CN112142813A - Dehalogenation method and application of 9-halogenated steroid compound - Google Patents
Dehalogenation method and application of 9-halogenated steroid compound Download PDFInfo
- Publication number
- CN112142813A CN112142813A CN201910652680.8A CN201910652680A CN112142813A CN 112142813 A CN112142813 A CN 112142813A CN 201910652680 A CN201910652680 A CN 201910652680A CN 112142813 A CN112142813 A CN 112142813A
- Authority
- CN
- China
- Prior art keywords
- compound
- dehalogenation
- reaction
- compounds
- hydrogen donor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
-
- 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
- C07J5/0061—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 substituted in position 16
- C07J5/0069—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 substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—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 substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- 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
- C07J5/0061—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 substituted in position 16
- C07J5/0092—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 substituted in position 16 by an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- 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
- C07J7/0015—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 not substituted in position 17 alfa
- C07J7/002—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 not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention provides a dehalogenation method of a 9-halogenated steroid compound and application thereof, relating to the technical field of chemical synthesis. A process for dehalogenation of a 9-halo steroid comprising the steps of: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound. According to the dehalogenation method of the 9-halogenated steroid compound, the hydrogen donor adopts one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organosilicon hydride, hydrazine compounds or cyclohexene, the initiator adopts azo free radical initiator, and reagents with high toxicity, such as chromium, divalent chromium salt, trivalent chromium salt or tributyltin hydride and the like, which cause serious pollution to the environment are not used in the reaction.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a dehalogenation method of a 9-halogenated steroid compound and application thereof.
Background
The corticoid drugs have various pharmacological actions such as anti-inflammation, anti-allergy, anti-shock and immunosuppression, so the corticoid drugs have wide application in the aspect of treating skin diseases and the like. The key step in the chemical synthesis process of this kind of medicine is the dehalogenation reaction of 9-halogenated steroid compound. The conventional dehalogenation method in the prior art is to add 9-halogenated steroid compounds into a solvent, and react with chromium, divalent chromium salt, trivalent chromium salt or tributyltin hydride at a certain temperature to generate dehalogenation products. The processes mostly use heavy metal raw materials, raw materials with high toxicity and the like, so that the environment is seriously polluted, the environmental protection treatment cost is high or the use of the raw materials is limited; thereby limiting the normal application of the reaction and influencing the normal production of the product.
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 method for dehalogenation of 9-halo steroids and the use thereof, in order to solve at least partially at least one of the above mentioned technical problems.
As one aspect of the present invention, there is provided a process for dehalogenation of a 9-halo steroid comprising the steps of: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H, OH, R6, OR6, OCOR6, OR OCOOR6, R6 is an alkyl group of up to six carbons;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are independently H or alkyl within six carbons;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH, halogen or OCOR10, R10 is alkyl of up to six carbons;
or, R4 ═ OCH2R11, R11 ═ halogen;
or, R4 ═ SCH 2F;
r5 ═ H, O, OH, OCOCF3 or OCOR12, R12 is H or alkyl of up to six carbons;
x ═ Cl, Br, or I;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
Further, the method comprises the following steps: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H or OH;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are independently H or alkyl within six carbons;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH or OCOR10, R10 is an alkyl group of up to six carbons;
r5 ═ H, O, OH, OCOCF3 or OCOR12, R12 is H or alkyl of up to six carbons;
x ═ Cl, Br, or I;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
Further, the method comprises the following steps: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H or OH;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are methyl independently;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH or OCOR10, R10 is an alkyl group of up to six carbons;
r5 ═ O, OH, OCOCF3 or OCOR12, R12 is H or methyl;
x ═ Cl or Br;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
Further, the hypophosphite is selected from sodium hypophosphite and/or potassium hypophosphite;
and/or, the organosilicon hydride is selected from triphenylsilanes;
and/or the formate is selected from one or a combination of more of sodium formate, potassium formate or ammonium formate;
and/or the hydrazine compound is selected from hydrazine and/or hydrazine hydrate.
Further, the azo free radical initiator is selected from one or a combination of more of azobisisobutyronitrile, azobisisoheptonitrile, azobisisobutyronitrile formamide, azobiscyclohexylcarbonitrile, dimethyl azobisisobutyrate, azobisisobutyric acid hydrochloride, azobisisopropylimidazoline hydrochloride or azobiscyanovaleric acid.
Further, the azo free radical initiator is selected from one or a combination of more of azoisobutyryl formamide, azodiisobutyl imidazole hydrochloride, azodiisopropyl imidazoline hydrochloride or azodicyano valeric acid.
Further, the molar ratio of the compound I, the azo radical initiator and the hydrogen donor in the reaction is 1: (0.15-0.4): (1.5-3).
Further, the method comprises the following steps: adding the compound I, a hydrogen donor and an azo free radical initiator into a solvent, and reacting at 40-90 ℃ to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound.
Further, the reaction temperature is 50-85 ℃.
Further, an alkali reagent is added in the reaction.
Further, the alkali agent is selected from an organic alkali and/or an inorganic alkali.
Further, the organic base is selected from one or a combination of several of diethylamine, triethylamine, tert-butylamine, pyridine or N, N-diisopropylethylamine.
Further, the inorganic base is selected from one or a combination of more of ammonia water, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
Further, the solvent is selected from one or a combination of more of C1-C6 alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide or ethyl acetate, or a mixture of water and the solvent.
Further, the solvent is selected from a mixture of C1-C6 alcohols and water.
As another aspect of the invention, the invention provides an application of the dehalogenation method of the 9-halogenated steroid compound in preparing corticoid medicaments and intermediates thereof.
Further, the corticoid drugs include methylprednisolone, methylprednisolone acetate, prednisolone acetate, prednisone, cortisone acetate, hydrocortisone acetate, ciclesonide, budesonide, and progesterone.
The corticoid drugs in the present invention include, but are not limited to, the above-mentioned drugs.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention provides a dehalogenation method of 9-halogenated steroid compounds, which is characterized in that a compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compounds, wherein the hydrogen donor adopts hypophosphorous acid and one or a combination of more of hypophosphite, formic acid and formate, organosilicon hydride, hydrazine compounds or cyclohexene, the initiator adopts an azo free radical initiator, and chromium, divalent chromium salt, trivalent chromium salt or tributyltin hydride and other reagents with high toxicity and serious pollution to the environment are not used in the reaction.
(2) The invention uses the dehalogenation method of the 9-halogenated steroid compound to prepare the corticoid drugs and the intermediates thereof, avoids using chemical reagents with higher toxicity and serious pollution to the environment in the synthetic route, has strong operability and high safety factor, and improves the production applicability.
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.
According to a first aspect of the present invention there is provided a process for the dehalogenation of a 9-halo steroid comprising the steps of: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H, OH, R6, OR6, OCOR6, OR OCOOR6, R6 is an alkyl group of up to six carbons;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are independently H or alkyl within six carbons;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH, halogen or OCOR10, R10 is alkyl of up to six carbons;
or, R4 ═ OCH2R11, R11 ═ halogen;
or, R4 ═ SCH 2F;
r5 ═ H, O, OH, OCOCF3 or OCOR12, R12 is H or alkyl of up to six carbons;
x ═ Cl, Br, or I;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
It should be noted that the dotted line between positions C1, C2 and the dotted line between positions R5, C11 in the structural formulae of compound I and compound II of the present invention are independently selected from each other, that is:
when the C1 and C2 positions are single bonds, the R5 and C11 positions may be connected by single bonds (i.e., R5 ═ H, OH, OCOCF3 or OCOR12) or double bonds (i.e., R5 ═ O, i.e., the C11 position is a carbonyl);
when a double bond is present between C1 and C2 positions, R5 and C11 positions may be connected by a single bond (i.e., R5 ═ H, OH, OCOCF3 or OCOR12), or may be connected by a double bond (i.e., R5 ═ O, i.e., C11 position is carbonyl).
The invention provides a dehalogenation method of 9-halogenated steroid compounds, which is characterized in that a compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compounds, wherein the hydrogen donor adopts hypophosphorous acid and one or a combination of more of hypophosphite, formic acid and formate, organosilicon hydride, hydrazine compounds or cyclohexene, the initiator adopts an azo free radical initiator, and chromium, divalent chromium salt, trivalent chromium salt or tributyltin hydride and other reagents with high toxicity and serious pollution to the environment are not used in the reaction.
In a preferred embodiment, the method comprises the following steps: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H or OH;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are independently H or alkyl within six carbons;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH or OCOR10, R10 is an alkyl group of up to six carbons;
r5 ═ H, O, OH, OCOCF3 or OCOR12, R12 is H or alkyl of up to six carbons;
x ═ Cl, Br, or I;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
In a preferred embodiment, the method comprises the following steps: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H or OH;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are methyl independently;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH or OCOR10, R10 is an alkyl group of up to six carbons;
r5 ═ O, OH, OCOCF3 or OCOR12, R12 is H or methyl;
x ═ Cl or Br;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
In a preferred embodiment, the hypophosphite salt is selected from sodium hypophosphite and/or potassium hypophosphite;
and/or, the organosilicon hydride is selected from triphenylsilanes;
and/or the formate is selected from one or a combination of more of sodium formate, potassium formate or ammonium formate;
and/or the hydrazine compound is selected from hydrazine and/or hydrazine hydrate.
Various hydrogen donors include but are not limited to the reagents, so that the use of more toxic chemical reagents can be avoided, the operability is high, the safety factor is high, the environment is friendly, and the production applicability is improved.
In a preferred embodiment, the azo-based free radical initiator is selected from one or a combination of several of Azobisisobutyronitrile (AIBN), Azobisisoheptonitrile (ABVN), azobisisobutyronitrile formamide (CABN), Azobiscyclohexylcarbonitrile (ACCN), dimethyl Azobisisobutyrate (AIBME), azobisisobutyronitrile hydrochloride (AIBA), azobisisopropylimidazoline hydrochloride (AIBI), or azobiscyanovaleric acid (ACVA).
In a preferred embodiment of the present invention, the azo radical initiator is selected from one or more of azoisobutyronitrile formamide (CABN), azodiisobutyl imidazole hydrochloride (AIBA), azodiisopropyl imidazoline hydrochloride (AIBI), and azodicyano valeric acid (ACVA).
In a preferred embodiment, the molar ratio of compound I, azo-based radical initiator and hydrogen donor in the reaction is 1: (0.15-0.4): (1.5-3).
Wherein, the typical but not limiting molar ratio of compound I, azo-based radical initiator and hydrogen donor is 1: 0.3: 2. 1: 0.15: 3. 1: 0.4: 1.5, 1: 0.16: 2.8, 1: 0.18: 2.6, 1: 0.2: 2.4 or 1: 0.25: 2.2.
when the molar ratio of the compound I, the azo radical initiator and the hydrogen donor is the above-mentioned ratio, the conversion of the compound I can be brought close to the quantitative conversion in the case where the amount of the azo radical initiator and the hydrogen donor is appropriate.
In a preferred embodiment, the method comprises the following steps: adding the compound I, a hydrogen donor and an azo free radical initiator into a solvent, and reacting at 40-90 ℃ to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound.
Typical but non-limiting temperatures for the reaction may be, for example, 40 ℃, 42 ℃, 44 ℃, 46 ℃, 48 ℃, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃, 60 ℃, 62 ℃, 64 ℃, 66 ℃, 68 ℃, 70 ℃, 72 ℃, 74 ℃, 76 ℃, 78 ℃, 80 ℃, 82 ℃, 84 ℃, 86 ℃, 88 ℃ or 90 ℃.
The dehalogenation method of the 9-halogenated steroid compound provided by the invention does not use highly toxic and high-risk chemical reagents, has mild reaction conditions, can complete the reaction at 40-90 ℃, has strong operability and high safety factor, and improves the production applicability.
In a preferred embodiment of this embodiment, the reaction temperature is 50-85 ℃.
In a preferred embodiment, an alkaline reagent is also added to the reaction.
The alkali reagent can be used as an acid-binding agent, mainly has the functions of absorbing hydrogen halide generated in the reaction, and also prevents the reaction liquid from being over-acid or over-alkali, so that the pH value of the reaction liquid is maintained at 3-9.
In a preferred embodiment, the alkaline agent is selected from organic and/or inorganic bases.
In a preferred embodiment of this embodiment, the organic base is selected from one or a combination of diethylamine, triethylamine, tert-butylamine, pyridine or N, N-diisopropylethylamine.
In a preferred embodiment of the present invention, the inorganic base is selected from one or a combination of ammonia, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
In a preferred embodiment, the solvent is selected from one or more of alcohols of C1-C6, tetrahydrofuran, 2-methyltetrahydrofuran, N-Dimethylformamide (DMF) or ethyl acetate, or a mixture with water.
In a preferred embodiment of this embodiment, the solvent is selected from a mixture of C1-C6 alcohols and water.
In the prior art, the adopted organic solvent is N, N-dimethylformamide or acetone, and the weight of the waste water generated in the post-treatment is about dozens of times of that of the raw materials; the solvent in the invention comprises but is not limited to one or a combination of more than one of C1-C6 alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide or ethyl acetate, or a mixture of the solvent and water, preferably a mixture of C1-C6 alcohols and water.
According to a second aspect of the present invention, there is provided the use of a process for dehalogenation of a 9-halo steroid as hereinbefore described in the preparation of a corticosteroid drug substance and intermediates therefor.
The invention uses the dehalogenation method of the 9-halogenated steroid compound to prepare the corticoid drugs and the intermediates thereof, avoids using chemical reagents with higher toxicity and serious pollution to the environment in the synthetic route, has strong operability and high safety factor, and improves the production applicability.
In a preferred embodiment of this embodiment, the corticosteroid drug includes methylprednisolone, methylprednisolone acetate, prednisolone, prednisone acetate, prednisone, cortisone acetate, hydrocortisone acetate, ciclesonide, budesonide, and progesterone.
The corticoid drugs in the present invention include, but are not limited to, the above-mentioned drugs.
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.
Example 1
Adding 200mL of 75% ethanol, 9.8g of potassium carbonate, 11mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-1 and 4.3g of AIBI into a reaction bottle in sequence at room temperature, heating to 70 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to precipitate a solid, filtering, and drying to obtain 15.2g of a compound II-1 solid, wherein the yield is 92.3% and the purity is 96.8%.
Example 2
Adding 200mL of 2-methyltetrahydrofuran, 9g of sodium carbonate, 9.9mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-2 and 3.3g of AIBA into a reaction flask in sequence at room temperature, heating to 65 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to separate out a solid, filtering, and drying to obtain 15.2g of a compound II-2 solid, wherein the yield is 91.5% and the purity is 96.5%.
Example 3
160mL of n-butanol, 13mL of 33% sodium hydroxide solution, 9.9mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-3 and 2.5g of CABN are sequentially added into a reaction bottle at room temperature, the temperature is raised to 80 ℃ for reaction, TLC is carried out until no raw material exists, solid is separated out through post-treatment, filtration is carried out, and drying is carried out, so that 15.3g of compound II-3 solid is obtained, the yield is 93.4%, and the purity is 97.0%.
Example 4
Adding 100mL of isopropanol, 7.5mL of N, N-diisopropylethylamine, 9.2mL of cyclohexene, 20g of compound I-4 and 2.5g of ACCN into a reaction bottle in sequence at room temperature, heating to 75 ℃ for reaction, performing TLC until no raw material exists, performing aftertreatment to separate out a solid, filtering, and drying to obtain 13.2g of a compound II-4 solid, wherein the yield is 81.2%, and the purity is 89.5%.
Example 5
160mL of 2-methyltetrahydrofuran, 2.6mL of formic acid, 4.4g of ammonium formate, 20g of compound I-5 and 3.3g of AIBA are sequentially added into a reaction bottle at room temperature, the temperature is raised to 70 ℃ for reaction, TLC is carried out until no raw material exists, solid is separated out through post-treatment, filtration is carried out, and drying is carried out to obtain 14.0g of compound II-5 solid, the yield is 83.0%, and the purity is 89.7%.
Example 6
160mL of 95% ethanol, 6.9g of potassium carbonate, 11g of sodium hypophosphite, 20g of compound I-6 and 5.4g of AIBI are sequentially added into a reaction bottle at room temperature, the temperature is increased to 70 ℃ for reaction, TLC is carried out until no raw material exists, solid is separated out through post-treatment, the solid is filtered and dried to obtain 15.7g of compound II-6 solid, the yield is 93.3%, and the purity is 97.7%.
Example 7
Adding 200mL of isopropanol, 11g of sodium bicarbonate, 6.8mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-7 and 4.2g of AIBI into a reaction bottle in sequence at room temperature, heating to 75 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to precipitate a solid, filtering, and drying to obtain 15.8g of compound II-7 solid, wherein the yield is 94.3% and the purity is 95.8%.
Example 8
Adding 100mL of isopropanol, 2.4g of sodium carbonate, 26g of triphenylsilane, 20g of compound I-8 and 2.6g of AIBN into a reaction bottle in sequence at room temperature, heating to 80 ℃ for reaction, carrying out TLC until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 13.6g of compound II-8 solid, wherein the yield is 82.3%, and the purity is 90.3%.
Example 9
Adding 200mL of 2-methyltetrahydrofuran, 9g of potassium carbonate, 8.7mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-9 and 3.5g of ACCN into a reaction bottle in sequence at room temperature, heating to 70 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to separate out a solid, filtering, and drying to obtain 14.2g of a compound II-9 solid, wherein the yield is 85.3%, and the purity is 90.8%.
Example 10
Adding 200mL of isopropanol, 7.5mL of 40% hydrazine hydrate, 20g of compound I-10 and 3.4g of AIBA into a reaction bottle in sequence at room temperature, heating to 75 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 12.6g of compound II-10 solid, wherein the yield is 81.3%, and the purity is 86.7%.
Example 11
400mL of tetrahydrofuran, 7.5mL of triethylamine, 22g of triphenylsilane, 20g of compound I-11 and 1.6g of AIBN are sequentially added into a reaction bottle at room temperature, the temperature is increased to 50 ℃ for reaction, TLC is carried out until no raw material exists, solid is separated out through post-treatment, the solid is filtered and dried to obtain 13.8g of compound II-11 solid, the yield is 81.3%, and the purity is 89.3%.
Example 12
Adding 140mL of 70% ethanol, 12mL of triethylamine, 9.3mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-12 and 3.6g of AIBI into a reaction bottle in sequence at room temperature, heating to 70 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to precipitate a solid, filtering, and drying to obtain 15.3g of compound II-12 solid, wherein the yield is 90.3% and the purity is 94.8%.
Example 13
Adding 200mL of isopropanol, 6.7g of sodium carbonate, 9.7mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-13 and 3.3g of AIBA into a reaction flask at room temperature in sequence, heating to 80 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to precipitate a solid, filtering, and drying to obtain 17.1g of compound II-13 solid, wherein the yield is 92.5% and the purity is 95.5%.
Example 14
Adding 100mL of n-butanol, 18mL of ammonia water and 9.6mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-14 and 2.1g of CABN into a reaction bottle in sequence at room temperature, heating to 85 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 15.5g of compound II-14 solid, wherein the yield is 93.4% and the purity is 96.6%.
Example 15
Adding 200mL of 95% ethanol, 8mL of ammonia water, 8.4mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-15 and 2.1g of CABN into a reaction flask at room temperature in sequence, heating to 70 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 15.9g of a compound II-15 solid, wherein the yield is 93.8% and the purity is 97.5%.
Example 16
Adding 200mL of isopropanol, 3.5mL of triethylamine, 13mL of cyclohexene, 20g of compound I-16 and 2.6g of ACVA into a reaction bottle in sequence at room temperature, heating to 75 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out aftertreatment to precipitate a solid, filtering, and drying to obtain 15.0g of compound II-16 solid, wherein the yield is 92.2%, and the purity is 96.5%.
Example 17
Adding 100mL of isopropanol, 6mL of triethylamine, 13mL of cyclohexene, 20g of compound I-17 and 2.5g of ACVA into a reaction bottle in sequence at room temperature, heating to 75 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out aftertreatment to separate out solid, filtering, and drying to obtain 15.7g of compound II-17 solid, wherein the yield is 94.5%, and the purity is 95.5%.
Example 18
400mL of isopropanol, 7.8g of sodium carbonate, 12mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-18 and 4.0g of AIBA are sequentially added into a reaction bottle at room temperature, the temperature is raised to 80 ℃ for reaction, TLC is carried out until no raw material exists, solid is separated out through post-treatment, filtration is carried out, and drying is carried out to obtain 16.8g of compound II-18 solid, the yield is 92.6%, and the purity is 97.1%.
Example 19
400mL of isopropanol, 6.9g of sodium carbonate, 12mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-19 and 5.1g of AIBA are sequentially added into a reaction bottle at room temperature, the temperature is raised to 80 ℃ for reaction, TLC is carried out until no raw material exists, solid is separated out through post-treatment, filtration is carried out, and drying is carried out to obtain 14.9g of compound II-19 solid, the yield is 91.6%, and the purity is 94.9%.
Example 20
Adding 200mL of isopropanol, 6.9g of sodium carbonate, 12mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-20 and 2.0g of AIBA into a reaction bottle in sequence at room temperature, heating to 80 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 14.8g of compound II-20 solid, wherein the yield is 91.6% and the purity is 96.1%.
Example 21
Adding 200mL of 95% ethanol, 11mL of triethylamine, 8.4mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-21 and 1.9g of AIBN into a reaction bottle in sequence at room temperature, heating to 70 ℃ for reaction, performing TLC (thin layer chromatography) until no raw material exists, performing aftertreatment to precipitate a solid, filtering, and drying to obtain 14.2g of a compound II-21 solid, wherein the yield is 83.8% and the purity is 90.5%.
Example 22
Adding 140mL of isopropanol, 168mL of triethylamine, 89mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-22 and 3.3g of AIBN into a reaction bottle in sequence at room temperature, heating to 80 ℃ for reaction, carrying out TLC until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 12.6g of compound II-22 solid, wherein the yield is 75.2%, and the purity is 85.0%.
Example 23
And (2) sequentially adding 120mL of DMF, 5.8mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-23 and 1.4g of ABVN into a reaction bottle at room temperature, heating to 90 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out aftertreatment to precipitate a solid, filtering, and drying to obtain 14.0g of compound II-23 solid, wherein the yield is 81.5% and the purity is 90.3%.
Example 24
Adding 120mL of ethyl acetate, 7.2mL of 50% hypophosphorous acid aqueous solution, 20g of compound I-24 and 1.7g of AIBME into a reaction flask in sequence at room temperature, heating to 40 ℃ for reaction, carrying out TLC (thin layer chromatography) until no raw material exists, carrying out post-treatment to precipitate a solid, filtering, and drying to obtain 14.1g of compound II-24 solid, wherein the yield is 82.3%, and the purity is 89.6%.
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 process for dehalogenation of a 9-halo steroid comprising the steps of: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H, OH, R6, OR6, OCOR6, OR OCOOR6, R6 is an alkyl group of up to six carbons;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are independently H or alkyl within six carbons;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH, halogen or OCOR10, R10 is alkyl of up to six carbons;
or, R4 ═ OCH2R11, R11 ═ halogen;
or, R4 ═ SCH 2F;
r5 ═ H, O, OH, OCOCF3 or OCOR12, R12 is H or alkyl of up to six carbons;
x ═ Cl, Br, or I;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
2. A process for the dehalogenation of 9-halo steroids according to claim 1 including the steps of: the compound I reacts with a hydrogen donor and an azo free radical initiator to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound, and the reaction formula is as follows:
wherein R1, R2, R3, R4 and R5 shown in the structural formulae of compound I and compound II are selected independently of each other, and:
r1 ═ H or methyl;
r2 ═ H, OH or methyl; r3 ═ H or OH;
or, the compounds of R2,
namely C16, the C17 positions are also connected through an oxygen bridge, and R7 and R8 are independently H or alkyl within six carbons;
or, the compounds of R2,
namely C16, the C17 position is also connected through epoxy;
or, R2 and R3 are single bonds, i.e., C16 and C17 are also connected by double bonds;
r4 ═ CH2R9, R9 ═ H, OH or OCOR10, R10 is an alkyl group of up to six carbons;
r5 ═ H, O, OH, OCOCF3 or OCOR12, R12 is H or alkyl of up to six carbons;
x ═ Cl, Br, or I;
the dotted line is a single or double bond;
wherein, the hydrogen donor is selected from one or a combination of more of hypophosphorous acid and hypophosphite, formic acid and formate, organic silicon hydride, hydrazine compounds or cyclohexene.
3. Process for the dehalogenation of 9-halo-steroids according to claim 1 or 2 wherein the hypophosphite salt is selected from sodium hypophosphite and/or potassium hypophosphite;
and/or, the organosilicon hydride is selected from triphenylsilanes;
and/or the formate is selected from one or a combination of more of sodium formate, potassium formate or ammonium formate;
and/or the hydrazine compound is selected from hydrazine and/or hydrazine hydrate.
4. The process for dehalogenation of 9-halo-steroids according to claim 1 or 2 wherein the azo-based free radical initiator is selected from one or a combination of azodiisobutyronitrile, azodiisoheptanonitrile, azoisobutyrylcyanecarboxamide, azodicyclohexylcarbonitrile, dimethyl azodiisobutyrate, azodiisobutyronitrile hydrochloride, azodiisopropylimidazoline hydrochloride or azodicyanopropionic acid.
5. A process according to claim 1 or 2 for the dehalogenation of 9-halo-steroidal compounds, characterised in that the molar ratio of compound I, azo-based radical initiator and hydrogen donor in the reaction is 1: (0.15-0.4): (1.5-3).
6. A process for the dehalogenation of 9-halo steroids according to claim 1 or 2 including the steps of: adding the compound I, a hydrogen donor and an azo free radical initiator into a solvent, and reacting at 40-90 ℃ to obtain a 9-bit dehalogenation product compound II of the 9-halogenated steroid compound.
7. The process of claim 6 wherein a base reagent is also added to the reaction.
8. The process for the dehalogenation of 9-halo-steroidal compounds according to claim 7, wherein the basic reagent is selected from organic and/or inorganic bases.
9. The process of claim 6, wherein the solvent is selected from the group consisting of C1-C6 alcohols, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, ethyl acetate, and mixtures thereof with water.
10. Use of the process for dehalogenation of 9-halo steroids according to any one of claims 1 to 9 in the manufacture of corticosteroids and intermediates therefor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019105814371 | 2019-06-29 | ||
| CN201910581437 | 2019-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112142813A true CN112142813A (en) | 2020-12-29 |
Family
ID=73891694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910652680.8A Pending CN112142813A (en) | 2019-06-29 | 2019-07-19 | Dehalogenation method and application of 9-halogenated steroid compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112142813A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112375114A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of prednisolone acetate |
| WO2024152955A1 (en) * | 2023-01-18 | 2024-07-25 | 奥锐特药业股份有限公司 | Dehalogenation method for 9-halogenated steroid compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746357A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Technology for synthesizing reduced steroid |
| CN109851653A (en) * | 2018-11-21 | 2019-06-07 | 奥锐特药业股份有限公司 | The preparation method of 16 alpha-hydroxy prednisonlones |
| CN111499677A (en) * | 2019-01-31 | 2020-08-07 | 奥锐特药业股份有限公司 | Preparation method of steroid hormone compound 9-position dehalogenation |
-
2019
- 2019-07-19 CN CN201910652680.8A patent/CN112142813A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746357A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Technology for synthesizing reduced steroid |
| CN109851653A (en) * | 2018-11-21 | 2019-06-07 | 奥锐特药业股份有限公司 | The preparation method of 16 alpha-hydroxy prednisonlones |
| CN111499677A (en) * | 2019-01-31 | 2020-08-07 | 奥锐特药业股份有限公司 | Preparation method of steroid hormone compound 9-position dehalogenation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112375114A (en) * | 2020-11-12 | 2021-02-19 | 湖南新合新生物医药有限公司 | Preparation method of prednisolone acetate |
| WO2024152955A1 (en) * | 2023-01-18 | 2024-07-25 | 奥锐特药业股份有限公司 | Dehalogenation method for 9-halogenated steroid compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112142813A (en) | Dehalogenation method and application of 9-halogenated steroid compound | |
| TWI753336B (en) | Process for the preparation of a diarylthiohydantoin compound | |
| KR101778603B1 (en) | METHOD FOR MAKING 3α-HYDROXY, 3β- METHYL-5α-PREGNAN-20-ONE (GANAXOLONE) | |
| JP5639895B2 (en) | Stereoselective reduction method | |
| CN107266514A (en) | Method for producing E4 intermediate | |
| WO2021175296A1 (en) | Intermediate of remdesivir and preparation method therefor | |
| SG172951A1 (en) | Method for manufacturing a boronic acid ester compound | |
| CN113767096B (en) | Preparation method of 6-substituted aminobenzofuran compound | |
| Srivastava et al. | OF IMIDAZO [4, 5-C] PYRAZOLE-2-THIONE-N-NUCLEOSIDES | |
| CN103965089A (en) | Stereselective synthesis method for lipid-lowering drug ezetimibe | |
| TW202009232A (en) | Compound of pyrrole fused aminopyridazinone, and manufacturing method and intermediate thereof | |
| JP2011001372A (en) | Inosine derivative and process for producing the same | |
| EP3199532A1 (en) | Intermediate for the synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione | |
| WO2016088094A1 (en) | Process for the preparation of baricitinib and an intermediate thereof | |
| CN111094274A (en) | Preparation method and intermediate of pyrroloaminopyridazinone compound | |
| Kitamura et al. | Synthesis of Diazonaphthoquinones from Naphthols by Diazo-Transfer Reaction | |
| CN112375068A (en) | Terminal alkenyl indole derivative and preparation method thereof | |
| CN110041202B (en) | Preparation method of 1, 8-disubstituted naphthalene mononitration derivative | |
| CN102850390B (en) | Intermediate of ezetimibe and its preparation method | |
| CN113121438A (en) | Preparation method of isoquinolone compound | |
| CN105566235B (en) | The method of the substep synthesis triazoles of NH 1,2,3 is catalyzed using aluminium salt | |
| KR20200061058A (en) | Method for producing bisfluorosulfonyl imide alkali metal salt and bisfluorosulfonyl imide alkali metal salt produced by same | |
| CN106977569A (en) | The preparation method of the α hydroxyprogesterone acetates of 6 methylene 17 | |
| CN114524800A (en) | Synthesis method of nilapanib intermediate | |
| CN102964336A (en) | Refining method of proton pump inhibitor and reducing method of N-oxide of proton pump inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |