyst and an alkaline reagent to obtain a compound shown as a formula 03;
step (2), in water and an organic solvent, in the presence of an acidic reagent, carrying out the reaction shown as the following on the compound shown as the formula 03 in the step (1) to obtain a compound shown as a formula 04;
2. the method according to claim 1, wherein in the step (1), the organic solvent is a pyridine solvent and/or a cyclic ether solvent;
and/or, in the step (1), the zinc is zinc powder;
and/or, in the step (1), the catalyst is nickel chloride hexahydrate;
and/or, in the step (1), the alkaline reagent is an organic base;
and/or, in the step (2), the organic solvent is a cyclic ether solvent;
and/or, in the step (2), the acid is p-toluenesulfonic acid and/or methanesulfonic acid.
3. The method according to claim 2, wherein in the step (1), when the organic solvent is a pyridine solvent, the pyridine solvent is pyridine;
and/or, in the step (1), when the organic solvent is a cyclic ether solvent, the cyclic ether solvent is tetrahydrofuran;
and/or, in the step (1), when the alkaline reagent is an organic base, the organic base is pyridine;
and/or, in the step (2), when the organic solvent is a cyclic ether solvent, the cyclic ether solvent is dioxane and/or tetrahydrofuran.
4. The method according to claim 1, wherein in the step (1), the mass-to-volume ratio of the compound represented by the formula 02 to the organic solvent is 0.01g/mL to 1 g/mL;
and/or in the step (1), the molar ratio of the zinc to the compound shown in the formula 02 is 5: 1-10: 1;
and/or in the step (1), the molar ratio of the catalyst to the compound shown in the formula 02 is 1: 1-2: 1;
and/or in the step (1), the molar ratio of the alkaline reagent to the compound shown in the formula 02 is 7.5: 1-25: 1;
and/or in the step (1), the molar ratio of the ethyl acrylate to the compound shown in the formula 02 is 5: 1-10: 1;
and/or, in the step (1), the temperature of the alkylation reaction is 0-80 ℃.
5. The method according to claim 4, wherein in the step (1), the mass-to-volume ratio of the compound represented by the formula 02 to the organic solvent is 0.25 g/mL-0.4 g/mL;
and/or in the step (1), the molar ratio of the zinc to the compound shown in the formula 02 is 6: 1-8: 1; preferably 7.5: 1;
and/or, in the step (1), the molar ratio of the catalyst to the compound shown in the formula 02 is 1: 1;
and/or, in the step (1), the molar ratio of the alkaline reagent to the compound shown in the formula 02 is 22: 1;
and/or in the step (1), the molar ratio of the ethyl acrylate to the compound shown in the formula 02 is 6: 1-8: 1; preferably 7.5: 1;
and/or, in the step (1), the temperature of the alkylation reaction is 10-70 ℃;
and/or, in the step (1), the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps of filtering, washing, concentrating and purifying by column chromatography to obtain the compound shown as the formula 03 after the alkylation reaction is finished.
6. The method according to claim 1, wherein in the step (2), the volume ratio of the water to the organic solvent is 2:1 to 1: 2;
and/or, in the step (2), the mass-to-volume ratio of the compound of formula 03 to the organic solvent is 0.01 g/mL-0.5 g/mL;
and/or in the step (2), the molar ratio of the acid to the compound shown in the formula 03 is 0.05: 1-0.5: 1;
and/or, in the step (2), the reaction temperature is 80-100 ℃.
7. The method according to claim 6, wherein in the step (2), the volume ratio of the water to the organic solvent is 1: 1;
and/or, in the step (2), the mass-to-volume ratio of the compound of formula 03 to the organic solvent is 0.09 g/mL-0.12 g/mL;
and/or in the step (2), the molar ratio of the acid to the compound shown in the formula 03 is 0.08: 1-0.1: 1;
and/or, in the step (2), the method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps of extracting, washing and concentrating a reaction system after the reaction is finished to obtain the compound shown as the formula 04.
8. The preparation method according to any one of claims 1 to 7, further comprising a step of subjecting a compound represented by the formula 01 and iodine to an iodination reaction in an organic solvent in the presence of an alkaline agent and a ligand to obtain the compound represented by the formula 02;
9. the process according to claim 8, wherein the organic solvent used in the iodination is a halogenated alkane solvent;
and/or, in the iodination reaction, the ligand is a phosphine ligand;
and/or, in the iodination reaction, the alkaline reagent is an organic base;
and/or, in the iodination reaction, the mass-to-volume ratio of the compound shown in the formula 01 to the organic solvent is 0.01 g/mL-0.2 g/mL;
and/or in the iodination reaction, the molar ratio of the iodine to the compound shown in the formula 01 is 2.3: 1-1.5: 1;
and/or in the iodination reaction, the molar ratio of the ligand to the compound shown in the formula 01 is 2.3: 1-1.5: 1;
and/or in the iodination reaction, the molar ratio of the alkaline reagent to the compound shown in the formula 01 is 3: 1-6: 1;
and/or the temperature of the iodination reaction is 10-30 ℃;
and/or, the preparation method further comprises a post-treatment operation, wherein the post-treatment operation comprises the following steps of washing, concentrating and pulping a reaction system after the iodination reaction is finished in an organic solvent to obtain the compound shown as the formula 02.
10. The process according to claim 9, wherein in the iodination, when the organic solvent is a halogenated alkane solvent, the halogenated alkane solvent is dichloromethane;
and/or, in the iodination reaction, when the ligand is a phosphine ligand, the phosphine ligand is triphenylphosphine;
and/or, in the iodination reaction, when the basic reagent is an organic base, the organic base is imidazole;
and/or, in the iodination reaction, the mass-to-volume ratio of the compound shown in the formula 01 to the organic solvent is 0.07 g/mL-0.09 g/mL;
and/or in the iodination reaction, the molar ratio of the iodine to the compound shown in the formula 01 is 2.3: 1-2: 1;
and/or in the iodination reaction, the molar ratio of the ligand to the compound shown in the formula 01 is 2.3: 1-2: 1;
and/or in the iodination reaction, the molar ratio of the alkaline reagent to the compound shown in the formula 01 is 4: 1-6: 1;
and/or, the preparation method also comprises the following step, after the post-treatment operation, the compound shown as the formula 02 is directly used for the alkylation reaction to prepare the compound 03.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811528872.XA CN111320664B (en) | 2018-12-13 | 2018-12-13 | Preparation method of 24-cholenenoic acid ethyl ester |
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| CN113968888A (en) * | 2020-07-24 | 2022-01-25 | 上海医药工业研究院 | Preparation method of cholesteric derivative, intermediate and application thereof |
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| CN113968888A (en) * | 2020-07-24 | 2022-01-25 | 上海医药工业研究院 | Preparation method of cholesteric derivative, intermediate and application thereof |
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