CN105622698B - New steroid 11-keto oxidation synthesis process - Google Patents
New steroid 11-keto oxidation synthesis process Download PDFInfo
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Abstract
The invention discloses a new process for synthesizing steroid 11-keto by oxidation, which comprises the step of carrying out oxidation reaction on a steroid 11- α hydroxyl compound in an aprotic organic solvent in the presence of DMSO (dimethyl sulfoxide) as an oxidant, organic base, phenyl dichlorophosphate and piperidine nitroxide free radicals at a temperature of between 10 ℃ below zero and the reflux temperature of the solvent, wherein the piperidine nitroxide free radicals are selected from 2,2,6, 6-tetramethylpiperidine-1-oxyl or analogues thereof.
Description
The technical field is as follows:
the invention relates to a new process for synthesizing steroid 11-keto by oxidation.
Background art:
the C-11 oxygen-containing functional group in the steroid structure is important and is indispensable for anti-inflammatory action and glycometabolism, prednisone, cortisone, methylprednisolone and the like all contain C-11 ketone groups, the high-potency corticoid drugs reported at present almost invariably contain 11 β -hydroxyl groups, and an important method for introducing 11 β -hydroxyl groups into steroid molecules is to introduce 11 α -hydroxyl groups by a microbiological method, oxidize the 11-ketone groups into 11-ketone groups, and reduce the 11-ketone groups into 11 β -hydroxyl groups.
At present, the industry mainly uses an oxidant containing chromium (6 valent) to oxidize the hydroxyl at the 11 position to obtain 11-ketone, and Cr6+The material has strong oxidability, can affect double bonds and hydroxyl groups on other positions of the steroid to a certain extent, generates more impurities, and simultaneously the material and a product Cr obtained after the reaction thereof2+All cause certain environmental problems, so in recent years researchers have been looking for more environmentally friendly and selective oxidants. Documents such as CN200910302305 report that a Swern oxidation reaction is utilized, and specifically DMSO is used as an oxidizing agent and an organic base is subjected to a synergistic reaction with acid anhydride or acyl chloride compounds such as trifluoroacetic anhydride, oxalyl chloride and phenyl dichlorophosphate at a low temperature to prepare the 11-keto-steroid compound. However, the Swern oxidation reaction has the outstanding disadvantages of very low reaction temperature and long reaction time, which are not suitable for industrialization, for example, two examples reported in CN200910302305 are respectively carried out at-10 ℃ and-20 ℃, and we found in experiments that as the reaction temperature increases, the by-products increase and the yield decreases, for example, the yield of the final product at 0 ℃ is only about 5%. The document CN201110101279 discloses a new process for preparing steroid 11-keto group by using piperidine nitroxide radical, such as TEMPO, as oxidation catalyst and normal halide as oxidant. We found in experiments that the use of piperidine nitroxide radicals with positive valencyThe oxidation reaction system consisting of halide oxidizes the hydroxyl at the 11-position, the purity of the obtained 11-keto-steroid compound is low, most products are not target products, and the products are not easy to repeat.
Therefore, it is important to find a new process for synthesizing steroid 11-keto group by oxidation, which has mild conditions, is green and environment-friendly and is suitable for industrialization.
Disclosure of Invention
The invention relates to a new process for synthesizing steroid 11-keto by oxidation.
The invention relates to a method for preparing a compound shown in formula 1, which is characterized in that in an aprotic organic solvent, in the presence of DMSO as oxidant, organic alkali, phenyl dichlorophosphate and piperidine nitroxide free radical, the compound of formula 2 is oxidized to generate the compound of formula 1, the reaction temperature is-10 ℃ to the reflux temperature of the solvent, the piperidine nitroxide free radical is selected from at least one of 2,2,6, 6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl and 4-acetamido-2, 2,6, 6-tetramethylpiperidine-1-oxyl:
r1, R2, R3, R4 are selected independently of each other and wherein:
r1 ═ H, I, Br, Cl or OCOR5, R5 is alkyl of up to six carbons;
r2 ═ H, α -OH or α -OCOR6, R6 is alkyl of up to six carbons;
r3 ═ H, α -methyl, β -methyl;
or R2, R3 ═ single bonds or epoxides, i.e. double bonds between positions 16 and 17 or linked by oxygen bridges,
or R2 and R3 may together form a moiety having formula I:
wherein X and Y are independently selected from hydrogen or alkyl, provided that when one of X or Y is hydrogen, the other is alkyl; r4 ═ H, F, or methyl,
1,2 positionRepresents a single bond or a double bond.
The preparation method of the compound of the formula 1 is characterized in that
Wherein
R1 ═ H or OCOCH3,
r2 ═ H, α -OH or α -OCOCH3,
r3 ═ H or α -methyl,
or R2, R3 ═ single bonds or epoxides, i.e. double bonds between positions 16 and 17 or linked by oxygen bridges,
R4＝H，
1,2 position
Represents a single bond or a double bond.
The preparation method of the compound of the formula 1 is characterized in that
Wherein
R1＝H,
R2 is α -OH or α -OCOCH3,
R3＝H,
or R2, R3 ═ single bonds or epoxides, i.e. double bonds between positions 16 and 17 or linked by oxygen bridges,
R4＝H，
1,2 positionRepresents a single bond.
The preparation method of the compound of the formula 1 is characterized in that
Wherein
R1＝H,
R2＝H，
R3＝H,
Or R2, R3 ═ single bonds or epoxides, i.e. double bonds between positions 16 and 17 or linked by oxygen bridges,
R4＝H,
1,2 position
Represents a single bond.
The preparation method of the compound of the formula 1 is characterized in that
Wherein
R1＝H,
R2, R3 ═ epoxy, i.e. the 16 and 17 positions are connected by an oxygen bridge,
R4＝H,
1,2 position
Represents a single bond.
The preparation method of the compound shown in the formula 1 is characterized in that the feeding ratio of the compound shown in the formula 2, dimethyl sulfoxide and phenyl dichlorophosphate is 1:2-20:0.75-3 calculated by molar ratio.
The preparation method of the compound shown in the formula 1 is characterized in that the feeding ratio of the compound shown in the formula 2 to the piperidine nitroxide radical is 1:0.01-0.2 calculated by molar ratio.
The preparation method of the compound shown in the formula 1 is characterized in that the piperidine nitroxide radical is selected from 2,2,6, 6-tetramethyl piperidine-1-oxyl or 4-hydroxy-2, 2,6, 6-tetramethyl piperidine-1-oxyl.
The preparation method of the compound shown in the formula 1 is characterized in that the piperidine nitroxide radical is 2,2,6, 6-tetramethyl piperidine-1-oxyl.
The preparation method of the compound shown in the formula 1 is characterized in that the organic base is tertiary amine.
The preparation method of the compound shown in the formula 1 is characterized in that the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine.
The preparation method of the compound shown in the formula 1 is characterized in that the aprotic organic solvent is selected from one or more of halogenated alkyl containing 1-3 halogens, halogenated aromatic hydrocarbon, alkane, aromatic hydrocarbon, ether and ester.
The preparation method of the compound shown in the formula 1 is characterized in that the aprotic organic solvent is one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, 1-dichloroethane, toluene, n-hexane, chlorobenzene, tetrahydrofuran, 1, 4-dioxane and ethyl acetate.
The preparation method of the compound shown in the formula 1 is characterized in that the aprotic organic solvent is one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane and 1, 1-dichloroethane.
The preparation method of the compound of the formula 1 is characterized in that the reaction temperature is 0-30 ℃.
The preparation method of the compound of the formula 1 is characterized in that the reaction temperature is 0-10 ℃.
The preparation method of the compound of the formula 1 is characterized in that a compound of the formula 2 is subjected to oxidation reaction in an aprotic organic solvent in the presence of DMSO (dimethyl sulfoxide) as an oxidant and organic base, phenyl dichlorophosphate and piperidine nitroxide free radicals at the reaction temperature of 0-45 ℃ to generate the compound of the formula 1, wherein the aprotic organic solvent is one or more selected from halogenated alkyl containing 1-3 halogens, halogenated aromatic hydrocarbon, alkane, aromatic hydrocarbon, ether and ester, and the organic base is tertiary amine.
The preparation method of the compound of the formula 1 is characterized in that a compound of a formula 2 is subjected to oxidation reaction in an aprotic organic solvent in the presence of organic base, phenyl dichlorophosphate and piperidine nitroxide free radical by taking DMSO as an oxidant at the reaction temperature of 0-30 ℃ to generate the compound of the formula 1, the aprotic organic solvent is one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, 1-dichloroethane, toluene, n-hexane, chlorobenzene, tetrahydrofuran, 1, 4-dioxane and ethyl acetate, the organic base is tertiary amine, and the piperidine nitroxide radical is selected from 2,2,6, 6-tetramethylpiperidine-1-oxyl or 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl.
The preparation method of the compound shown in the formula 1 is characterized in that in an aprotic organic solvent, DMSO is used as an oxidant, and under the condition that organic base, phenyl dichlorophosphate and piperidine nitroxide radical exist, the compound shown in the formula 2 is subjected to oxidation reaction to generate the compound shown in the formula 1, the reaction temperature is 0-10 ℃, the aprotic organic solvent is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane and 1, 1-dichloroethane, the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine, and the piperidine nitroxide radical is 2,2,6, 6-tetramethylpiperidine-1-oxyl.
The preparation method of the compound shown in the formula 1 is characterized in that the feeding ratio of the compound shown in the formula 2, dimethyl sulfoxide and phenyl dichlorophosphate is 1:2-20:0.75-3 calculated by molar ratio.
The preparation method of the compound shown in the formula 1 is characterized in that the feeding ratio of the compound shown in the formula 2 to the piperidine nitroxide radical is 1:0.01-0.2 calculated by molar ratio.
The preparation method of the compound shown in the formula 1 is characterized in that the feeding ratio of the compound shown in the formula 2, dimethyl sulfoxide and phenyl dichlorophosphate is 1:2.6:1.25 calculated by molar ratio.
The influence of the temperature on the reaction is investigated, and the experiment shows that the reaction time is longer when the reaction temperature is-5 to-10 ℃; the yield and the content of the target product are highest at 0-10 ℃; as the temperature increases, the reaction time is shortened but the content of the target product tends to decrease, for example, in example 1. At the same time, the optimum charge ratios of TEMPO, phenyl dichlorophosphate and dimethyl sulfoxide to the starting material were investigated. It was found experimentally that the amount of TEMPO fed as catalyst had a major effect on the reaction time but not on the yield and content of the desired product, as in example 2. When the molar ratio of the starting material to DMSO and phenyl dichlorophosphate is 1:2.6:1.25, the reaction of the starting material is complete. If the charge of phenyl dichlorophosphate and DMSO is reduced, the reaction of the starting materials is not complete, for example, from example 3 to example 4.
The method has the advantages of simple and mild reaction conditions, easy operation, high yield and content, good reproducibility, environmental protection and suitability for industrialization.
The specific implementation mode is as follows:
the examples in the embodiments are only for further illustrating the technical solutions of the invention and should not be construed as limiting the embodiments of the invention.
In the following examples:
TEMPO is 2,2,6, 6-tetramethylpiperidine-1-oxyl, 4-hydroxy-TEMPO is 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-TEMPO is 4-benzoyloxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl, 4-acetamido-TEMPO is 4-acetamido-2, 2,6, 6-tetramethylpiperidine-1-oxyl, DMSO is dimethyl sulfoxide
Example 1 examination of the Effect of temperature on the reaction
Examples 1 to 1
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to-5 to-10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 6 hours after dropwise adding, monitoring by TLC (thin layer chromatography) until the raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake in an oven to obtain 9.7g of a product with the purity of 96% (HPLC area normalization method).
Examples 1 to 2
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 0 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 4 hours after dropwise adding, monitoring by TLC that a raw material disappears, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solid from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.7g with the purity of 97% (HPLC area normalization method).
Examples 1 to 3
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of the reaction liquid to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, monitoring by TLC that the raw materials disappear, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solid from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.6g with the purity of 97% (HPLC area normalization method).
Examples 1 to 4
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, heating to 30 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 2 hours after the dropwise adding is finished, monitoring by TLC (thin layer chromatography) that the raw materials disappear, concentrating to a small amount under reduced pressure, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.8g with the purity of 95% (HPLC area normalization method).
Examples 1 to 5
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, heating to 45 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 2 hours after the dropwise adding is finished, monitoring by TLC (thin layer chromatography) that the raw materials disappear, concentrating under reduced pressure to a small amount, pouring 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.8g with the purity of 93% (HPLC area normalization method).
Examples 1 to 6
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, heating to reflux, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 1 hour after the dropwise addition is finished, monitoring by TLC (thin layer chromatography) that the raw materials disappear, concentrating under reduced pressure to a small amount, pouring 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.8g with the purity of 90% (HPLC area normalization method).
Example 2 examination of the Effect of the amount of piperidine nitroxide free radicals on the reaction
Example 2-1
Adding 10.4g of an initiator 2.2, 6g of dimethyl sulfoxide, 10g of triethylamine, 40ml of 1, 2-dichloromethane and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, after TLC (thin layer chromatography) monitoring raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake in an oven to obtain 9.8g of a product with the purity of 95% (HPLC area normalization method).
Examples 2 to 2
Adding 10.4g of an initiator 2.2, 6g of dimethyl sulfoxide, 10g of triethylamine, 40ml of 1, 2-dichloromethane and 0.05g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 6 hours after dropwise adding, monitoring by TLC (thin layer chromatography) to remove raw materials, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake in an oven to obtain a product 9.6g with the purity of 97% (HPLC area normalization method).
Examples 2 to 3
Adding 10.4g of an initiator 2.2, 6g of dimethyl sulfoxide, 10g of triethylamine, 40ml of 1, 2-dichloromethane and 1g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 2.5 hours after dropwise adding, after TLC (thin layer chromatography) monitoring of raw materials disappears, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake in an oven to obtain 9.6g of a product with the purity of 96% (HPLC area normalization method).
Example 3 examination of the Effect of the charged amount of phenyl dichlorophosphate on the reaction
Example 3-1
Adding 11.8g of an initiator 2.3, 6g of dimethyl sulfoxide, 10g of triethylamine, 40ml of chloroform and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, after TLC monitoring raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake oven to obtain a product 9.8g with the purity of 95% (HPLC area normalization method).
Examples 3 to 2
Adding 11.8g of an initiator 2.3, 6g of dimethyl sulfoxide, 10g of triethylamine, 40ml of chloroform and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 5g of phenyl dichlorophosphate, continuing to react for 48 hours after dropwise adding, monitoring by TLC that the raw materials are not completely reacted, stopping the reaction, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake in an oven to obtain a product 9.5g with purity of 92% and the content of the initiator of 6% (HPLC area normalization method).
Examples 3 to 3
Adding 11.8g of an initiator 2.3, 6g of dimethyl sulfoxide, 10g of triethylamine, 40ml of chloroform and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 20g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, monitoring by TLC (thin layer chromatography) that raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, and drying a filter cake oven to obtain a product 9.8g with the purity of 94% (HPLC area normalization method).
Example 4 examination of the Effect of DMSO loading on the reaction
Example 4-1
Adding 13.9g of an initiator 2.4, 6g of dimethyl sulfoxide, 8g of triethylamine, 40ml of chloroform and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, monitoring by TLC (thin layer chromatography) that raw materials disappear, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.6g with the purity of 97% (HPLC area normalization method).
Example 4 to 2
Adding 13.9g of an initiator 2.4, 2g of dimethyl sulfoxide, 8g of triethylamine, 40ml of chloroform and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 48 hours after dropwise adding, monitoring by TLC that the raw materials are not completely reacted, stopping the reaction, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake in an oven to obtain a product 9.5g, the purity of which is 91 percent and the content of the initiator of which is 6 percent (HPLC area normalization method).
Examples 4 to 3
Adding 13.9g of an initiator 2.4, 5g of dimethyl sulfoxide, 8g of triethylamine, 40ml of chloroform and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 48 hours after dropwise adding, monitoring by TLC that the raw materials are not completely reacted, stopping the reaction, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake in an oven to obtain a product 9.7g, the purity of which is 93 percent and the content of the initiator of which is 3 percent (HPLC area normalization method).
Examples 4 to 4
Adding 13.9g of an initiator 2.4, 50g of dimethyl sulfoxide, 8g of triethylamine, 40ml of chloroform and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, monitoring by TLC (thin layer chromatography) that raw materials disappear, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.6g with the purity of 97% (HPLC area normalization method).
Example 5
Adding 14.7g of an initiator 2.5, 6g of dimethyl sulfoxide, 10g of 4-dimethylaminopyridine, 40ml of chloroform and 0.8g of 4-benzoyloxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, after TLC (thin layer chromatography) monitoring raw materials disappear, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake in an oven to obtain 9.7g of a product with the purity of 96% (HPLC area normalization method).
Example 6
Adding 10.4g of an initiator 2.6, 6g of dimethyl sulfoxide, 8g of 4-dimethylaminopyridine, 40ml of chlorobenzene and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, heating to reflux, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 1 hour after dropwise adding, after TLC (thin layer chromatography) monitoring raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake oven to obtain a product 9.7g with the purity of 92% (HPLC area normalization method).
Example 7
Adding 2.7g of an initiator, 6g of dimethyl sulfoxide, 8g of 4-dimethylaminopyridine, 60ml of chloroform, 10ml of n-hexane and 0.65g of 4-acetamido-TEMPO into a 250ml four-mouth bottle, heating to 45 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 2 hours after dropwise adding, after TLC monitoring raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake oven to obtain 9.2g of a product with the purity of 91% (HPLC area normalization method).
Example 8
Adding 15g of an initiator 2.8, 6g of dimethyl sulfoxide, 8g of 4-dimethylaminopyridine, 40ml of dichloromethane and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to-10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 6 hours after dropwise adding, monitoring by TLC (thin layer chromatography) until the raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, and drying a filter cake in an oven to obtain a product 9.6g with the purity of 97% (HPLC area normalization method).
Example 9
Adding 11.4g of an initiator 2.9, 6g of dimethyl sulfoxide, 8g of 4-dimethylaminopyridine, 40ml of tetrahydrofuran and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, monitoring by TLC (thin layer chromatography) that raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake in an oven to obtain a product 9.8g with the purity of 95% (HPLC area normalization method).
Example 10
Adding 14.3g of an initiator 2.10, 6g of dimethyl sulfoxide, 8g of 4-dimethylaminopyridine, 400ml of ethyl acetate and 0.5g of 4-hydroxy-TEMPO into a 250ml four-mouth bottle, cooling to 0 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 4 hours after dropwise adding, after TLC (thin layer chromatography) monitoring raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, carrying out suction filtration, drying a filter cake in an oven to obtain 9.6g of a product with the purity of 96% (HPLC area normalization method).
Example 11
Adding 16.8g of an initiator 2.11, 6g of dimethyl sulfoxide, 8g of 4-dimethylaminopyridine, 40ml of 1, 4-dioxane and 0.5g of TEMPO into a 250ml four-mouth bottle, heating to 30 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 2.5 hours after dropwise adding, concentrating under reduced pressure to a small amount after TLC monitoring raw materials disappear, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a product 9.8g with the purity of 93% (HPLC area normalization method).
Example 12
Adding 10g of compound 2.12, 6g of dimethyl sulfoxide, 10g of pyridine, 40ml of dichloromethane and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of the reaction liquid to 10 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3 hours after dropwise adding, monitoring by TLC (thin layer chromatography), reducing the pressure and concentrating to a small amount after the raw materials disappear, flushing 10ml of ethanol, reducing the temperature to room temperature, diluting in ice water, separating out a large amount of white-like solid from water, performing suction filtration, and drying a filter cake oven to obtain 9.8g of a product with the purity of 96% (HPLC area normalization method).
Example 13
Adding 10.5g of compound 2.13, 6g of dimethyl sulfoxide, 10g of pyridine, 40ml of 1, 2-dichloroethane and 0.65g of 4-acetamido-TEMPO into a 250ml four-mouth bottle, reducing the temperature of the reaction liquid to 0 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 3.5 hours after dropwise adding, after TLC monitoring raw materials disappear, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solid from water, performing suction filtration, drying a filter cake in an oven to obtain 9.7g of product with the purity of 97% (HPLC area normalization method).
Example 14
Adding 17.8g of compound 2.14, 6g of dimethyl sulfoxide, 10g of pyridine, 40ml of 1, 1-dichloroethane and 0.65g of 4-acetamido-TEMPO into a 250ml four-mouth bottle, heating to 30 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing to react for 2 hours after dropwise adding, monitoring by TLC (thin layer chromatography) until the raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solid from water, carrying out suction filtration, drying a filter cake in an oven to obtain 9.7g of product with the purity of 94% (HPLC area normalization method).
Comparative example
Comparative example 1
Comparative example 1-1
Preparation method reference CN201110101279 example 1.1
Adding 10g of 2.1 starting material into 30ml of dichloromethane, adding 20ml of NaOCl 12mmol aqueous solution under stirring, adding 0.15mmol TEMPO and 1mmol NaBr, stirring thoroughly at 20 ℃, monitoring by TLC until no starting material is present, adding saturated Na2SO3The organic phase was washed several times with aqueous solution to remove TEMPO and inorganic salts, the organic layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated in vacuo to remove the organic solvent to give 8.9g of crude product with a HPLC content of compound 1.1 of 40%.
Comparative example 1-2 reaction System without TEMPO, other conditions were identical to those of inventive examples 1-2
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine and 40ml of toluene into a 250ml four-opening bottle, reducing the temperature of a reaction solution to 0 ℃, dropwise adding 8g of phenyl dichlorophosphate, continuing the reaction after the dropwise addition, monitoring by TLC (thin layer chromatography) until the raw materials disappear, concentrating under reduced pressure to a small amount, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, and drying a filter cake oven to obtain a crude product 9.6g and the HPLC content of a compound 1.1 is 10% (HPLC area normalization method).
Comparative examples 1 to 3 replacement of phenyl dichlorophosphate with acetyl chloride and other conditions were in accordance with inventive examples 1 to 2
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 0 ℃, dropwise adding 8g of acetyl chloride, continuing the reaction after dropwise adding, after TLC monitoring raw materials disappear, concentrating under reduced pressure to a small amount, flushing 10ml of ethanol, reducing the temperature to room temperature, diluting the mixture in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake oven to obtain a crude product 9.0g, and determining by HPLC that the obtained product does not contain a compound 1.1.
Comparative examples 1 to 4 Using trifluoroacetic anhydride in place of phenyl dichlorophosphate, other conditions were the same as in inventive examples 1 to 2
Adding 10g of an initiator 2.1, 6g of dimethyl sulfoxide, 10g of diisopropylethylamine, 40ml of toluene and 0.5g of TEMPO into a 250ml four-mouth bottle, reducing the temperature of a reaction solution to 0 ℃, dropwise adding 8g of trifluoroacetic anhydride, continuing the reaction after dropwise adding, monitoring by TLC (thin layer chromatography) that the raw materials disappear, concentrating to a small amount under reduced pressure, adding 10ml of ethanol, cooling to room temperature, diluting in ice water, separating out a large amount of white-like solids from water, performing suction filtration, drying a filter cake oven to obtain 9.3g of a crude product, and determining by HPLC that the obtained product does not contain a compound 1.1.
Claims (22)
1. A kind of formula
The preparation method of the compound is characterized in that the compound is prepared in an aprotic organic solvent in the presence of DMSO (dimethyl sulfoxide) as an oxidant, organic base, phenyl dichlorophosphate and piperidine nitroxide free radical
The compound is oxidized to generate the formula
A compound, wherein the reaction temperature is 0 ℃ to the solvent reflux temperature, and the piperidine nitroxide radical is selected from at least one of 2,2,6, 6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl, and 4-acetamido-2, 2,6, 6-tetramethylpiperidine-1-oxyl:
r1, R2, R3, R4 are selected independently of each other and wherein:
r1= H, I, Br, Cl or OCOR5, R5 is an alkyl group within six carbons;
r2= H, α -OH or α -OCOR6, R6 is an alkyl group up to six carbons;
r3= H, α -methyl, β -methyl;
or R2, R3= single bond or epoxy, i.e. double bond between positions 16,17 or connected by an oxygen bridge,
or R2 and R3 may together form a moiety having formula I:
I
wherein X and Y are independently selected from hydrogen or alkyl, provided that when one of X or Y is hydrogen, the other is alkyl;
r4= H, F or a methyl group,
1,2 position
Represents a single bond or a double bond.
2. The formula as claimed in claim 1A process for the preparation of the compounds, characterized in that
Wherein
R1= H or OCOCH3,
r2= H, α -OH or OCOCH3,
r3= H or α -methyl,
or R2, R3= single bond or epoxy, i.e. double bond between positions 16,17 or connected by an oxygen bridge,
R4=H，
1,2 position
Represents a single bond or a double bond.
3. The formula as claimed in claim 1
A process for the preparation of the compounds, characterized in that
Wherein
R1=H，
R2=H，
R3=H，
Or R2, R3= single bond or epoxy, i.e. double bond between positions 16,17 or connected by an oxygen bridge,
R4=H，
1,2 position
Represents a single bond.
4. The formula as claimed in claim 1
A process for the preparation of the compounds, characterized in that
Wherein
R1=H，
R2, R3= epoxy, i.e. the 16,17 positions are connected by an oxygen bridge,
R4=H，
1,2 position
Represents a single bond.
5. The formula as claimed in claim 1
A process for the preparation of the compounds, characterized in that
Wherein
R1=H，
R2=H，
R3=H，
R4=H，
1,2 position
Represents a single bond.
6. The compound of any one of claims 1 to 5
A process for the preparation of a compound characterized in that it is a compound of formula (I) in terms of molar ratio
The feeding ratio of the compound, dimethyl sulfoxide and phenyl dichlorophosphate is 1:2-20: 0.75-3.
7. The formula as claimed in claim 6
A process for the preparation of a compound characterized in that it is a compound of formula (I) in terms of molar ratioThe feeding ratio of the compound to the piperidine nitroxide radical is 1: 0.01-0.2.
8. The compound of any one of claims 1 to 5The preparation method of the compound is characterized in that the piperidine nitroxide radical is selected from 2,2,6, 6-tetramethyl piperidine-1-oxyl or 4-hydroxy-2, 2,6, 6-tetramethyl piperidine-1-oxyl.
9. The formula as claimed in claim 8
The preparation method of the compound is characterized in that the piperidine nitroxide radical is 2,2,6, 6-tetramethyl piperidine-1-oxylA free radical.
10. The compound of any one of claims 1 to 5
A process for the preparation of a compound, characterized in that the organic base is a tertiary amine.
11. A compound of claim 10 of the formula
The preparation method of the compound is characterized in that the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine.
12. The compound of any one of claims 1 to 5
The preparation method of the compound is characterized in that the aprotic organic solvent is selected from one or more of halogenated alkyl containing 1-3 halogens, halogenated aromatic hydrocarbon, alkane, aromatic hydrocarbon, ether and ester.
13. The compound of claim 12 of the formula
The preparation method of the compound is characterized in that the aprotic organic solvent is one or more selected from dichloromethane, chloroform, 1, 2-dichloroethane, 1-dichloroethane, toluene, n-hexane, chlorobenzene, tetrahydrofuran, 1, 4-dioxane and ethyl acetate.
14. The compound of claim 13Process for the preparation of a compound, characterized in that the aprotic organic solvent isIs selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane and 1, 1-dichloroethane.
15. The compound of any one of claims 1 to 5
A process for the preparation of a compound, characterized in that the reaction temperature is 0-30 ℃.
16. The compound of claim 15 of the formula
A process for the preparation of a compound, characterized in that the reaction temperature is 0-10 ℃.
17. The compound of any one of claims 1 to 5
The preparation method of the compound is characterized in that the compound is prepared in an aprotic organic solvent in the presence of DMSO (dimethyl sulfoxide) as an oxidant, organic base, phenyl dichlorophosphate and piperidine nitroxide free radical
The compound is oxidized to generate the formula
The reaction temperature of the compound is 0-45 ℃, the aprotic organic solvent is selected from one or more of halogenated alkyl containing 1-3 halogens, halogenated aromatic hydrocarbon, alkane, aromatic hydrocarbon, ether and ester, and the organic base is tertiary amine.
18. The compound of claim 17
The preparation method of the compound is characterized in thatIn an aprotic organic solvent, DMSO is used as an oxidant, and the mixture is prepared in the presence of organic base, phenyl dichlorophosphate and piperidine nitroxide free radical
The compound is oxidized to generate the formulaThe compound is prepared by reacting at 0-30 ℃, wherein the aprotic organic solvent is one or more of dichloromethane, chloroform, 1, 2-dichloroethane, 1-dichloroethane, toluene, n-hexane, chlorobenzene, tetrahydrofuran, 1, 4-dioxane and ethyl acetate, the organic base is tertiary amine, and the piperidine nitroxide radical is selected from 2,2,6, 6-tetramethylpiperidine-1-oxyl or 4-hydroxy-2, 2,6, 6-tetramethylpiperidine-1-oxyl.
19. The compound of claim 18
The preparation method of the compound is characterized in that the compound is prepared in an aprotic organic solvent in the presence of DMSO (dimethyl sulfoxide) as an oxidant, organic base, phenyl dichlorophosphate and piperidine nitroxide free radical
The compound is oxidized to generate the formula
The reaction temperature of the compound is 0-10 ℃, the aprotic organic solvent is selected from one or more of dichloromethane, chloroform, 1, 2-dichloroethane and 1, 1-dichloroethane, the organic base is selected from one or more of pyridine, 4-dimethylaminopyridine, triethylamine and diisopropylethylamine, and the piperidine nitroxide radical is 2,2,6, 6-tetramethylpiperidine-1-oxyl.
20. As claimed in claim 18 to 19 of the formulaA process for the preparation of a compound characterized in that it is a compound of formula (I) in terms of molar ratio
The feeding ratio of the compound, dimethyl sulfoxide and phenyl dichlorophosphate is 1:2-20: 0.75-3.
21. The compound of claim 20 of the formulaA process for the preparation of a compound characterized in that it is a compound of formula (I) in terms of molar ratio
The feeding ratio of the compound to the piperidine nitroxide radical is 1: 0.01-0.2.
22. The compound of claim 21
A process for the preparation of a compound characterized in that it is a compound of formula (I) in terms of molar ratio
The feeding ratio of the compound, dimethyl sulfoxide and phenyl dichlorophosphate is 1:2.5: 1.25.
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