CN114685591A - Refining method and application of C1, 2-position dehydrosteroid compound - Google Patents
Refining method and application of C1, 2-position dehydrosteroid compound Download PDFInfo
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- CN114685591A CN114685591A CN202011624829.0A CN202011624829A CN114685591A CN 114685591 A CN114685591 A CN 114685591A CN 202011624829 A CN202011624829 A CN 202011624829A CN 114685591 A CN114685591 A CN 114685591A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
- C07J5/0023—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16
- C07J5/003—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes
- C07J5/0038—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes by an alkyl group
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
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Abstract
The invention provides a refining method and application of a C1, 2-dehydrogenation steroid compound, and relates to the technical field of chemical synthesis. The refining method of the C1, 2-position dehydrosteroid compound comprises the following steps: treating the compound of the formula I with an oxidizing agent under an acidic condition to obtain a purified compound of the formula I. The compound of the formula I is refined and purified by a chemical method, and under an acidic condition, the oxidant selectively reacts with the C1, 2-bit non-dehydrogenated impurity and other impurities to destroy the impurities and is removed along with the mother liquor, so that the effect of removing the impurities without introducing new impurities is achieved, the content of the C1, 2-bit non-dehydrogenated impurity and other impurities in a product is reduced, and the product quality is improved. In addition, repeated refining operation is not needed, the process steps are shortened, and the treatment cost is reduced.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a refining method and application of a C1, 2-position dehydrogenated steroid compound.
Background
The steroid medicine has strong pharmacological actions of resisting infection, anaphylaxis, virus and shock. With the continuous development of the times, steroid drugs have become the second largest class of drugs after antibiotics. Classification of steroid hormones drugs: adrenocortical hormones, including hydrocortisone, prednisone, etc., for treating addison's disease, anti-inflammatory, antiallergic, antishock, etc.; the protein assimilation hormone has the main physiological functions of inhibiting protein dissimilation and promoting protein synthesis, and is mainly used for treating diseases caused by protein increase and synthesis deficiency; sex hormones, including estrogen, androgen and progestin.
After double bonds are introduced into the C1, 2-position of the A ring of the parent nucleus of the steroid drug, the anti-inflammatory activity can be increased by times. At present, the production of a plurality of clinically important steroids is frequently used, and most of adrenal cortical hormones with anti-inflammatory capability are produced by C1, 2-position dehydrogenation reactions, such as prednisone acetate and the like. Methods for the 1, 2-position dehydrogenation of steroids generally include chemical methods and microbial fermentation methods. Chemical dehydrogenation generally requires the use of SeO2Low yield and SeO2The pollution to the environment is great, and the biological method is gradually replaced at present. The microorganism fermentation method is used for dehydrogenation, and the currently applied strain is arthrobacter, so that the defects of a chemical method are overcome, but the disadvantages of low substrate concentration, long conversion time, low conversion rate and yield, difficult separation and purification and the like exist. The biological dehydrogenation product often contains a plurality of impurities, particularly C1, 2-position non-dehydrogenation impurities, because the properties of the biological dehydrogenation product are close to those of the dehydrogenation product, and the molecular weight difference is very small, so that the conventional silica gel column separation method and the gel column separation method based on molecular weight separation have poor effect on removing the C1 and 2-position non-dehydrogenation impurities in the dehydrogenation product, and therefore, the C1 and 2-position dehydrogenation steroid compound is still difficult to remove the C1 and 2-position non-dehydrogenation impurities at present. German patent DE1252677 reports a refining process of prednisone acetate by using dichloroethane for crystallization, but the process has low yield of only 75 percent, and a large amount of dichloroethane as a solvent is required for refining, thus posing a threat to the environment and the health of people.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The main object of the present invention is to provide a refining method and application of C1, 2-dehydrosteroid, in order to at least partially solve at least one of the above technical problems.
The invention provides a refining method of C1, 2-position dehydrogenation steroid compound, which comprises the following steps:
treating a compound of formula I with an oxidizing agent under an acidic condition to obtain a refined compound of formula I, wherein the structural formula of the compound of formula I is as follows:
wherein, R shown in the structural formula of the compound of the formula I1、R2、R3、R4、R5And R6Are selected independently of each other, and:
R1h, methyl or halogen, halogen ═ F, Cl, Br or I;
R2h or halogen, halogen ═ F, Cl, Br, or I;
R3h, carbonyl or OH;
or, R2，
R4H, OH or methyl;
R5＝H、OH、R7、OR7、OCOR7or OCOOR7，R7Alkyl groups up to six carbons;
R6＝COCH2OH、COCH2OCOR8、OCOR8、COR8，R8alkyl groups up to six carbons.
The compound of formula I is obtained by introducing a double bond into C1,2 position of mother nucleus A ring of the compound of formula II, and the structural formula of the compound of formula II is as follows:
wherein, R shown in the structural formula of the compound of formula II1、R2、R3、R4、R5And R6Are selected independently of each other, and:
R1h, methyl or halogen, halogen ═ F, Cl, Br or I;
R2h or halogen, halogen ═ F, Cl, Br, or I;
R3h, carbonyl or OH;
or, R2，
R4H, OH or methyl;
R5＝H、OH、R7、OR7、OCOR7or OCOOR7，R7Alkyl groups up to six carbons;
R6＝COCH2OH、COCH2OCOR8、OCOR8、COR8，R8alkyl groups up to six carbons.
The existing biological dehydrogenation process can not completely dehydrogenate the C1, 2-position of the parent nucleus A ring of the compound in the formula II, and the dehydrogenation product, namely the compound in the formula I, is close to the compound in the formula II in nature, and has small molecular weight difference, so that the compound in the formula II, which is not dehydrogenated in the C1 and 2-position, becomes one of impurities of the compound in the formula I. In addition, impurities in the dehydrogenation product compounds of formula I include, but are not limited to, compounds of formula II. The purification methods of the prior art are not ideal.
The compound of the formula I is refined and purified by a chemical method, and under an acidic condition, the oxidant selectively reacts with the C1, 2-bit non-dehydrogenated impurity and other impurities to destroy the impurities and is removed along with the mother liquor, so that the effect of removing the impurities without introducing new impurities is achieved, the content of the C1, 2-bit non-dehydrogenated impurity and other impurities in a product is reduced, and the product quality is improved. In addition, repeated refining operation is not needed, the process steps are shortened, and the treatment cost is reduced.
Further, R shown in the structural formula of the compound of the formula I1、R2、R3、R4、R5And R6Are selected independently of each other, and:
R1h, methyl or halogen, halo ═ F;
R2h or halogen, halogen ═ F;
R3h, carbonyl or OH;
or, R2，
R4H or methyl;
R5h, OH or OCOR7，R7Alkyl groups within four carbons;
R6＝COCH2OH、COCH2OCOR8、OCOR8、COR8，R8alkyl groups up to four carbons.
Further, the compound of the formula I is added into a solvent, is adjusted to be acidic by an acid reagent, and is added with an oxidant at a certain temperature for reaction to obtain the refined compound of the formula I.
Further, the compound of formula I is added to a solvent, the pH is adjusted to 2-5 with an acid reagent, and an oxidizing agent is added at 0-20 ℃ to react to obtain a purified compound of formula I.
In the present invention, a typical but non-limiting pH of the reaction may be, for example, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8, 4, 4.2, 4.4, 4.6, 4.8 or 5; typical but non-limiting temperatures for the reaction may be, for example, 0 ℃, 1 ℃,2 ℃, 3 ℃, 4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃ or 20 ℃.
Further, the oxidant is selected from hypochlorite or hydrogen peroxide.
Further, the acid reagent is selected from organic acids.
Further, the solvent is selected from one or a combination of several of lower alcohol solvents, chlorinated hydrocarbon solvents, ester solvents or ketone solvents.
Further, the oxidant is selected from hypochlorite, and the hypochlorite is selected from sodium hypochlorite, calcium hypochlorite or zinc hypochlorite.
Further, the acid reagent is selected from formic acid, acetic acid or succinic acid.
Further, the lower alcohol solvent is selected from C1-C3 alcohol solvents.
Further, the chlorinated hydrocarbon solvent is selected from chloroform or dichloromethane.
Further, the ester solvent is selected from one or a combination of ethyl acetate, methyl acetate or n-butyl acetate.
Further, the ketone solvent is selected from one or a combination of acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and butanone.
The content of the non-dehydrogenated impurities at the C1 and 2-position in the compound of the formula I is related to the synthetic route of the compound of the formula I, and the content of the non-dehydrogenated impurities at the C1 and 2-position is different according to the synthetic route, and is generally about 1.5-2.5%. The amount of the oxidant added can be adjusted according to the content of the non-dehydrogenated impurity at C1 and 2 position in the compound of formula I, therefore, the present invention is not particularly limited, and the method for removing the non-dehydrogenated impurity at C1 and 2 position and other impurities by the refining method of the present invention falls within the protection scope of the present invention.
As a second aspect of the invention, the invention also provides the application of the refining method in preparing the C1, 2-dehydrogenation steroid compound.
Further, the C1, 2-position dehydrosteroid compound is obtained by dehydrogenation of C1, 2-position non-dehydrosteroid compound C1, 2-position; the C1, 2-position dehydrosteroid compound is selected from prednisone, methylprednisolone acetate, methylprednisolone, prednisone acetate, prednisolone valerate, diprosone, isoflupredone acetate, 17-acetic acid, prednisolone epoxy or diflucortolone valerate.
Further, the C1, 2-dehydrosteroid compound is selected from prednisone or prednisone acetate.
The C1, 2-dehydrosteroid compounds in the present invention include, but are not limited to, the above compounds.
Compared with the prior art, the invention has the following beneficial effects:
(1) the compound of the formula I is refined and purified by a chemical method, and under an acidic condition, the oxidant selectively reacts with the C1, 2-bit non-dehydrogenated impurities and other impurities to destroy the impurities and is removed along with the mother liquor, so that the effect of removing the impurities without introducing new impurities is achieved, the content of the C1, 2-bit non-dehydrogenated impurities and other impurities in a product is greatly reduced, and the product quality is improved. After the refining by the method, the HPLC content of the total impurities can be reduced to be below 0.2 percent, wherein the HPLC content of the non-dehydrogenated impurities at the 2-position of C1 is reduced to be below 0.05 percent, and the HPLC content meets the international standard. In addition, the method of the invention does not need repeated refining operation, shortens the process steps and reduces the treatment cost.
(2) The refining method is used for preparing the C1, 2-position dehydrosteroid compound, so that the product quality is improved, repeated refining operation is not needed, the process steps are shortened, and the treatment cost is reduced.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is an HPLC chromatogram of prednisone acetate refined in example 4-1;
FIG. 2 is an HPLC chromatogram of prednisone acetate (crude) before purification in example 4-1.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples were carried out under the conventional conditions, unless otherwise specified. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In order to facilitate a clearer understanding of the present invention, the following will further describe the technical solutions of the present invention with reference to examples.
The pre-refined C1, 2-position dehydrosteroid compounds used in the examples, such as prednisone crude product, methylprednisolone acetate crude product, methylprednisolone crude product, prednisone acetate crude product, prednisolone valerate crude product, diprosone crude product, isoflupredone acetate crude product, 17-acetic acid crude product, prednisone epoxy acetate crude product, and diflucortolone valerate crude product, are all prepared by tianjin pharmaceutical research institute corporation, wherein the HPLC content of C1, 2-position non-dehydrogenated impurities is about 1.5% -2.5%.
EXAMPLE 1 purification of prednisone
Adding 400mL of dichloromethane, 400mL of acetone and 100g of prednisone crude product into a reaction bottle, cooling to 10 ℃, adding acetic acid to adjust the pH value to 4, dropwise adding 115mL of 8% sodium hypochlorite solution, reacting at 10 ℃, and monitoring by HPLC until no C1 exists and 2-position non-dehydrogenated impurities exist. And dropwise adding 10% sodium sulfite solution until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone 97.5g with yield of 97.5%. HPLC purity 99.87%, C1, 0.03% non-dehydrogenated impurity at position 2, total impurity 0.13%.
EXAMPLE 2 purification of Methylprednisolone acetate
Adding 1000mL of ethyl acetate and 100g of methylprednisolone acetate crude product into a reaction bottle, cooling to 0 ℃, adding acetic acid to adjust the pH to 3, dropwise adding 120mL of 10% sodium hypochlorite solution, reacting at 0 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. 8% sodium sulfite solution is added dropwise until the starch potassium iodide paper is not blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined methylprednisolone acetate 97.4g with yield of 97.4%. HPLC purity 99.87%, C1, 0.04% non-dehydrogenated impurity at position 2, total impurity 0.13%.
EXAMPLE 3 purification of Methylprednisolone
1000mL of ethanol and 100g of methylprednisolone crude product are added into a reaction bottle, the temperature is reduced to 20 ℃, formic acid is added to adjust the pH value to 5, 22g of calcium hypochlorite is added, the reaction is carried out at 20 ℃, and HPLC (high performance liquid chromatography) monitors that no C1 exists and no dehydrogenation impurity exists at the 2-position. 12% sodium thiosulfate solution is added dropwise until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined methylprednisolone 97.3g with yield of 97.3%. HPLC purity 99.80%, C1, 0.05% non-dehydrogenated impurity at position 2, total impurity 0.20%.
EXAMPLE 4 purification of prednisone acetate
Example 4-1
Adding 500mL of chloroform, 200mL of methanol and 100g of prednisone acetate crude product into a reaction bottle, cooling to 10 ℃, adding glacial acetic acid to adjust the pH to 4, dropwise adding 115mL of 8% sodium hypochlorite solution, reacting at 10 ℃, and monitoring by HPLC until no C1 exists and no 2-position dehydrogenized impurity exists. And dropwise adding 10% sodium sulfite solution until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone acetate 97.9g with yield of 97.9%. The HPLC purity is 99.97%, the non-dehydrogenated impurity at C1, 2-position is not detected, and the total impurity is 0.03%.
Example 4 to 2
Adding 1000mL of ethyl acetate and 100g of prednisone acetate crude product into a reaction bottle, cooling to 0 ℃, adding glacial acetic acid to adjust the pH to 3, dropwise adding 120mL of 10% sodium hypochlorite solution, reacting at 0 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. 8% sodium sulfite solution is added dropwise until the starch potassium iodide paper is not blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone acetate 97.4g with yield of 97.4%. The HPLC purity is 99.96 percent, the non-dehydrogenated impurity at the C1,2 position is not detected, and the total impurity is 0.04 percent.
Examples 4 to 3
Adding 1000mL of acetone and 100g of prednisone acetate crude product into a reaction bottle, cooling to 20 ℃, adding formic acid to adjust the pH value to 5, adding 22g of calcium hypochlorite, reacting at 20 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. 12% sodium thiosulfate solution is added dropwise until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone acetate 97.3g with yield of 97.3%. The HPLC purity is 99.95%, the non-dehydrogenated impurity at C1, 2-position is not detected, and the total impurity is 0.05%.
Examples 4 to 4
Adding 500mL of dichloromethane, 500mL of ethanol and 100g of prednisone acetate crude product into a reaction bottle, cooling to 5 ℃, adding formic acid to adjust the pH to 2, adding 30g of zinc hypochlorite, reacting at 5 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. And dropwise adding 10% sodium sulfite solution until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone acetate 97.5g with yield of 97.5%. The HPLC purity is 99.96 percent, the non-dehydrogenated impurity at the C1,2 position is not detected, and the total impurity is 0.04 percent.
Examples 4 to 5
Adding 1000mL of ethanol and 100g of prednisone acetate crude product into a reaction bottle, cooling to 8 ℃, adding succinic acid to adjust the pH value to 1, dropwise adding 17mL of 30% hydrogen peroxide, reacting at 8 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. 8% sodium sulfite solution is added dropwise until the starch potassium iodide paper is not blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone acetate 96.8g with yield 96.8%. The HPLC purity is 99.96 percent, the non-dehydrogenated impurity at the C1,2 position is not detected, and the total impurity is 0.04 percent.
Examples 4 to 6
Adding 1000mL of acetone and 100g of prednisone acetate crude product into a reaction bottle, cooling to 15 ℃, adding succinic acid to adjust the pH to 6, dropwise adding 20mL of 30% hydrogen peroxide, reacting at 15 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. 12% sodium thiosulfate solution was added dropwise until the starch potassium iodide paper became blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisone acetate 97.0g with yield of 97.0%. The HPLC purity is 99.95%, the non-dehydrogenated impurity at C1, 2-position is not detected, and the total impurity is 0.05%.
EXAMPLE 5 purification of prednisolone
Adding 1000mL of dichloromethane and 100g of prednisolone crude product into a reaction bottle, cooling to 5 ℃, adding formic acid to adjust the pH value to 2, adding 30g of zinc hypochlorite, reacting at 5 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. And dropwise adding 10% sodium sulfite solution until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisolone 97.2g with yield of 97.2%. HPLC purity 99.85%, C1, 0.04% of non-dehydrogenated impurity at position 2, 0.15% of total impurities.
EXAMPLE 6 purification of prednisolone valerate
Adding 1000mL of ethanol and 100g of prednisolone valerate crude product into a reaction bottle, cooling to 8 ℃, adding succinic acid to adjust the pH to 1, dropwise adding 17mL of 30% hydrogen peroxide, reacting at 8 ℃, and monitoring by HPLC until C1 and 2-bit non-dehydrogenated impurities are obtained. 8% sodium sulfite solution is added dropwise until the starch potassium iodide paper is not blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisolone valerate 96.5g with yield 96.5%. HPLC purity 99.84%, C1, 0.05% non-dehydrogenated impurity at position 2, total impurity 0.16%.
EXAMPLE 7 purification of Diprenone
Adding 1000mL of ethyl acetate and 100g of crude diprosone into a reaction bottle, cooling to 15 ℃, adding succinic acid to adjust the pH to 6, dropwise adding 20mL of 30% hydrogen peroxide, reacting at 15 ℃, and monitoring by HPLC (high performance liquid chromatography) until no C1 exists and no dehydrogenation impurity exists at the 2-position. 12% sodium thiosulfate solution is added dropwise until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, drying to constant weight to obtain refined diprosone 96.8g with yield 96.8%. HPLC purity 99.86%, C1, 2-undehydrogenate impurity 0.04%, total impurity 0.14%.
EXAMPLE 8 purification of Isofluprednisone acetate
Adding 800mL of ethyl acetate and 100g of crude isoproflunisolone acetate into a reaction bottle, cooling to 10 ℃, adding acetic acid to adjust the pH to 4, dropwise adding 8% sodium hypochlorite solution, reacting at 10 ℃, and monitoring by HPLC (high performance liquid chromatography) until no C1 exists and no dehydrogenation impurity exists at 2 position. And dropwise adding 10% sodium sulfite solution until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined acetic acid isofluprednisone 97.5g with yield of 97.5%. HPLC purity 99.83%, C1, 0.05% non-dehydrogenated impurity at position 2, total impurity 0.17%.
EXAMPLE 917 purification of Boletin acetate
1000mL of ethanol and 100g of crude 17-acetic acid bodhidone are added into a reaction bottle, the temperature is reduced to 20 ℃, formic acid is added to adjust the pH value to 5, 22g of calcium hypochlorite is added, the reaction is carried out at 20 ℃, and the reaction is monitored by HPLC to be free of C1 and non-dehydrogenated impurities at the 2-position. 12% sodium thiosulfate solution was added dropwise until the starch potassium iodide paper became blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, drying to constant weight to obtain refined 17-acetic acid bodilidone 97.3g with yield 97.3%. HPLC purity 99.85%, C1, 0.03% of non-dehydrogenated impurity at position 2, total impurity 0.15%.
EXAMPLE 10 purification of prednisolone acetate epoxy
Adding 1000mL of ethanol and 100g of prednisone acetate epoxy crude product into a reaction bottle, cooling to 15 ℃, adding succinic acid to adjust the pH to 6, dropwise adding 20mL of 30% hydrogen peroxide, reacting at 15 ℃, and monitoring by HPLC until no C1 exists and no 2-position dehydrogenized impurity exists. 12% sodium thiosulfate solution is added dropwise until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined prednisolone acetate epoxy 96.7g with yield 96.7%. HPLC purity 99.82%, C1, 0.04% non-dehydrogenated impurity at position 2, total impurity 0.18%.
Example 11 Difluorocolone valerate
Adding 400mL of acetone, 400mL of ethanol and 100g of crude diflucortolone valerate into a reaction bottle, cooling to 10 ℃, adding acetic acid to adjust the pH to 4, dropwise adding 8% sodium hypochlorite solution, reacting at 10 ℃, and monitoring by HPLC until no C1 exists and no dehydrogenation impurity exists at the 2-position. And dropwise adding 10% sodium sulfite solution until the starch potassium iodide paper does not turn blue. Concentrating under reduced pressure, adding purified water, cooling to 15 deg.C, crystallizing for 1h, filtering to obtain filter cake, and drying to constant weight to obtain refined diflucortolone valerate 97.6g with yield 97.6%. HPLC purity 99.84%, C1, 2-undehydrogenate impurity 0.05%, total impurity 0.16%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A refining method of a C1, 2-position dehydrogenation steroid compound is characterized by comprising the following steps:
treating a compound of formula I with an oxidizing agent under an acidic condition to obtain a refined compound of formula I, wherein the structural formula of the compound of formula I is as follows:
wherein, R shown in the structural formula of the compound of the formula I1、R2、R3、R4、R5And R6Are selected independently of each other, and:
R1h, methyl or halogen, halo ═ F, Cl, Br or I;
R2h or halogen, halo ═ F, Cl, Br or I;
R3h, carbonyl or OH;
or, R2，
R4H, OH or methyl;
R5＝H、OH、R7、OR7、OCOR7or OCOOR7，R7Alkyl groups up to six carbons;
R6＝COCH2OH、COCH2OCOR8、OCOR8、COR8，R8alkyl groups up to six carbons.
2. The method for purifying C1, 2-dehydrosteroid compounds according to claim 1, wherein R is represented by formula I1、R2、R3、R4、R5And R6Are selected independently of each other, and:
R1h, methyl or halogen, halo ═ F;
R2h or halo, halo ═ F;
R3h, carbonyl or OH;
or, R2，
R4H or methyl;
R5h, OH or OCOR7，R7Alkyl groups within four carbons;
R6＝COCH2OH、COCH2OCOR8、OCOR8、COR8，R8alkyl groups up to four carbons.
3. The method for purifying C1, 2-dehydrosteroid compounds according to claim 1 or 2, wherein the compound of formula I is added to a solvent, the solution is adjusted to acidity with an acid reagent, and an oxidizing agent is added at a certain temperature to react, thereby obtaining the purified compound of formula I.
4. The method for purifying C1, 2-dehydrosteroid compounds according to claim 3, wherein the compound of formula I is added to a solvent, the pH is adjusted to 2-5 with an acid reagent, and an oxidizing agent is added at 0-20 ℃ to react, thereby obtaining the purified compound of formula I.
5. The method for refining the C1, 2-dehydrosteroid compound according to claim 4, wherein the oxidant is selected from hypochlorite and hydrogen peroxide;
and/or, the acid agent is selected from organic acids;
and/or the solvent is selected from one or a combination of a plurality of lower alcohol solvents, chlorinated hydrocarbon solvents, ester solvents or ketone solvents.
6. The method of refining a dehydrosteroid compound at the C1,2 position according to claim 5, wherein the oxidizing agent is selected from hypochlorite salts selected from sodium hypochlorite, calcium hypochlorite and zinc hypochlorite;
the acid reagent is selected from formic acid, acetic acid or succinic acid.
7. The method for purifying C1, 2-dehydrosteroid compounds according to claim 5 or 6, wherein the lower alcohol solvent is selected from C1-C3 alcohol solvents;
and/or, the chlorinated hydrocarbon solvent is selected from chloroform or dichloromethane;
and/or the ester solvent is selected from one or more of ethyl acetate, methyl acetate or n-butyl acetate;
and/or the ketone solvent is selected from one or a combination of more of acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone and butanone.
8. Use of the purification process according to any one of claims 1 to 7 for the preparation of dehydrosteroids at the C1, 2-position.
9. Use according to claim 8, wherein the C1,2 dehydrosteroid compound is obtained by dehydrogenation of the non-dehydrosteroid compound at C1,2 position C1; the C1, 2-position dehydrosteroid compound is selected from prednisone, methylprednisolone acetate, methylprednisolone, prednisone acetate, prednisolone valerate, diprosone, isoflupredone acetate, 17-acetic acid, prednisolone epoxy or diflucortolone valerate.
10. The use according to claim 9, wherein the C1, 2-dehydrosteroid is selected from prednisone or prednisone acetate.
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