CN117924397A - Preparation process and application of diflorasone acetate and derivatives thereof - Google Patents
Preparation process and application of diflorasone acetate and derivatives thereof Download PDFInfo
- Publication number
- CN117924397A CN117924397A CN202410072191.6A CN202410072191A CN117924397A CN 117924397 A CN117924397 A CN 117924397A CN 202410072191 A CN202410072191 A CN 202410072191A CN 117924397 A CN117924397 A CN 117924397A
- Authority
- CN
- China
- Prior art keywords
- kettle
- derivatives
- acetate
- reaction
- mass ratio
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 229960004154 diflorasone Drugs 0.000 title claims abstract description 37
- WXURHACBFYSXBI-XHIJKXOTSA-N diflorasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-XHIJKXOTSA-N 0.000 title claims abstract description 37
- 230000032050 esterification Effects 0.000 claims abstract description 29
- 238000005886 esterification reaction Methods 0.000 claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 claims abstract description 21
- 239000004593 Epoxy Substances 0.000 claims abstract description 19
- 239000000413 hydrolysate Substances 0.000 claims abstract description 19
- 229960002537 betamethasone Drugs 0.000 claims abstract description 18
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims abstract description 18
- 238000007670 refining Methods 0.000 claims abstract description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 28
- 239000012043 crude product Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 20
- 239000012025 fluorinating agent Substances 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 238000004321 preservation Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 239000012065 filter cake Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical group CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 238000005187 foaming Methods 0.000 claims description 7
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 claims description 5
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 2
- 238000013329 compounding Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 abstract description 23
- 229960000616 diflunisal Drugs 0.000 abstract description 23
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 230000001276 controlling effect Effects 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229960003957 dexamethasone Drugs 0.000 description 6
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 230000006203 ethylation Effects 0.000 description 2
- 238000006200 ethylation reaction Methods 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- ZGMNAIODRDOMEK-UHFFFAOYSA-N 1,1,1-trimethoxypropane Chemical compound CCC(OC)(OC)OC ZGMNAIODRDOMEK-UHFFFAOYSA-N 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- LXHKBFMMWHZQBY-UHFFFAOYSA-N pyrimidine;hydrofluoride Chemical compound F.C1=CN=CN=C1 LXHKBFMMWHZQBY-UHFFFAOYSA-N 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- -1 steroid compounds Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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
- C07J5/0061—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The application relates to the field of medicinal compounds, in particular to a preparation process and application of diflorasone acetate and derivatives thereof. The preparation process of the diflorasone acetate and the derivatives thereof at least comprises the steps of esterification, fluorination, hydrolysis, esterification and refining by taking betamethasone epoxy hydrolysate as an initial raw material in sequence. The application provides a novel preparation process of the diflunisal acetate and the derivatives thereof, which is different from the existing preparation process of the diflunisal acetate and the derivatives thereof, provides a new thought and way for the diflunisal acetate, is beneficial to reducing the production cost of manufacturers and improving the production efficiency, and has very excellent market prospect.
Description
Technical Field
The invention relates to the field of medicinal compounds, in particular to a preparation process and application of diflorasone acetate and derivatives thereof.
Background
Corticoids (i.e., steroids) have remarkable therapeutic effects on a large number of skin diseases such as atopic dermatitis, eczema and dermatitis, urticaria, etc., and psoriasis, and are widely used clinically as external drugs. The diflorasone acetate is used as an anti-inflammatory steroid compound commonly used in recent years and is mainly applied to skin diseases such as eczema, chronic discoid lupus erythematosus, hypertrophic scars, alopecia areata and the like.
The existing preparation of the diflora acetate is carried out by referring to the patent PH14703A, but the preparation method and the unstable factors in the technical process are more, the reaction is unstable, the yield and the purity of the product are low, and the stable large-scale stable production cannot be realized.
Therefore, in order to solve the problems, the application provides a novel preparation process of the diflorasone acetate and the derivatives thereof, which has stable preparation process, obviously improved yield and purity of the final product and is suitable for stable mass production.
Disclosure of Invention
In order to solve the above problems, the first aspect of the present invention provides a process for preparing diflorasone acetate and derivatives thereof, which at least comprises the steps of esterification-fluorination, fluorination-hydrolysis, esterification and refining sequentially using betamethasone epoxy hydrolysate as an initial raw material.
As a preferred embodiment, the esterification-fluorination step is:
S1: adding the betamethasone epoxy hydrolysate and the esterification auxiliary agent into a reaction kettle in a compounding way, heating to 50-70 ℃, carrying out heat preservation reaction for 2-5 h, dropwise adding triethylamine, and then carrying out heat preservation for 10-30 min at 55-65 ℃;
S2: concentrating the feed liquid under reduced pressure to obtain oily matter, dissolving and transferring the oily matter into a reaction kettle by acetonitrile, cooling to ensure that the temperature in the kettle is reduced to-20-10 ℃;
S3: adding a fluorinating agent 1 into a reaction kettle, controlling the temperature to be minus 20-10 ℃ in the kettle after the material feeding is finished, adding purified water into the reaction kettle after the reaction is finished, controlling the temperature to be minus 20-10 ℃, preserving heat and stirring for more than 0.5h, transferring the material liquid to a filter for filtering, washing a filter cake with the purified water, collecting the filter cake, and drying the filter cake to obtain an intermediate 1.
As a preferable scheme, the esterification auxiliary agent is isopropenyl acetate and p-toluenesulfonic acid, and the mass ratio of the isopropenyl acetate to the p-toluenesulfonic acid is 28-40: 0.1 to 1; the fluorinating agent 1 is at least one of F-TEDA-BF4 and hydrogen fluoride pyridine.
As a preferred embodiment, the fluorinating agent 1 is F-TEDA-BF4.
As a preferable scheme, the mass ratio of the betamethasone epoxy hydrolysate to the isopropenyl acetate to the p-toluenesulfonic acid is 3-6: 28-40: 0.1 to 0.4; the mass ratio of the betamethasone epoxy hydrolysate to the fluorinating agent 1 is 3-6: 4 to 6.5.
As a preferable scheme, the mass ratio of the acetonitrile to the betamethasone epoxy hydrolysate is 24-40: 3 to 6.
As a preferred embodiment, the fluorination-hydrolysis step is:
S4: adding a fluorinating agent 2 into a reaction kettle, cooling to enable the temperature in the kettle to be reduced to minus 20-10 ℃, adding an intermediate 1 (formula II) through a feed port, and carrying out heat preservation and stirring reaction until the reaction is finished; after the reaction is finished, adding dichloromethane through a feed inlet, and dripping a pH regulator to regulate the pH to 4-6;
s5: after the dripping is finished, stirring and layering, and concentrating the organic phase under reduced pressure until no liquid flows out to obtain an intermediate 2-1; transferring the intermediate 2-1 (formula III) to a reaction kettle by using an organic solvent, controlling the temperature in the kettle to be 0-10 ℃, adding metal carbonate, preserving heat, stirring and reacting until the reaction is finished; after the reaction is finished, filtering the feed liquid in the kettle to a reaction kettle, and adding a pH regulator to adjust the pH to 6-8; concentrating the feed liquid to obtain yellow solid, pulping with water, filtering and drying to obtain crude intermediate 2;
S6: recrystallizing the crude product of the intermediate 2 in methanol, ethyl acetate or dichloromethane, filtering and drying to obtain the intermediate 2 (formula IV).
As a preferable scheme, the fluorinating agent 2 is at least one of F-TEDA-BF4 and hydrogen fluoride pyridine; the mass ratio of the intermediate 1 to the fluorinating agent 2 is 1: 4-6, wherein the mass ratio of the dichloromethane to the intermediate 1 is 3-5: 1, a step of; the mass ratio of the methanol to the intermediate 1 is 3-5: 1, a step of; the metal carbonate is at least one of potassium carbonate and sodium carbonate; the mass ratio of the metal carbonate to the intermediate 1 is 0.1-0.5: 1.
As a preferred embodiment, the fluorinating agent 2 is hydrogen fluoride pyridine.
As a preferable scheme, the mass ratio of the crude product of the intermediate 2, methanol and ethyl acetate is 1:0.1 to 0.3:1.6 to 2.
As a preferable scheme, the mass ratio of the crude product of the intermediate 2, methanol and ethyl acetate is 1:0.2:1.8.
As a preferable embodiment, the pH adjuster is any one of potassium hydroxide, citric acid monohydrate, ammonia water, and potassium citrate.
As a preferred embodiment, the esterification comprises 17-position esterification and 21-position esterification.
As a preferable scheme, the 17-position esterification step is as follows:
S7: adding the intermediate 2, trimethyl orthoacetate into a reaction kettle, controlling the temperature in the kettle to be less than or equal to 15 ℃, dropwise adding concentrated sulfuric acid, controlling the temperature in the kettle to be 10-30 ℃, and keeping the temperature and stirring to react completely; then controlling the internal temperature of the reaction kettle to be 10-30 ℃, dripping purified water, crystallizing and drying to obtain a crude product of the intermediate 3; adding the crude product of the intermediate 3 and methanol or ethyl acetate or ethanol into a reaction kettle, crystallizing, filtering and drying to obtain the intermediate 3 (formula V).
As a preferable scheme, the 21-position esterification step is as follows:
The 21-bit esterification step comprises the following steps:
s8: adding the intermediate 3 and acetone into a reaction kettle, after materials in the kettle are completely dissolved, sequentially adding acetic anhydride and potassium carbonate into the kettle, controlling the temperature in the kettle to be 20-30 ℃, carrying out heat preservation and stirring reaction until the reaction is finished, filtering, collecting filtrate, concentrating under reduced pressure to obtain a foaming solid, adding the foaming solid into the reaction kettle, adding ethanol or methanol for crystallization and drying to obtain a crude product (formula VI).
As a preferred scheme, the mass ratio of the intermediate 2 to trimethyl orthoacetate is 1:3 to 5; the mass ratio of the intermediate 3 to the acetone is 1:4 to 6.
As a preferred scheme, the mass ratio of the intermediate 2 to trimethyl orthoacetate and sulfuric acid is 1:3 to 5:0.07 to 0.15; the mass ratio of the intermediate 3 to the acetone, the acetic anhydride and the potassium carbonate is 1:4 to 6:0.27 to 0.75:0.37 to 0.65.
As a preferred scheme, the mass ratio of the intermediate 2 to trimethyl orthoacetate is 1:5, a step of; the mass ratio of the intermediate 3 to the acetone is 1:5.
As a preferred embodiment, the metal carbonate is potassium carbonate.
As a preferable scheme, the mass ratio of the crude product to the ethanol in the S8 is 1:5 to 8.
As a preferable scheme, the mass ratio of the crude product to methanol in S8 is 1:5 to 8.
As a preferable scheme, the refining step is as follows:
S9: and (3) putting the crude product into a reaction kettle, adding a refining solvent, recrystallizing and drying to obtain a finished product of diflorasone acetate (formula VI).
As a preferred embodiment, the refining solvent is at least one of ethanol or acetone methanol or acetone ethanol or acetone water.
As a preferable scheme, the acetone-methanol is a mixture of acetone and methanol, and the mass ratio is 1-4:6-9; the acetone-ethanol is a mixture of acetone and ethanol, and the mass ratio is 1-4:6-9; the acetone water is an acetone-water mixture, and the mass ratio is 5-8:2-5;
As a preferable scheme, the mass ratio of the refining solvent to the crude product is 6-9: 1 (ethanol); 4-8: 1 (acetone methanol); 4-8: 1 (acetone ethanol); 4-8: 1 (acetone water).
In some preferred embodiments, the process for preparing diflunisal acetate and derivatives thereof comprises a process for preparing dexamethasone, diflunisal acetate and derivatives thereof.
As a preferable scheme, the preparation method of the dexamethasone, the diflunisal acetate and the derivatives thereof comprises the steps of esterifying the formula I at the 21-position, fluorinating the 6-position, fluorinating the 9-position and hydrolyzing to form the formula IV (such as the diflunisal and the diflunisal), esterifying the formula IV at the 17-position and esterifying the formula I at the 21-position to form the formula VI (such as the diflunisal acetate and the diflunisal dipropionate); or formula I may be directly fluorinated to give formula VII (e.g., dexamethasone).
Wherein R 1 can be a (C1-C4) alkyl group, such as an alpha or beta methyl group; wherein R 2、R3 can be H or C (O) -R 4 alkyl, wherein R 4 can be (C1-C4) alkyl, aryl, heteroaryl; r 2、R3 may be the same or different.
The correlation is as follows:
The reaction general formula 1 is:
as a preferred scheme, the preparation method of the diflorasone and the diflorasone comprises the following steps:
; wherein R 1 is beta methyl, and the preparation method is carried out in steps 1, 2-1 and 2-2 (without carrying out the subsequent steps 3-5 in the general formula 1) according to the process; wherein R 1 is alpha methyl, and the preparation method is carried out completely according to the process steps 1, 2-1 and 2-2 (without carrying out the subsequent steps 3-5 in the general formula 1).
As a preferable scheme, the preparation method of the diflunisal acetate and diflunisal dipropionate comprises the following steps:
; when R 1 is beta methyl and R 2、R3 is acetyl, the preparation method is to prepare diflorasone acetate by using acetic acid, trimethyl orthoacetate and acetic anhydride reagent when 17-position esterification is carried out in the step 3 and using acetic acid and acetic anhydride reagent when 21-position esterification is carried out in the step 4; preparing diflunisal dipropionate when R 1 is beta methyl and R 2、R3 is propionyl in the general formula; the preparation method is carried out completely according to the general formula 1, but the ethylation reagent in the steps 3 and 4 for preparing the diflorasone acetate is replaced by a propyl esterification reagent, namely trimethyl orthopropionate, propionic acid and propionic anhydride reagent are used in the step 3 for 17-position esterification, and propionic acid and propionic anhydride reagent are used in the step 4 for 21-position esterification, so as to prepare the diflorasone dipropionate.
As a preferred scheme, the preparation method of dexamethasone comprises the following steps:
betamethasone epoxy hydrolysate was directly subjected to step 2-1 (step 1 and steps 2-2, 3, 4, 5 were not performed) to prepare dexamethasone.
The second aspect of the invention provides an application of the preparation process of the diflunisal acetate and the derivatives thereof, comprising an application of the preparation process of the diflunisal acetate and the derivatives thereof in the preparation process of steroid skin drug compounds.
The beneficial effects are that:
1. The application provides a novel preparation process of the diflunisal acetate and the derivatives thereof, which is different from the existing preparation process of the diflunisal acetate and the derivatives thereof, provides a new thought and way for the diflunisal acetate, is beneficial to reducing the production cost of manufacturers and improving the production efficiency, and has very excellent market prospect.
2. The application provides a novel preparation process of diflunisal acetate and derivatives thereof, which is characterized in that the diflunisal acetate is finally prepared through the steps of esterification, fluorination-hydrolysis, esterification and refining by taking betamethasone epoxy hydrolysate as an initial raw material.
3. Compared with the existing diflunisal acetate process, the novel preparation process for the diflunisal acetate and the derivatives thereof has a more stable intermediate reaction process, and the yield of reaction products in the intermediate process is higher, so that the final yield is improved.
4. The application provides a novel preparation process of the diflora acetate and the derivatives thereof, which ensures the purity of the products in each process flow and finally ensures that the diflora acetate product has higher product purity through the multistage refining and impurity removing processes in the process.
5. The application provides a novel preparation process of diflorasone acetate and derivatives thereof, wherein corresponding process steps can be respectively and correspondingly applied to preparation processes of other steroid compounds, an alternative scheme is provided for the novel preparation process, and the novel preparation process is beneficial to improving the production efficiency and purity of corresponding products.
Detailed Description
The expressions concerning parts appearing in the following examples and comparative examples are all referred to in parts by mass.
Example 1
Embodiment 1 provides a process for preparing diflorasone acetate and derivatives thereof, comprising the steps of esterification-fluorination, fluorination-hydrolysis, esterification and refining sequentially by taking betamethasone epoxy hydrolysate as an initial raw material.
The method comprises the following specific steps (in parts by mass):
S1: 4 parts of betamethasone epoxy hydrolysate and 40 parts of isopropenyl acetate are mixed, added into a reaction kettle, heated to 60 ℃, reacted for 4 hours under heat preservation, 0.5 part of triethylamine is added dropwise, and then the temperature is kept at 60 ℃ for 15 minutes.
S2: the feed solution was then transferred to a concentrating apparatus, concentrated under reduced pressure until substantially no liquid flowed out to give an oil, which was dissolved with 32 parts of acetonitrile and transferred to a reaction vessel, and cooled to-5 ℃.
S3: 5.7 parts of fluorinating agent 1 (F-TEDA-BF 4) is put into a reaction kettle, the temperature is controlled to be minus 5 ℃, the temperature in the kettle is controlled to be minus 5 ℃ after the material feeding is finished, 30 parts of purified water is added into the reaction kettle for crystallization and filtration after the reaction is finished, 4 parts of purified water is used for washing a filter cake, the filter cake is collected, and 3.25 parts of intermediate is obtained after drying.
S4: 14 parts of fluorinating agent 2 (hydrogen fluoride pyridine) is added into a reaction kettle, and the temperature is reduced to minus 15 ℃; the internal temperature of the tank is controlled at minus 15 ℃, 1.25 parts of intermediate is put into the tank through a feed inlet, and the tank is stirred and reacted under heat preservation until the reaction is qualified. After the reaction, 12 parts of methylene chloride was added through a feed port, and the temperature in the tank was controlled at 5℃and a pH adjustor (20 wt% aqueous potassium hydroxide solution) was added dropwise to adjust the pH to 4.5.
S5: after the dripping is finished, stirring and layering, collecting a lower organic phase, and concentrating the organic phase under reduced pressure to obtain an intermediate 2-1; adding 14.5 parts of organic solvent (methanol), controlling the temperature in a kettle to be 5 ℃, adding 0.5 part of metal carbonate (potassium carbonate), and carrying out heat preservation and stirring reaction until the reaction is qualified; after the reaction is finished, filtering the feed liquid in the kettle, adding the feed liquid into the reaction kettle, adding a pH regulator (citric acid), and regulating the pH to 6.5; the feed liquid is decompressed and concentrated to obtain yellow solid, 12 parts of water is used for pulping, filtering and drying are carried out to obtain 2.5 parts of crude intermediate 2.
S6: recrystallizing the crude product of the intermediate 2 in methanol, collecting a filter cake, and drying to obtain 1.78 parts of the intermediate 2.
S7: adding 2.8 parts of intermediate and 8 parts of trimethyl orthoacetate into a reaction kettle, controlling the temperature in the kettle to be 10-15 ℃, dropwise adding 0.20 part of concentrated sulfuric acid, controlling the temperature in the kettle to be 25 ℃, keeping the temperature, stirring and reacting to be complete, dropwise adding 17.8 parts of purified water, crystallizing and drying to obtain 1.76 parts of intermediate 3 crude product.
1.76 Parts of crude intermediate 3 and 3.52 parts of methanol are added into a reaction kettle, and crystallization and drying are carried out to obtain 1.13 parts of intermediate 3.
S8: 31.1 parts of intermediate and 6 parts of acetone are added into a reaction kettle, after materials in the kettle are completely dissolved, 0.7 part of acetic anhydride and 0.45 part of metal carbonate (potassium carbonate) are sequentially added into the kettle, the temperature in the kettle is controlled at 25 ℃, the reaction is carried out under the condition of heat preservation and stirring until the reaction is qualified, the filtration is carried out, the filtrate is collected, the filtrate is concentrated under reduced pressure to obtain foaming solid, 7 parts of ethanol is added, and the crystallization and the drying are carried out to obtain 0.9 part of crude product.
S9, adding 0.9 part of crude product into a reaction kettle, adding 7 parts of acetone/water (the mass ratio is 6/4), recrystallizing and drying to obtain 0.72 part of finished product of diflorasone acetate.
In this example, betamethasone epoxy hydrolysate was purchased from the Hunan Yunew pharmaceutical Co., ltd.
In this example, F-TEDA-BF4 was purchased from Jiangxi Corp pharmaceutical technology Co., ltd.
In this example, the hydrogen fluoride pyrimidine was purchased from Suzhou Ku New materials Co., ltd.
Example 2
The specific implementation of this example is the same as example 1, except that:
S4: 14 parts of fluorinating agent 2 (hydrogen fluoride pyridine) is added into a reaction kettle, and the temperature is reduced to minus 15 ℃; 3.25 parts of intermediate is put into the tank through a feed port at the temperature of-15 ℃, and the tank is stirred for reaction under heat preservation.
S8: 31.1 parts of intermediate and 4.5 parts of acetone are added into a reaction kettle, and after materials in the kettle are completely dissolved, 0.72 part of acetic anhydride and 0.62 part of metal carbonate (potassium carbonate) are sequentially added into the kettle.
S9, adding 0.9 part of crude product into a reaction kettle, adding 5 parts of acetone/methanol (mass ratio of 45/55), recrystallizing and drying to obtain 0.72 part of finished product of diflorasone acetate.
Comparative example 1
The specific implementation of this example is the same as example 1, except that:
s8: 31.1 parts of intermediate and 6.6 parts of acetone are added into a reaction kettle, after materials in the kettle are completely dissolved, 0.66 parts of acetic anhydride and 0.65 parts of metal carbonate (sodium carbonate) are added into the kettle in sequence,
S8: to obtain foaming solid, and put it into a reaction bottle, add 6.6 parts of ethanol, crystallize and dry to obtain 0.8 parts of crude product.
Comparative example 2
The specific embodiment of this comparative example is the same as example 1, except that:
S3: 4.95 parts of fluorinating agent 1 (F-TEDA-BF 4) is put into the reaction kettle, the temperature is controlled to be minus 5 ℃, and after the material feeding is finished, the temperature in the kettle is controlled to be 20 ℃.
S4: 14 parts of fluorinating agent 2 (hydrogen fluoride pyridine) is added into a reaction kettle, and the temperature is reduced to minus 15 ℃; the internal temperature of the tank is controlled at 20 ℃.
Comparative example 3
The specific embodiment of this comparative example is the same as example 1, except that:
s8: and (3) adding 0.9 part of crude product into a reaction kettle, adding 5.4 parts of methanol, recrystallizing and drying to obtain 0.5 part of finished product of diflorasone acetate.
Examples of derivatives are specifically as follows:
examples of diflorasone preparation:
Preparation of diflorasone according to S1-S6 of example 1;
examples of preparation of diflumetone:
The specific implementation of this example is the same as S1 to S6 of example 1, except that:
s1: replacing betamethasone epoxy hydrolysate with 9 beta, 11 beta-epoxy-16 beta-methyl pregna-1, 4-diene-17 alpha, 21-diol-3, 20-dione;
dexamethasone preparation example:
The specific implementation manner of the embodiment is as follows: directly carrying out S4-S6 step experiments on betamethasone epoxy hydrolysate:
S4: 13 parts of fluorinating agent 2 (hydrogen fluoride pyridine) is added into a reaction kettle, and the temperature is reduced to minus 15 ℃; 3.2 parts of epoxy hydrolysate is added through a feed port by controlling the internal temperature of the tank at-15 ℃, and the reaction is carried out under the condition of heat preservation and stirring until the reaction is qualified. After the reaction, 12 parts of methylene chloride was added through a feed port, and the temperature in the tank was controlled at 5℃and a pH adjustor (20 wt% aqueous potassium hydroxide solution) was added dropwise to adjust the pH to 4.5.
S5: after the dripping is finished, stirring and layering, collecting a lower organic phase, and concentrating the organic phase under reduced pressure to obtain an intermediate 2-1; adding 14.5 parts of organic solvent (methanol), controlling the temperature in a kettle to be 5 ℃, adding 0.5 part of metal carbonate (potassium carbonate), and carrying out heat preservation and stirring reaction until the reaction is qualified; after the reaction is finished, filtering the feed liquid in the kettle, adding the feed liquid into the reaction kettle, adding a pH regulator (citric acid), and regulating the pH to 6.5; the feed liquid is decompressed and concentrated to obtain yellow solid, 12 parts of water is used for pulping, filtering and drying are carried out to obtain 2.5 parts of crude intermediate 2.
S6: recrystallizing the crude product of the intermediate 2 in methanol, collecting a filter cake, and drying to obtain 21.78 parts of intermediate.
Examples of preparation of diflunisal dipropionate:
the specific implementation of this example is the same as example 1, except that:
The preparation of diflorasone dipropionate is carried out exactly according to formula 1, but with the need to replace the ethylation reagent with a propyl esterification reagent.
S7: adding 1.8 parts of intermediate 2 and 9 parts of trimethyl orthoacetate into a reaction kettle, controlling the temperature in the kettle to be 10-15 ℃, dropwise adding 0.25 part of concentrated sulfuric acid, controlling the temperature in the kettle to be 25 ℃, keeping the temperature, stirring and reacting to be complete, dropwise adding 17.8 parts of purified water, crystallizing and drying to obtain 1.77 parts of intermediate 3 crude product.
1.76 Parts of crude intermediate 3 and 3.52 parts of methanol are added into a reaction kettle, and crystallization and drying are carried out to obtain 31.13 parts of intermediate.
S8: 31.1 parts of intermediate and 6 parts of acetone are added into a reaction kettle, after materials in the kettle are completely dissolved, 0.75 part of propionic anhydride and 0.55 part of metal carbonate (potassium carbonate) are sequentially added into the kettle, the temperature in the kettle is controlled at 25 ℃, the reaction is carried out under the condition of heat preservation and stirring until the reaction is qualified, the filtration is carried out, the filtrate is collected, the filtrate is concentrated under reduced pressure to obtain foaming solid, 7 parts of ethanol is added, and the crystallization and the drying are carried out to obtain 0.9 part of crude product.
Evaluation of Performance
Product yield (%): the final product yields of the products obtained for each example and comparative example were tested, 5 samples were tested for each example and comparative example, and the average of the values measured are reported in Table 1.
Purity (%) of product: the final product purity of the products obtained for each example and comparative example was tested, 5 samples were tested for each example comparative example, and the average of the values measured is reported in table 1.
The data during the reaction are recorded in table 2.
TABLE 1
Examples | Yield (%) | Purity (%) |
Example 1 | 14% | 99.9% |
Example 2 | 10% | 99.9% |
Comparative example 1 | 11% | 99.0% |
Comparative example 2 | 7% | 98.5% |
Comparative example 3 | 8% | 99.7% |
TABLE 2
Claims (13)
1. A preparation process of diflorasone acetate and derivatives thereof is characterized in that: the method at least sequentially comprises the steps of esterification, fluorination, hydrolysis, esterification and refining by taking betamethasone epoxy hydrolysate as an initial raw material.
2. The process for preparing diflorasone acetate and derivatives thereof according to claim 1, wherein the process comprises the steps of: the esterification-fluorination step is as follows:
S1: adding the betamethasone epoxy hydrolysate and the esterification auxiliary agent into a reaction kettle in a compounding way, heating to 50-70 ℃, carrying out heat preservation reaction for 2-5 h, dropwise adding triethylamine, and then carrying out heat preservation for 10-30 min at 55-65 ℃;
S2: concentrating the feed liquid under reduced pressure to obtain oily matter, dissolving and transferring the oily matter into a reaction kettle by acetonitrile, cooling to ensure that the temperature in the kettle is reduced to-20-10 ℃;
S3: adding a fluorinating agent 1 into a reaction kettle, controlling the temperature to be minus 20-10 ℃ in the kettle after the material feeding is finished, adding purified water into the reaction kettle after the reaction is finished, controlling the temperature to be minus 20-10 ℃, preserving heat and stirring for more than 0.5h, transferring the material liquid to a filter for filtering, washing a filter cake with the purified water, collecting the filter cake, and drying the filter cake to obtain an intermediate 1.
3. The process for preparing diflorasone acetate and derivatives thereof according to claim 2, wherein the process comprises the steps of: the esterification auxiliary agent is isopropenyl acetate and p-toluenesulfonic acid, and the mass ratio of the isopropenyl acetate to the p-toluenesulfonic acid is 28-40: 0.1 to 0.4; the fluorinating agent 1 is at least one of F-TEDA-BF4 and hydrogen fluoride pyridine.
4. A process for the preparation of diflorasone acetate and derivatives thereof according to claim 3 wherein: the mass ratio of the betamethasone epoxy hydrolysate to the isopropenyl acetate to the p-toluenesulfonic acid is 3-6: 28-40: 0.1 to 0.4; the mass ratio of the betamethasone epoxy hydrolysate to the fluorinating agent 1 is 3-6: 4 to 6.5.
5. The process for preparing diflorasone acetate and derivatives thereof according to claim 2, wherein the process comprises the steps of: the mass ratio of the acetonitrile to the betamethasone epoxy hydrolysate is 24-40: 3 to 6.
6. The process for preparing diflorasone acetate and derivatives thereof according to claim 1, wherein the process comprises the steps of: the fluorination-hydrolysis step is:
S4: adding a fluorinating agent 2 into a reaction kettle, cooling to enable the temperature in the kettle to be reduced to minus 20-10 ℃, adding the intermediate 1 through a feed port, and carrying out heat preservation and stirring reaction until the reaction is finished; after the reaction is finished, adding dichloromethane through a feed inlet, and dripping a pH regulator to regulate the pH to 4-6;
S5: after the dripping is finished, stirring and layering, and concentrating the organic phase under reduced pressure until no liquid flows out to obtain an intermediate 2-1; transferring the intermediate 2-1 to a reaction kettle by using an organic solvent, controlling the temperature in the kettle to be 0-10 ℃, adding metal carbonate, preserving heat, stirring and reacting until the reaction is finished; after the reaction is finished, filtering the feed liquid in the kettle to a reaction kettle, and adding a pH regulator to adjust the pH to 6-8; concentrating the feed liquid to obtain yellow solid, pulping with water, filtering and drying to obtain crude intermediate 2;
s6: recrystallizing the crude product of the intermediate 2 in methanol, ethyl acetate or dichloromethane, filtering and drying to obtain the intermediate 2.
7. The process for preparing diflorasone acetate and derivatives thereof of claim 6 wherein the process comprises the steps of: the fluorinating agent 2 is at least one of F-TEDA-BF4 and hydrogen fluoride pyridine; the mass ratio of the intermediate 1 to the fluorinating agent 2 is 1: 4-6, wherein the mass ratio of the dichloromethane to the intermediate 1 is 3-5: 1, a step of; the mass ratio of the methanol to the intermediate 1 is 3-5: 1, a step of; the metal carbonate is at least one of potassium carbonate and sodium carbonate; the mass ratio of the metal carbonate to the intermediate 1 is 0.1-0.5: 1.
8. The process for preparing diflorasone acetate and derivatives thereof of claim 6 wherein the process comprises the steps of: the pH regulator is any one of potassium hydroxide, citric acid monohydrate, ammonia water and potassium citrate.
9. The process for preparing diflorasone acetate and derivatives thereof according to claim 1, wherein the process comprises the steps of: the esterification includes 17-position esterification and 21-position esterification;
The 17-bit esterification step comprises the following steps:
S7: adding the intermediate 2, trimethyl orthoacetate into a reaction kettle, controlling the temperature in the kettle to be less than or equal to 15 ℃, dropwise adding concentrated sulfuric acid, controlling the temperature in the kettle to be 10-30 ℃, and keeping the temperature and stirring to react completely; then controlling the internal temperature of the reaction kettle to be 10-30 ℃, dripping purified water, crystallizing and drying to obtain a crude product of the intermediate 3; adding the crude product of the intermediate 3 and methanol or ethyl acetate or ethanol into a reaction kettle, crystallizing, filtering and drying to obtain the intermediate 3;
The 21-bit esterification step comprises the following steps:
S8: adding the intermediate 3 and acetone into a reaction kettle, after materials in the kettle are completely dissolved, sequentially adding acetic anhydride and metal carbonate into the kettle, controlling the temperature in the kettle to be 20-30 ℃, carrying out heat preservation and stirring reaction until the reaction is finished, filtering, collecting filtrate, concentrating under reduced pressure to obtain a foaming solid, adding the foaming solid into the reaction kettle, adding ethanol or methanol for crystallization and drying to obtain a crude product.
10. The process for preparing diflorasone acetate and derivatives thereof according to claim 9 wherein the process comprises the steps of: the mass ratio of the intermediate 2 to trimethyl orthoacetate to sulfuric acid is 1:3 to 5:0.07 to 0.15; the mass ratio of the intermediate 3 to the acetone, the acetic anhydride and the metal carbonate is 1:4 to 6:0.27 to 0.75:0.37 to 0.65.
11. The process for preparing diflorasone acetate and derivatives thereof according to claim 1, wherein the process comprises the steps of: the refining steps are as follows:
s9: adding the crude product into a reaction kettle, adding a refining solvent, recrystallizing, filtering and drying to obtain a finished product of diflorasone acetate;
The refining solvent is at least one of ethanol or acetone methanol or acetone ethanol or acetone water.
12. The process for preparing diflorasone acetate and derivatives thereof according to claim 11 wherein the process comprises the steps of: the acetone-methanol is a mixture of acetone and methanol, and the mass ratio is 1-4:6-9; the acetone-ethanol is a mixture of acetone and ethanol, and the mass ratio is 1-4:6-9; the acetone water is an acetone-water mixture, and the mass ratio is 5-8:2-5; the mass ratio of the refining solvent to the crude product is 6-9: 1.
13. Use of a process for the preparation of diflorasone acetate and derivatives thereof according to any one of claims 1 to 12 characterized in that: comprises the application of the preparation process of the diflorasone acetate and the derivatives thereof in the preparation process of steroid skin drug compounds.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410072191.6A CN117924397A (en) | 2024-01-18 | 2024-01-18 | Preparation process and application of diflorasone acetate and derivatives thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410072191.6A CN117924397A (en) | 2024-01-18 | 2024-01-18 | Preparation process and application of diflorasone acetate and derivatives thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117924397A true CN117924397A (en) | 2024-04-26 |
Family
ID=90753262
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410072191.6A Pending CN117924397A (en) | 2024-01-18 | 2024-01-18 | Preparation process and application of diflorasone acetate and derivatives thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117924397A (en) |
-
2024
- 2024-01-18 CN CN202410072191.6A patent/CN117924397A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108373492B (en) | Preparation method of cortisone acetate | |
CN115011661B (en) | Synthesis method of 3 beta-ursodeoxycholic acid | |
CN111253457A (en) | Method for preparing 16 α -hydroxy prednisolone | |
CN117924397A (en) | Preparation process and application of diflorasone acetate and derivatives thereof | |
CN114276406B (en) | Preparation method of intermediate of deoxomilpine | |
CN112125943A (en) | Preparation method of high-purity 16 alpha-hydroxy prednisolone | |
CN114195844B (en) | Preparation method of dehydroepiandrosterone | |
CN111944004B (en) | Preparation method of halominosone | |
CN114478681B (en) | Preparation method of triamcinolone acetonide | |
CN115073546A (en) | Preparation method of novel androgen receptor inhibitor | |
CN112390843B (en) | Preparation method of high-yield spironolactone refined product | |
CN107814824B (en) | Preparation method of tetraene acetate | |
CN113024622A (en) | Process for continuously producing steroid hydroxyl bromide | |
CN114213494B (en) | Paramethosone acetate and preparation method of Paramethosone | |
EP2044098B1 (en) | Process for the preparation of 6-alpha ,9-alpha-difluoro-17-alpha - ((2-furanylcarbonyl)oxy)-11-beta -hydroxy-16-alpha -methyl-3-oxo-androsta-1,4-diene-17-beta- -carbothioic acid s-fluoromethyl ester | |
CN115785188B (en) | Preparation method of budesonide | |
CN112079894B (en) | Preparation method of Levonorgestrel pharmacopoeia impurity V | |
CN115109111B (en) | Production process of progestogen | |
CN113512085B (en) | Preparation method of mometasone furoate | |
CN113201038B (en) | Method for reducing erythromycin thiocyanate solvent residue | |
CN116768961A (en) | Preparation method of fluocinolone acetonide | |
CN112225776A (en) | Preparation method of betamethasone epoxy hydrolysate impurity | |
CN113637043A (en) | Preparation method of 5 alpha-androst-2-ene-17 ketone | |
CN115466295A (en) | Crystallization process for improving crystal form of daunorubicin hydrochloride | |
CN113698448A (en) | Preparation method of amcinonide |
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 |