CN109651477B - Method for preparing dehydrogenated intermediate product for alclometasone dipropionate - Google Patents
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- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 title claims abstract description 38
- 229960004229 alclometasone dipropionate Drugs 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 28
- 239000013067 intermediate product Substances 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 121
- 239000000047 product Substances 0.000 claims abstract description 53
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000012043 crude product Substances 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 17
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 16
- 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 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 230000032050 esterification Effects 0.000 claims abstract description 9
- 238000007670 refining Methods 0.000 claims abstract description 7
- 125000005594 diketone group Chemical group 0.000 claims abstract description 6
- 238000006266 etherification reaction Methods 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000005837 enolization reaction Methods 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims description 92
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- 239000000376 reactant Substances 0.000 claims description 52
- 239000003377 acid catalyst Substances 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- 238000003756 stirring Methods 0.000 claims description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 40
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 38
- 238000004809 thin layer chromatography Methods 0.000 claims description 38
- 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 38
- 238000001816 cooling Methods 0.000 claims description 35
- 239000012065 filter cake Substances 0.000 claims description 35
- 239000000706 filtrate Substances 0.000 claims description 35
- 239000000126 substance Substances 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 33
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 33
- 238000007599 discharging Methods 0.000 claims description 31
- 238000004065 wastewater treatment Methods 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000005406 washing Methods 0.000 claims description 29
- 150000005690 diesters Chemical class 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 25
- 230000015572 biosynthetic process Effects 0.000 claims description 25
- 238000003786 synthesis reaction Methods 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000003638 chemical reducing agent Substances 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- 239000007800 oxidant agent Substances 0.000 claims description 19
- 238000006722 reduction reaction Methods 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 230000001590 oxidative effect Effects 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000006555 catalytic reaction Methods 0.000 claims description 12
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 11
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical group O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 229910000423 chromium oxide Inorganic materials 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 230000003472 neutralizing effect Effects 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 150000002085 enols Chemical class 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- -1 inorganic base sodium hydroxide Chemical class 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N Hydrocortisone Natural products O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 abstract description 6
- 229960000890 hydrocortisone Drugs 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 22
- 239000007864 aqueous solution Substances 0.000 description 16
- 235000011121 sodium hydroxide Nutrition 0.000 description 13
- 239000007787 solid Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XWVAHGYBEBYHOF-UHFFFAOYSA-N OC(C(Cl)=C1Cl)=C(C2=CC=CC=C2)C(C2=CC=CC=C2)=C1O Chemical compound OC(C(Cl)=C1Cl)=C(C2=CC=CC=C2)C(C2=CC=CC=C2)=C1O XWVAHGYBEBYHOF-UHFFFAOYSA-N 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical class C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229960000552 alclometasone Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229950000210 beclometasone dipropionate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
A method for preparing a dehydrogenated intermediate product for alclometasone dipropionate comprises the steps of using 16 a-methyl epihydrocortisone as a raw material, carrying out 21-site propionic acid esterification, 7-site and 11-site dioxygenation to form diketone, 17-site propionic acid esterification, 3-site enolization etherification protection, 7-site and 11-site diketone reduction, acid hydrolysis deprotection, 1-site DDQ dehydrogenation and six-step reaction to synthesize a dehydrogenated intermediate crude product for alclometasone dipropionate, and refining to obtain the dehydrogenated intermediate product for alclometasone dipropionate. The method takes 16 a-methyl hydrocortisone as a raw material, and synthesizes a dehydrogenated intermediate for alclometasone dipropionate through six-step reaction, and the process has the advantages of short synthetic route, economic and environment-friendly process, simple and convenient production operation, high product yield and the like; the solvent used in the production can be recycled and reused, and the industrial production is easy to implement.
Description
Technical Field
The invention belongs to a preparation process technology of steroid hormone medicaments, and particularly relates to a method for preparing a dehydrogenated intermediate product for beclomethasone dipropionate.
Background
Alclometasone dipropionate (molecular formula C)28H37ClO7) The chemical name of the compound is 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-diketone-17, 21-dipropionate, the compound is a potent steroid cortical hormone drug, has potent local anti-inflammatory, itching relieving and blood vessel contraction effects, is mainly used for treating eczema, atopic dermatitis, psoriasis and other skin diseases clinically, and has low side effect, good effect and wide market prospect. The traditional production method of alclometasone dipropionate is characterized by using defluorinated dexamethasone acetate as a raw material, and carrying out six-step chemical reactions of DDQ 6-site dehydrogenation, 21-site base catalytic hydrolysis, 17-and 21-site triethyl propionate cycloesterification, acid-catalyzed cyclic ester hydrolysis, 21-site propyl esterification, and addition of 7a-Cl on 6-and 7-site HCl gas to prepare the alclometasone dipropionate, wherein the process route is shown in figure 1. The synthesis method has long synthesis route, total synthesis yield of 2.678 percent, particularly the final step of 6-position and 7-position HCl gas addition reaction, the synthesis yield of less than 20 percent, and the synthesis method has the advantages of low total synthesis yield, more side reactions of multi-step synthesis chemical reaction, large amount of generated impurities, difficult refining and purification, more three wastes, difficult treatment and easy environmental pollution, so that the double-effect synthesis method ensures that the double-effect synthesis method has double effects of generating three wastes and generating more wastes, is not easy to treat and pollutes the environmentThe production cost and the market price of the alclometasone propionate are high, and the medication burden of patients of the type is increased.
Therefore, there is a need in the art for a new method for preparing alclometasone dipropionate.
Disclosure of Invention
The invention provides a method for preparing a dehydrogenated intermediate product for alclometasone dipropionate.
The technical scheme of the invention is that the method for preparing the dehydrogenated intermediate product for alclometasone dipropionate comprises the following steps of using 16 a-methyl epihydrocortisone as a raw material, carrying out 21-site propionic acid esterification, 7-site and 11-site dioxygenation to obtain diketone, 17-site propionic acid esterification, 3-site enolization etherification protection, 7-site and 11-site diketone reduction and acid hydrolysis deprotection, and carrying out 1-site DDQ dehydrogenation and six-step reaction to synthesize the dehydrogenated intermediate crude product for alclometasone dipropionate, wherein the specific steps comprise:
A. synthesizing an esterified product, namely taking 16 a-methyl epihydrocortisone as a raw material, and carrying out esterification reaction on the raw material and 21-hydroxy of propionic anhydride in a first organic solvent under the catalysis of an acid catalyst to obtain the esterified product: 16 a-methyl epihydrocortisone-21 propionate;
B. the synthesis of oxide is carried out by carrying out 7, 11-site oxidation reaction on esterified substance and oxidant in acid-containing second organic solvent with 11a hydroxyl and 7-site active hydrogen in molecule to obtain oxide: 16 a-methyl-17 a-hydroxy-21-propionyloxy-pregn-4-ene-3, 7,11, 20-tetraone;
C. the diester is synthesized by the following steps that 17 a-hydroxyl of oxide and propionic anhydride are subjected to esterification reaction in a third organic solvent under the catalysis of an acid catalyst to generate the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone;
D. the synthesis of etherate is that double ester and triethyl orthoformate in a fourth organic solvent are subjected to enol etherification protection reaction with ketone group in 3-ketone-4-alkene structure in molecule under the catalysis of acid catalyst to obtain etherate: 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione;
E. synthesizing a reducing substance, namely, carrying out reduction reaction on etherate and reducing agents and ketone groups at 7 and 11 positions in molecules in a fifth organic solvent, and carrying out deprotection under the catalysis of acid to obtain the reducing substance: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione;
F. synthesizing 1-dehydrogenation product, namely, carrying out 1-bit dehydrogenation reaction on the reduction product and a dehydrogenation agent DDQ in a sixth organic solvent to obtain the 1-dehydrogenation product, namely a dehydrogenated intermediate crude product for alclometasone dipropionate: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione;
finally, recrystallizing and refining the crude product of the dehydrogenated intermediate for the alclometasone dipropionate to obtain the dehydrogenated intermediate product for the alclometasone dipropionate.
Further, the method comprises the following specific operation steps:
A. synthesizing an esterified substance: dissolving 16 a-methyl epihydrocortisone in a first organic solvent, adding propionic anhydride at 10-50 ℃, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), adding alkali for neutralization after the reaction is finished, recovering the organic solvent under reduced pressure, crystallizing by using ethanol water solution, and drying to obtain an ester: 16 a-methyl epihydrocortisone-21 propionate, the HPLC content is 97.0-98.5%, and the weight yield is 110-115%;
B. synthesizing an oxide: dissolving the esterified substance into a second organic solvent, slowly dripping an oxidant at 10-50 ℃ within 2-3 hours, keeping the temperature at 10-50 ℃ for continuously reacting for 1-2 hours after dripping, confirming the reaction end point by TLC, adding a proper amount of sodium hydrosulfite to remove excessive oxidant after the reaction is finished, concentrating under reduced pressure to recover 90-95% of the organic solvent, cooling, elutriating, centrifuging, discharging filtrate into a wastewater treatment pool, and drying a filter cake to obtain an oxide, wherein the HPLC content is 95.0-98.5%, and the weight yield is 95-100%;
C. synthesis of diester: dissolving the oxide into a third organic solvent, keeping the temperature at 10-80 ℃, adding propionic anhydride, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), cooling to 25-30 ℃ after the reaction is finished, adding a proper amount of alkali to neutralize until the pH value of the solution is 6.5-7.5, decompressing, concentrating and recovering 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring and crystallizing for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, the HPLC content is 98.0-99.0%, and the weight yield is 110-115%;
D. synthesizing an etherate: dissolving the diester into a fourth organic solvent, adding triethyl orthoformate and an acid catalyst, keeping the temperature at 10-80 ℃ for reaction for 3-4 hours, confirming the reaction end point by TLC (thin layer chromatography), adding a proper amount of alkali to neutralize the solution until the pH value of the solution is 6.5-7.5 after the reaction is finished, concentrating under reduced pressure to recover 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring for crystallization for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherate: 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, the HPLC content is 97.0-99.0%, and the weight yield is 100-105%;
E. synthesizing a reduced product: dissolving the etherate in a fifth organic solvent, keeping the temperature at 10-80 ℃, slowly adding a reducing agent, finishing the addition of the reducing agent for 1.5-2.5 hours, then continuing to keep the temperature at 10-80 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding a proper amount of acid catalyst water solution to ensure that the pH of the system is 2-3, then continuing to perform hydrolysis reaction for 2-3 hours at 10-80 ℃, confirming the reaction end point by TLC, after the reaction is finished, slowly adding a proper amount of alkali to neutralize the pH of the system to 6-7, then performing reduced pressure concentration to recover 90-95% of organic solvent, then cooling, slowly adding pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, drying filter cakes to obtain a crude product of the reduced product, and recrystallizing the crude product with an aqueous alcohol solution to obtain the reduced product: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, with HPLC content of 98.0-99.0% and weight yield of 70-75%;
F. synthesis of 1-dehydrogenate: dissolving the reduced matter in a sixth organic solvent, adding a dehydrogenating agent DDQ, stirring to completely dissolve the reduced matter, heating to 40-100 ℃, keeping the temperature and reacting for 6-10 hours, confirming the reaction end point by TLC, filtering hydroquinone generated by the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy the excessive dehydrogenating agent DDQ, then decompressing, concentrating and recovering 90-95% of the organic solvent, cooling, slowly adding pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, drying filter cakes to obtain a dehydrogenated intermediate crude product for alclometasone dipropionate, recrystallizing the crude product with an alcohol-alkali water solution to obtain a dehydrogenated intermediate product for alclometasone dipropionate: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, with an HPLC content of 98.0-99.0%.
Further, in the specific steps:
A. the first organic solvent in the synthesized esterified product is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst ═ 1 g: 0.3-0.5 g: 0.01-0.15 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent ═ 1 g: 1-5 ml;
B. the second organic solvent in the synthesized oxide is one of toluene, acetone, chloroform, DME, tetrahydrofuran, DMSO, dioxane and glacial acetic acid; the oxidant is one of chromium oxide, PPC and sodium hypohalite; the weight ratio of reactants is as follows: oxidant 1 g: 0.2-0.8 g; the ratio of reactants to solvent is, esterified: second organic solvent ═ 1 g: 3-10 ml;
C. the third organic solvent in the synthesized diester is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst ═ 1 g: 0.3-0.5 g: 0.05-0.25 g; the ratio of the reactants to the solvent is as follows: third organic solvent ═ 1 g: 1-8 ml;
D. the fourth organic solvent in the synthesized etherate is one of toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, DME and lower alcohol with the carbon number below 4; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid and trifluoroacetic acid; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst ═ 1 g: 0.6-1.2 ml: 0.05-0.25 g; the ratio of reactants to solvent is, diester: fourth organic solvent ═ 1 g: 2-8 ml.
Further, in the specific steps:
A. the first organic solvent in the synthetic ester is propionic acid; the reaction temperature is 25-30 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst ═ 1 g: 0.4 g: 0.05 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent ═ 1 g: 2 ml;
B. the second organic solvent in the synthetic oxide is glacial acetic acid; the reaction temperature is 20-25 ℃; the oxidizing agent is chromium oxide; the weight ratio of reactants is as follows: oxidant 1 g: 0.4 g; the ratio of reactants to solvent is, esterified: second organic solvent ═ 1 g: 5ml of the solution;
C. the third organic solvent in the synthesis of the diester is propionic acid; the reaction temperature is 30-35 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst ═ 1 g: 0.4 g: 0.1 g; the ratio of the reactants to the solvent is as follows: third organic solvent ═ 1 g: 3 ml;
D. the fourth organic solvent in the synthesis of the etherate is dichloromethane; the acid catalyst for the reaction is p-toluenesulfonic acid; the reaction temperature is 20-25 ℃; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst ═ 1 g: 0.9 ml: 0.10 g; the ratio of reactants to solvent is, diester: fourth organic solvent ═ 1 g: 6 ml.
Further, in the specific steps:
D. the base for synthesizing the etherified product and neutralizing acid is one of inorganic base sodium hydroxide, sodium carbonate or organic base pyridine and triethylamine;
E. the acid catalyst for hydrolysis reaction in the synthesis of the reduced product is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid.
Further, in the specific steps:
D. the base for neutralizing acid in the synthesized etherate is triethylamine;
E. the acid catalyst for the hydrolysis reaction in the synthesis of the reduced product is hydrochloric acid.
Further, in the specific steps:
E. the fifth organic solvent in the synthetic reduced product is one of toluene, dichloromethane, chloroform, tetrahydrofuran and lower alcohol with the carbon number below 4; the reducing agent is one of sodium borohydride, potassium borohydride and calcium borohydride; the weight ratio of reduction reactants is that etherified substances: reducing agent 1 g: 0.12-0.24 g; the weight ratio of hydrolysis reactants is that etherified substances: acid catalyst ═ 1 g: 0.2-0.5 g; the ratio of the reactants to the solvent is that etherified substances: fifth organic solvent ═ 1 g: 8-16 ml;
F. the sixth organic solvent in the synthesis of the 1-dehydrogenation product is one of toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and dioxane; the weight ratio of reactants is as follows: dehydrogenating agent DDQ ═ 1 g: 0.6-0.9 g; the ratio of reactants to solvent is: reduction product: sixth organic solvent ═ 1 g: 10-15 ml.
Further, in the specific steps:
E. the fifth organic solvent in the synthetic reduction is methanol; the reducing agent is sodium borohydride; the temperature of the reduction reaction and the hydrolysis reaction is 25-30 ℃; the weight ratio of reduction reactants is that etherified substances: reducing agent 1 g: 0.16 g; the weight ratio of hydrolysis reactants is that etherified substances: acid catalyst ═ 1 g: 0.3 g; the ratio of the reactants to the solvent is that etherified substances: fifth organic solvent ═ 1 g: 12 ml;
F. the sixth organic solvent in the synthesis of the 1-dehydrogen is dioxane; the dehydrogenation reaction temperature is 75-80 ℃; the weight ratio of reactants is as follows: dehydrogenating agent DDQ ═ 1 g: 0.8 g; the ratio of reactants to solvent is: reduction product: sixth organic solvent ═ 1 g: 12 ml.
The beneficial effects of the invention include:
the method takes 16 a-methyl surface hydrocortisone as a raw material, and synthesizes a dehydrogenated intermediate for alclometasone dipropionate through six-step reactions such as esterification, oxidation, double esterification, etherification, reduction, dehydrogenation and the like; the solvent used in the production can be recycled and reused, and the industrial production is easy to implement.
Drawings
FIG. 1 is a conventional synthesis route diagram of alclometasone dipropionate.
FIG. 2 is a synthesis route diagram of alclometasone dipropionate according to the present invention.
Detailed Description
In order to explain the gist and spirit of the present invention in more detail, several embodiments are described below.
Example 1
A. Preparation of an esterified substance: adding 100g of 16 a-methyl hydrocortisone, 200ml of propionic acid, 40g of propionic anhydride and 5g of p-toluenesulfonic acid into a 1000ml three-neck flask, reacting at 20-25 ℃ for 6-8 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding the reaction liquid into 5000ml three-neck flask filled with 2000ml of sodium hydroxide solution with the molar concentration of 5%, stirring and crystallizing at 0-5 ℃ for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, adding a filter cake into 600ml of ethanol aqueous solution with the molar concentration of 20%, stirring at 30-35 ℃ for 5-6 hours, cooling to 0-5 ℃ and stirring and crystallizing for 5-6 hours, filtering, applying the filtrate to the next refining process, washing and drying the filter cake to obtain an esterified substance: 112g of 16 a-methyl epihydrocortisone-21 propionate, 97.4 percent of HPLC content and 112 percent of weight yield;
B. preparation of oxides: adding 100g of the esterified substance prepared by the step A and 500ml of glacial acetic acid into a 1000ml three-neck flask, stirring to completely dissolve the esterified substance and the glacial acetic acid, then controlling the temperature to be 20-25 ℃, slowly dropwise adding an oxidant solution prepared from 40g of chromium oxide and 80g of water, completing dropwise addition within about 2.5-3 hours, keeping the temperature at 20-25 ℃ after completing dropwise addition, continuing to react for 1-2 hours, determining a reaction end point by TLC (thin layer chromatography), adding 10g of sodium hydrosulfite after completing the reaction to remove excessive oxidant, then performing reduced pressure concentration to recover about 90% of glacial acetic acid, cooling to 20-30 ℃, adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 3-4 hours, filtering, discharging a filter cake into a wastewater treatment tank, washing and drying to obtain 98g of oxide, wherein the HPLC content is 97.5%, and the weight yield is 98%;
C. preparation of diester: adding 100g of the oxide prepared by the B, 300ml of propionic acid, 40g of propionic anhydride and 10g of p-toluenesulfonic acid into a 1000ml three-necked bottle, keeping the temperature at 30-35 ℃ for reacting for 6-8 hours, confirming the reaction end point by TLC, cooling to 25-30 ℃ after the reaction is finished, slowly dropwise adding the reaction liquid into 5000ml of three-necked bottle filled with 2000ml of sodium hydroxide solution with the molar concentration of 5%, stirring at 0-5 ℃ for crystallizing for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a diester: 113.6g of 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, 98.5 percent of HPLC content and 113.6 percent of weight yield;
D. preparation of etherate: adding 100g of diester prepared by C into a 1000ml three-necked bottle, adding 600ml of dichloromethane, then adding 90ml of triethyl orthoformate and 10g of p-toluenesulfonic acid, keeping the temperature at 20-25 ℃ for reacting for 3-4 hours, confirming the reaction end point by TLC, after the reaction is finished, adding a proper amount of triethylamine to neutralize until the pH of the solution is 6.5-7.5, carrying out reduced pressure concentration to recover 90-95% of dichloromethane, cooling to 20-25 ℃, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 1.5-2.5 hours, filtering, discharging the filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain an etherate: 104g of 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, 97.6 percent of HPLC content and 104 percent of weight yield;
E. preparation of a reduced product: adding 100g of the etherate prepared by the step D and 1200ml of methanol into a 2000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring to completely dissolve the solid, slowly adding 16g of a sodium borohydride reducing agent, keeping the adding for about 1.5-2.5 hours, then continuing to keep the temperature at 25-30 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 100g of a hydrochloric acid aqueous solution with the molar concentration of 30% to ensure that the pH of the system is 2-3, continuing to perform hydrolysis reaction at 25-30 ℃ for 2-3 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly adding a proper amount of alkali to neutralize the pH of the system to 6-7, then performing reduced pressure concentration to recover 90-95% of organic solvent methanol, cooling, slowly adding 600ml of pure water for elutriation, filtering, discharging the filtrate into a waste water treatment pool, washing and drying a filter cake to obtain a reduced crude product, recrystallizing the crude product by using 500ml of an alcohol aqueous solution with, obtaining a reduced product: 74.2g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, 98.8 percent of HPLC content and 74.2 percent of weight yield;
F. 1-preparation of dehydrogenate: adding 100g of the reduced product prepared by the step E, 1200ml of dioxane and 80g of DDQ (dichloro-diphenyl-hydroquinone) dehydrogenating agent into a 2000ml three-necked bottle, stirring to completely dissolve the reduced product, heating to 75-80 ℃, keeping the temperature for reaction for 6-10 hours, confirming the reaction end point by TLC (thin layer chromatography), filtering out hydroquinone generated in the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy excessive DDQ, then decompressing and concentrating to recover 90-95% of organic solvent dioxane, cooling, slowly adding 600ml of pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a 1-dehydrogenated product crude product, recrystallizing the crude product by using 500ml of aqueous solution containing 20% alcohol and 10% caustic soda to obtain the 1-dehydrogenated product: 63.8g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, 98.2% HPLC content and 63.8% weight yield;
G. preparation of alclometasone dipropionate: adding 100g of the 1-dehydrogenized substance prepared by the F, 800ml of toluene and 200g of pyridine into a 2000ml three-necked bottle, heating and stirring to completely dissolve solids, then adding 80g of phosphorus trichloride chlorinating agent, keeping the temperature at 40-45 ℃, stirring and reacting for 4-6 hours, confirming the reaction end point by TLC, after the reaction is finished, adding 500g of caustic soda solution with the molar concentration of 30% for 2 times to neutralize and wash until the pH value of an aqueous solution layer is 6-7, concentrating under reduced pressure to recover 90-95% of organic solvent toluene, cooling to 20-25 ℃, adding 600ml of pure water, stirring and crystallizing at 0-5 ℃ for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a crude alclometasone dipropionate crude product, refluxing the crude product with 600ml of alcohol and 5g of activated carbon for 1 hour, filtering, decolorizing the filter cake, washing the filtrate, combining the filtrate and a washing solution, concentrating 80% alcohol, and (3) stirring and crystallizing at 0-5 ℃ for 3-4 hours, treating the obtained solid, and adding methanol-acetone-isopropyl ether: 1: 3, recrystallizing the mixed solvent to obtain alclometasone dipropionate: 64.2g of 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate, mp: the HPLC content is 99.4 percent at the temperature of 214-216 ℃, and the weight yield is 64.2 percent.
Example 2
A. Preparation of an esterified substance: adding 100g of 16 a-methyl hydrocortisone, 500ml of chloroform, 40g of propionic anhydride and 8g of p-toluenesulfonic acid into a 1000ml three-neck flask, reacting at 20-25 ℃ for 6-8 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 20ml of sodium hydroxide solution with the molar concentration of 50%, concentrating under reduced pressure after water separation to recover 90-95% of chloroform, then adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, adding the filter cake into 600ml of ethanol aqueous solution with the molar concentration of 20%, stirring at 30-35 ℃ for 5-6 hours, cooling to 0-5 ℃, stirring and crystallizing for 5-6 hours, filtering, mechanically applying the filtrate to the next refining process, washing and drying the filter cake to obtain an esterified substance: 109.5g of 16 a-methyl-epi-hydrocortisone-21 propionate, 97.8% HPLC content and 109.5% weight yield;
B. preparation of oxides: adding 100g of the esterified substance prepared by the step A and 600ml of acetone into a 1000ml three-necked bottle, stirring to completely dissolve the esterified substance, controlling the temperature to be 20-25 ℃, slowly dropwise adding an oxidant solution prepared from 40g of chromium oxide and 80g of pure water, completing dropwise addition within about 2.5-3 hours, keeping the temperature at 20-25 ℃ after completing dropwise addition, continuing to react for 1-2 hours, confirming the reaction end point by TLC, adding 10g of sodium hydrosulfite after completing the reaction to remove excessive oxidant, then performing reduced pressure concentration to recover about 90% of acetone, cooling to 20-30 ℃, adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying filter cakes to obtain 97.4g of oxides, wherein the HPLC content is 96.6%, and the weight yield is 97.4%;
C. preparation of diester: adding 100g of the oxide prepared by the B, 300ml of chloroform, 40g of propionic anhydride and 10g of p-toluenesulfonic acid into a 1000ml three-necked bottle, keeping the temperature at 50-55 ℃ for reacting for 6-8 hours, confirming the reaction end point by TLC, cooling to 25-30 ℃ after the reaction is finished, slowly dropwise adding the mixture into the reaction solution to 50ml of sodium hydroxide solution with the molar concentration of 30%, removing a water layer, washing once by 50ml of pure water, draining off water, concentrating under reduced pressure to recover 90-95% of chloroform solvent, cooling, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, washing a filter cake with water, and drying to obtain the diester: 112.2g of 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetrone, 97.8 percent of HPLC content and 112.2 percent of weight yield;
D. preparation of etherate: adding 100g of diester prepared by C, 600ml of THF, 90ml of triethyl orthoformate and 10g of concentrated sulfuric acid into a 1000ml three-necked bottle, keeping the temperature at 20-25 ℃ for reacting for 3-4 hours, confirming the reaction end point by TLC, adding a proper amount of sodium carbonate solid to neutralize the pH of the solution to 6.5-7.5 after the reaction is finished, concentrating under reduced pressure to recover 90-95% of THF, cooling to 20-25 ℃, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 1.5-2.5 hours, filtering, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherate: 101.8g of 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, 96.4 percent of HPLC content and 101.8 percent of weight yield;
E. preparation of a reduced product: adding 100g of the etherate prepared by the step D and 1200ml of DME into a 2000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring to completely dissolve the solid, slowly adding 18g of a sodium borohydride reducing agent, keeping the adding for about 1.5-2.5 hours, then continuing to keep the temperature at 25-30 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 120g of a hydrochloric acid aqueous solution with the molar concentration of 30% to ensure that the PH of the system is 2-3, continuing to perform hydrolysis reaction at 25-30 ℃ for 2-3 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly adding an appropriate amount of alkali to neutralize the PH of the system to 6-7, then performing reduced pressure concentration to recover 90-95% of organic solvent DME, cooling, slowly adding 600ml of pure water for elutriation, filtering, discharging the filtrate into a waste water treatment pool, washing and drying a filter cake to obtain a reduced crude product, recrystallizing the crude product by using 500ml of an alcohol aqueous solution, obtaining a reduced product: 72.6g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, 97.2 percent of HPLC content and 72.6 percent of weight yield;
F. 1-preparation of dehydrogenate: adding 100g of the reduced product prepared by the step E, 1200ml of toluene and 80g of DDQ (dichloro-diphenyl-hydroquinone) dehydrogenating agent into a 2000ml three-necked bottle, stirring to completely dissolve the reduced product, heating to 75-80 ℃, keeping the temperature and reacting for 6-10 hours, confirming the reaction end point by TLC (thin layer chromatography), filtering out hydroquinone generated in the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy excessive DDQ, then decompressing and concentrating to recover 90-95% of organic solvent toluene, cooling, slowly adding 600ml of pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain a 1-dehydrogenated product crude product, recrystallizing the crude product by using 500ml of aqueous solution containing 20% alcohol and 10% of caustic soda to obtain the 1-dehydrogenated product: 61.5g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, 97.8 percent of HPLC content and 61.5 percent of weight yield;
G. preparation of alclometasone dipropionate: adding 100G of the 1-dehydrogenized substance prepared by the F, 800ml of chloroform and 200G of triethylamine into a 2000ml three-necked bottle, heating and stirring to completely dissolve solids, then adding 80G of phosphorus trichloride chlorinating agent, keeping the temperature at 40-45 ℃, stirring and reacting for 4-6 hours, confirming the reaction end point by TLC, after the reaction is finished, adding 500G of caustic soda solution with the molar concentration of 30% for 2 times to neutralize and wash the aqueous solution layer until the pH of the aqueous solution layer is 6-7, concentrating under reduced pressure to recover 90-95% of organic solvent chloroform, cooling to 20-25 ℃, adding 600ml of pure water, stirring and crystallizing at 0-5 ℃ for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a crude alclometasone dipropionate product, and recrystallizing the crude product according to the method G in example 1 to obtain alclometasone dipropionate: 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate 61.6g, m.p.: 214-215.5 ℃, HPLC content 99.3% and weight yield 61.6%.
Example 3
A. Preparation of an esterified substance: adding 100g of 16 a-methyl hydrocortisone, 500ml of toluene, 40g of propionic anhydride and 6g of trifluoroacetic acid into a 1000ml three-necked bottle, reacting at 20-25 ℃ for 6-8 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 20ml of sodium hydroxide solution with the molar concentration of 50%, concentrating under reduced pressure after water separation to recover 90-95% of toluene, then adding 500ml of pure water, stirring and crystallizing at 0-5 ℃ for 4-5 hours, filtering, discharging the filtrate into a wastewater treatment tank, adding the filter cake into 600ml of ethanol aqueous solution with the molar concentration of 20%, stirring at 30-35 ℃ for 5-6 hours, cooling to 0-5 ℃, stirring and crystallizing for 5-6 hours, filtering, mechanically applying the filtrate to the next refining process, washing and drying the filter cake to obtain an ester: 106.8g of 16 a-methyl-epi-hydrocortisone-21 propionate, 97.2% HPLC content and 106.8% weight yield;
B. preparation of oxides: adding 100g of the esterified substance prepared by the step A and 600ml of chloroform into a 1000ml three-necked bottle, stirring to completely dissolve the esterified substance, then slowly dropwise adding an oxidant solution prepared from 40g of chromium oxide and 80g of pure water at the temperature of 20-25 ℃, completing dropwise adding within 2.5-3 hours, keeping the temperature at 20-25 ℃ after completing dropwise adding, continuing to react for 1-2 hours, confirming the reaction end point by TLC, adding 10g of sodium hydrosulfite after completing the reaction to remove excessive oxidant, then decompressing and concentrating to recover 90% of chloroform, cooling to 20-30 ℃, adding 500ml of pure water, stirring and crystallizing at the temperature of 0-5 ℃ for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying filter cakes to obtain 98.2g of oxide, the HPLC content is 97.5%, and the weight yield is 98.2%;
C. preparation of diester: adding 100g of the oxide prepared by the B, 300ml of toluene, 40g of propionic anhydride and 12g of phosphoric acid into a 1000ml three-necked bottle, reacting for 6-8 hours at 50-55 ℃ while keeping the temperature, confirming the reaction end by TLC, cooling to 25-30 ℃ after the reaction is finished, slowly dripping the mixture into a reaction solution until 80ml of a sodium hydroxide solution with the molar concentration of 30%, removing a water layer, washing once by using 50ml of pure water, draining off water, concentrating under reduced pressure to recover 90-95% of solvent toluene, adding 500ml of pure water after cooling, stirring and crystallizing for 4-5 hours at 0-5 ℃, filtering, discharging filtrate into a wastewater treatment tank, washing filter cakes with water, and drying to obtain the diester: 111.8g of 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, 98.2 percent of HPLC content and 111.8 percent of weight yield;
D. preparation of etherate: adding 100g of diester prepared by the C, 600ml of ethanol, 90ml of triethyl orthoformate and 10g of trifluoroacetic acid into a 1000ml three-necked bottle, keeping the temperature at 20-25 ℃ for reacting for 3-4 hours, confirming the reaction end point by TLC, adding an appropriate amount of pyridine solid for neutralizing until the pH of the solution is 6.5-7.5 after the reaction is finished, concentrating under reduced pressure for recovering 90-95% of ethanol, cooling to 20-25 ℃, adding 500ml of pure water, stirring at 0-5 ℃ for crystallizing for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherate: 102.6g of 3-vinyl alcohol ether-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, 96.8 percent of HPLC content and 102.6 percent of weight yield;
E. preparation of a reduced product: adding 100g of etherate prepared by the step D and 1200ml of THF into a 2000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring to completely dissolve the solid, slowly adding 18g of potassium borohydride reducing agent, keeping the adding for about 1.5-2.5 hours, then continuing to keep the temperature at 25-30 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 100g of sulfuric acid aqueous solution with the molar concentration of 50% to ensure that the pH of the system is 2-3, continuing to hydrolyze at 25-30 ℃ for 2-3 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly adding a proper amount of alkali to neutralize the pH of the system to 6-7, then decompressing and concentrating to recover 90-95% of organic solvent THF, cooling, slowly adding 600ml of pure water for elutriation, filtering, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain a reduced product, recrystallizing the crude product by using 500ml of alcohol aqueous solution with the molar concentration of 50%, obtaining a reduced product: 70.8g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, 97.6 percent of HPLC content and 70.8 percent of weight yield;
F. 1-preparation of dehydrogenate: adding 100g of the reduced product prepared by the step E, 1200ml of ethyl acetate and 85g of DDQ (dichloro-diphenyl-hydroquinone) dehydrogenating agent into a 2000ml three-necked bottle, stirring to completely dissolve the reduced product, heating to 75-80 ℃, keeping the temperature for reaction for 6-10 hours, confirming the reaction end point by TLC (thin layer chromatography), filtering out hydroquinone generated in the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy excessive DDQ, then decompressing and concentrating to recover 90-95% of organic solvent ethyl acetate, cooling, slowly adding 600ml of pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain a 1-dehydrogenated product crude product, recrystallizing the crude product by using 500ml of aqueous solution containing 20% alcohol and 10% caustic soda to obtain the 1-dehydrogenated product: 62.4g of 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, 97.2 percent of HPLC content and 62.4 percent of weight yield;
G. preparation of alclometasone dipropionate: adding 100G of the 1-dehydrogenized substance prepared by the F, 800ml of toluene and 200G of pyridine into a 2000ml three-necked bottle, heating and stirring to completely dissolve solids, then adding 80G of thionyl chloride chlorinating agent, keeping the temperature at 40-45 ℃, stirring and reacting for 4-6 hours, confirming the reaction end point by TLC, after the reaction is finished, adding 500G of caustic soda solution with the molar concentration of 30% for 2 times to neutralize and wash the aqueous solution layer PH 6-7, concentrating under reduced pressure to recover 90-95% of organic solvent toluene, cooling to 20-25 ℃, adding 600ml of pure water, stirring and crystallizing at 0-5 ℃ for 1.5-2.5 hours, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain crude alclometasone dipropionate, and recrystallizing the crude product according to the method G in example 1 to obtain alclometasone dipropionate: 7 a-chloro-16 a-methyl-11-hydroxy-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate 62.8g, m.p.: 214-215.5 ℃, HPLC content of 99.2% and weight yield of 62.8%.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions and substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (8)
1. A method for preparing a dehydrogenated intermediate product for alclometasone dipropionate is characterized in that the method comprises the following steps of taking 16 a-methyl epihydrocortisone as a raw material, carrying out 21-site propionic acid esterification, 7-site and 11-site dioxygenation to obtain diketone, 17-site propionic acid esterification, 3-site enolization etherification protection, 7-site and 11-site diketone reduction and acid hydrolysis deprotection, and carrying out six-step reaction of 1-site DDQ dehydrogenation to synthesize a dehydrogenated intermediate crude product for alclometasone dipropionate, wherein the specific steps comprise:
A. synthesizing an esterified product, namely taking 16 a-methyl epihydrocortisone as a raw material, and carrying out esterification reaction on the raw material and 21-hydroxy of propionic anhydride in a first organic solvent under the catalysis of an acid catalyst to obtain the esterified product: 16 a-methylepihydrocortisone-21-propionate;
B. the synthesis of oxide is carried out by carrying out 7, 11-site oxidation reaction on esterified substance and oxidant in acid-containing second organic solvent with 11a hydroxyl and 7-site active hydrogen in molecule to obtain oxide: 16 a-methyl-17 a-hydroxy-21-propionyloxy-pregn-4-ene-3, 7,11, 20-tetraone; the second organic solvent containing acid is glacial acetic acid, and the oxidant is chromium oxide;
C. the diester is synthesized by the following steps that 17 a-hydroxyl of oxide and propionic anhydride are subjected to esterification reaction in a third organic solvent under the catalysis of an acid catalyst to generate the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone;
D. the synthesis of etherate is that double ester and triethyl orthoformate in a fourth organic solvent are subjected to enol etherification protection reaction with ketone group in 3-ketone-4-alkene structure in molecule under the catalysis of acid catalyst to obtain etherate: 3-ethoxy-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione;
E. synthesizing a reducing substance, namely, carrying out reduction reaction on etherate and reducing agents and ketone groups at 7 and 11 positions in molecules in a fifth organic solvent, and carrying out deprotection under the catalysis of acid to obtain the reducing substance: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione;
F. synthesizing 1-dehydrogenation product, namely, carrying out 1-bit dehydrogenation reaction on the reduction product and a dehydrogenation agent DDQ in a sixth organic solvent to obtain the 1-dehydrogenation product, namely a dehydrogenated intermediate crude product for alclometasone dipropionate: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione;
finally, recrystallizing and refining the crude product of the dehydrogenated intermediate for the alclometasone dipropionate to obtain the dehydrogenated intermediate product for the alclometasone dipropionate.
2. The method according to claim 1, characterized in that the method comprises the following specific operating steps:
A. synthesizing an esterified substance: dissolving 16 a-methyl epihydrocortisone in a first organic solvent, adding propionic anhydride at 10-50 ℃, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), adding alkali for neutralization after the reaction is finished, recovering the organic solvent under reduced pressure, crystallizing by using ethanol water solution, and drying to obtain an ester: 16 a-methyl epihydrocortisone-21-propionate, the HPLC content is 97.0-98.5%, and the weight yield is 110-115%;
B. synthesizing an oxide: dissolving the esterified substance into a second organic solvent, slowly dripping an oxidant at 10-50 ℃ within 2-3 hours, keeping the temperature at 10-50 ℃ for continuously reacting for 1-2 hours after dripping, confirming the reaction end point by TLC, adding a proper amount of sodium hydrosulfite to remove excessive oxidant after the reaction is finished, concentrating under reduced pressure to recover 90-95% of the organic solvent, cooling, elutriating, centrifuging, discharging filtrate into a wastewater treatment pool, and drying a filter cake to obtain an oxide, wherein the HPLC content is 95.0-98.5%, and the weight yield is 95-100%;
C. synthesis of diester: dissolving the oxide into a third organic solvent, keeping the temperature at 10-80 ℃, adding propionic anhydride, reacting for 6-8 hours under the catalysis of an acid catalyst, confirming the reaction end point by TLC (thin layer chromatography), cooling to 25-30 ℃ after the reaction is finished, adding a proper amount of alkali to neutralize until the pH value of the solution is 6.5-7.5, decompressing, concentrating and recovering 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring and crystallizing for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain the diester: 16 a-methyl-17 a, 21-dipropionyloxy-pregn-4-ene-3, 7,11, 20-tetraone, the HPLC content is 98.0-99.0%, and the weight yield is 110-115%;
D. synthesizing an etherate: dissolving the diester into a fourth organic solvent, adding triethyl orthoformate and an acid catalyst, keeping the temperature at 10-80 ℃ for reaction for 3-4 hours, confirming the reaction end point by TLC (thin layer chromatography), adding a proper amount of alkali to neutralize the solution until the pH value of the solution is 6.5-7.5 after the reaction is finished, concentrating under reduced pressure to recover 90-95% of the organic solvent, cooling to 10-25 ℃, adding pure water, stirring for crystallization for 1.5-2.5 hours, centrifuging, discharging the filtrate into a wastewater treatment pool, washing and drying a filter cake to obtain an etherate: 3-ethoxy-16 a-methyl-17 a, 21-dipropionyloxy-pregna-3, 5-diene-7, 11, 20-trione, the HPLC content is 97.0-99.0%, and the weight yield is 100-105%;
E. synthesizing a reduced product: dissolving the etherate in a fifth organic solvent, keeping the temperature at 10-80 ℃, slowly adding a reducing agent, finishing the addition of the reducing agent for 1.5-2.5 hours, then continuing to keep the temperature at 10-80 ℃ for reaction for 1-2 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding a proper amount of acid catalyst water solution to ensure that the pH of the system is 2-3, then continuing to perform hydrolysis reaction for 2-3 hours at 10-80 ℃, confirming the reaction end point by TLC, after the reaction is finished, slowly adding a proper amount of alkali to neutralize the pH of the system to 6-7, then performing reduced pressure concentration to recover 90-95% of organic solvent, then cooling, slowly adding pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, drying filter cakes to obtain a crude product of the reduced product, and recrystallizing the crude product with an aqueous alcohol solution to obtain the reduced product: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregn-4-ene-3, 20-dione, with HPLC content of 98.0-99.0% and weight yield of 70-75%;
F. synthesis of 1-dehydrogenate: dissolving the reduced matter in a sixth organic solvent, adding a dehydrogenating agent DDQ, stirring to completely dissolve the reduced matter, heating to 40-100 ℃, keeping the temperature and reacting for 6-10 hours, confirming the reaction end point by TLC, filtering hydroquinone generated by the reaction after the reaction is finished, adding a proper amount of sodium bisulfite solution to destroy the excessive dehydrogenating agent DDQ, then decompressing, concentrating and recovering 90-95% of the organic solvent, cooling, slowly adding pure water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, drying filter cakes to obtain a dehydrogenated intermediate crude product for alclometasone dipropionate, recrystallizing the crude product with an alcohol-alkali water solution to obtain a dehydrogenated intermediate product for alclometasone dipropionate: 16 a-methyl-7, 11-dihydroxy-17 a, 21-dipropionyloxy-pregna-1, 4-diene-3, 20-dione, with an HPLC content of 98.0-99.0%.
3. The method according to claim 1 or 2, characterized in that in said specific steps:
A. the first organic solvent in the synthesized esterified product is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst =1 g: 0.3-0.5 g: 0.01-0.15 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent =1 g: 1-5 ml;
B. the weight ratio of reactants in the synthesized oxide is that esterified substances: oxidant =1 g: 0.2-0.8 g; the ratio of reactants to solvent is, esterified: second organic solvent =1 g: 3-10 ml;
C. the third organic solvent in the synthesized diester is one of propionic anhydride, toluene, propionic acid, chloroform, DME and dioxane; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst =1 g: 0.3-0.5 g: 0.05-0.25 g; the ratio of the reactants to the solvent is as follows: third organic solvent =1 g: 1-8 ml;
D. the fourth organic solvent in the synthesized etherate is one of toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane, DME and lower alcohol with the carbon number below 4; the acid catalyst for the reaction is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid and trifluoroacetic acid; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst =1 g: 0.6-1.2 ml: 0.05-0.25 g; the ratio of reactants to solvent is, diester: fourth organic solvent =1 g: 2-8 ml.
4. The method according to claim 3, characterized in that in said specific steps:
A. the first organic solvent in the synthetic ester is propionic acid; the reaction temperature is 25-30 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is that 16 a-methyl epihydrocortisone: propionic anhydride: acid catalyst =1 g: 0.4 g: 0.05 g; the ratio of the reactants to the solvent is 16 a-methyl epihydrocortisone: first organic solvent =1 g: 2 ml;
B. the reaction temperature in the synthesis of the oxide is 20-25 ℃; the weight ratio of reactants is as follows: oxidant =1 g: 0.4 g; the ratio of reactants to solvent is, esterified: second organic solvent =1 g: 5ml of the solution;
C. the third organic solvent in the synthesis of the diester is propionic acid; the reaction temperature is 30-35 ℃; the acid catalyst for the reaction is p-toluenesulfonic acid; the weight ratio of the reactants is as follows: propionic anhydride: acid catalyst =1 g: 0.4 g: 0.1 g; the ratio of the reactants to the solvent is as follows: third organic solvent =1 g: 3 ml;
D. the fourth organic solvent in the synthesis of the etherate is dichloromethane; the acid catalyst for the reaction is p-toluenesulfonic acid; the reaction temperature is 20-25 ℃; the weight ratio of reactants is as follows: triethyl orthoformate: acid catalyst =1 g: 0.9 ml: 0.10 g; the ratio of reactants to solvent is, diester: fourth organic solvent =1 g: 6 ml.
5. The method according to claim 2, characterized in that in said specific steps:
D. the base for synthesizing the etherified product and neutralizing acid is one of inorganic base sodium hydroxide, sodium carbonate or organic base pyridine and triethylamine;
E. the acid catalyst for hydrolysis reaction in the synthesis of the reduced product is one of inorganic strong acid sulfuric acid, hydrochloric acid or organic strong acid p-toluenesulfonic acid.
6. The method according to claim 5, characterized in that in the specific steps:
D. the base for neutralizing acid in the synthesized etherate is triethylamine;
E. the acid catalyst for the hydrolysis reaction in the synthesis of the reduced product is hydrochloric acid.
7. The method according to claim 1 or 2, characterized in that in said specific steps:
E. the fifth organic solvent in the synthetic reduced product is one of toluene, dichloromethane, chloroform, tetrahydrofuran and lower alcohol with the carbon number below 4; the reducing agent is one of sodium borohydride, potassium borohydride and calcium borohydride; the weight ratio of reduction reactants is that etherified substances: reducing agent =1 g: 0.12-0.24 g; the weight ratio of hydrolysis reactants is that etherified substances: acid catalyst =1 g: 0.2-0.5 g; the ratio of the reactants to the solvent is that etherified substances: fifth organic solvent =1 g: 8-16 ml;
F. the sixth organic solvent in the synthesis of the 1-dehydrogenation product is one of toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran and dioxane; the weight ratio of reactants is as follows: dehydrogenating agent DDQ =1 g: 0.6-0.9 g; the ratio of reactants to solvent is: reduction product: sixth organic solvent =1 g: 10-15 ml.
8. The method according to claim 7, characterized in that in the specific steps:
E. the fifth organic solvent in the synthetic reduction is methanol; the reducing agent is sodium borohydride; the temperature of the reduction reaction and the hydrolysis reaction is 25-30 ℃; the weight ratio of reduction reactants is that etherified substances: reducing agent =1 g: 0.16 g; the weight ratio of hydrolysis reactants is that etherified substances: acid catalyst =1 g: 0.3 g; the ratio of the reactants to the solvent is that etherified substances: fifth organic solvent =1 g: 12 ml;
F. the sixth organic solvent in the synthesis of the 1-dehydrogen is dioxane; the dehydrogenation reaction temperature is 75-80 ℃; the weight ratio of reactants is as follows: dehydrogenating agent DDQ =1 g: 0.8 g; the ratio of reactants to solvent is: reduction product: sixth organic solvent =1 g: 12 ml.
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