CN106518945A - Preparation method of 6a-methyl hydrocortisone - Google Patents
Preparation method of 6a-methyl hydrocortisone Download PDFInfo
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- 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 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229960000890 hydrocortisone Drugs 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- 239000003960 organic solvent Substances 0.000 claims abstract description 46
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 16
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 42
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 32
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 32
- 229960004544 cortisone Drugs 0.000 claims description 32
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 32
- 230000015572 biosynthetic process Effects 0.000 claims description 30
- 238000003786 synthesis reaction Methods 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000005406 washing Methods 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- 238000011084 recovery Methods 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 20
- 239000012065 filter cake Substances 0.000 claims description 19
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 16
- 239000006210 lotion Substances 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 239000000376 reactant Substances 0.000 claims description 15
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 10
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 10
- 239000010808 liquid waste Substances 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000006386 neutralization reaction Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006073 displacement reaction Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 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 6
- 230000005945 translocation Effects 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- -1 enol form hydrocortisones Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 241000790917 Dioxys <bee> Species 0.000 claims description 2
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000008331 Pinus X rigitaeda Nutrition 0.000 claims 1
- 235000011613 Pinus brutia Nutrition 0.000 claims 1
- 241000018646 Pinus brutia Species 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 17
- 238000000034 method Methods 0.000 abstract description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 2
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 abstract 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 abstract 1
- 229960005471 androstenedione Drugs 0.000 abstract 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 abstract 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 abstract 1
- 150000002085 enols Chemical class 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 20
- 238000001035 drying Methods 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 5
- 240000001811 Dioscorea oppositifolia Species 0.000 description 5
- 229960004584 methylprednisolone Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
- 229930182490 saponin Natural products 0.000 description 4
- 150000007949 saponins Chemical class 0.000 description 4
- 235000002722 Dioscorea batatas Nutrition 0.000 description 3
- 235000006536 Dioscorea esculenta Nutrition 0.000 description 3
- 235000003416 Dioscorea oppositifolia Nutrition 0.000 description 3
- 150000001886 cortisols Chemical class 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- OXIKLRTYAYRAOE-CMDGGOBGSA-N (e)-3-(1-benzyl-3-pyridin-3-ylpyrazol-4-yl)prop-2-enoic acid Chemical compound N1=C(C=2C=NC=CC=2)C(/C=C/C(=O)O)=CN1CC1=CC=CC=C1 OXIKLRTYAYRAOE-CMDGGOBGSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000165940 Houjia Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 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
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention provides a preparation method of 6a-methyl hydrocortisone. The preparation method comprises the steps that hydrocortisone prepared from 4-androstene-3,17-dione (called as 4AD for short) is adopted as a raw material to generate an acid catalytic reaction with triethyl orthoformate in an organic solvent, and etherate 3-ether enol hydrocortisone is obtained; the etherate generates a Manlixi reaction with N-methylaniline and formaldehyde in an organic solvent, and a methylene product 6-methylene hydrocortisone is obtained; the methylene product generates a catalytic hydrogenation reaction in an organic solvent, and 6a-methyl hydrocortisone is obtained. Compared with a production method achieved by taking a mold removal product obtained by processing diosgenin as a raw material, the method for producing 6a-methyl hydrocortisone has the advantages that raw material sources are wide, the processes are economical and environmentally friendly, production operation is easy and convenient, the synthetic route is short, and the product yield is high; by producing 6a-methyl hydrocortisone through the method, the production cost is reduced by 40%-50% compared with a traditional method; the solvents used in production can be recycled and cyclically reused, and implementation of industrialized production is promoted.
Description
Technical field
The invention belongs to the fabricating technology of steroid hormone medicine and its intermediate, and in particular to a kind of Methyllprednisolone
The preparation method of the key intermediate 6a- hydrogenated methyl cortisones of dragon.
Background technology
Methylprednisolone (molecular formula C22H32O5), chemical entitled 6a- methyl isophthalic acids 1b, 17a, 21- trihydroxy-pregnant steroid-
Isosorbide-5-Nitrae-diene -3,20- diketone is a kind of second generation steroidal glucocorticoid medicine.Clinically it is mainly used in primary and secondary
Cortical hypofunction, rheumatism, day born of the same parents' sore, acute bronchial asthma, allergic rhinitis, lupus erythematosus, shock, children on property kidney
The treatment of the numerous diseases such as the hypercalcinemia that acute leukemia, tumour cause, side effect are low, and effect is good, wide market.
6a- hydrogenated methyl cortisones are the key intermediates for producing methylprednisolone, by which with the dehydrogenation of DDQ1 positions or additive method 1
Dehydrogenation obtains methylprednisolone.
The conventional production methods of 6a- methylprednisolones are, with the Chinese yam saponin extracted in Chinese yam plant, six steps of Jing chemistry
The important hormone pharmaceutical intermediate 21 that reaction, a step microbial fermentation, then tri- step chemical reactions of Jing are obtained deoxygenates cortisone for original
The six-step processes such as material, 3 alkene etherificates of Jing, 6 precedences methylate, 6 hydrogenations, 3,20 ketal protections, 11 reduction, deprotections,
Prepared key intermediate P6, on P6 Jing, iodine, displacement two-step reaction, are obtained 6a- hydrogenated methyl cortisones, and its process route is shown in accompanying drawing
1.Its synthetic route is long, and synthesis total recovery is low, and wherein the extraction of Chinese yam saponin and the chemical reaction of multistep synthesis thereafter are produced
Waste water is more, and not disposable, easily pollutes environment.Importantly, with wild Chinese yam plant resources increasingly depleted, and plant
Chinese yam plant causes saponin, the production cost of mould oxygen to be doubled and redoubled, causes because of the increasingly rising of the planting costs such as artificial, chemical fertilizer
The production cost of 6- hydrogenated methyls cortisone and methylprednisolone is doubled and redoubled, already the world market to methylprednisolone
Generate significant impact.
The content of the invention
It is an object of the invention to provide with hydrocortisone as raw material, Jing three-step reactions synthesis 6- hydrogenated methyl cortisones
Preparation method, greatly improves synthesis total recovery, significantly reduces its production cost, it is to avoid 6a- hydrogenated methyl cortisone traditional modes of production
In technique, raw materials for production are expensive, sewage disposal is difficult, complex operation, many defects such as production cost height.
The technical scheme is that：The preparation method of 6a- hydrogenated methyl cortisones, using by 4-AD（Referred to as
4AD）The hydrocortisone of preparation is raw material, and the etherificate of Jing 3,6 precedences methylate, hydrogenate, three-step reaction synthesis 6a- hydrogenated methyls
Cortisone, i.e.,：
A, synthesis etherate, it is with the hydrocortisone prepared by 4AD, anti-with triethyl orthoformate acid catalysis in organic solvent
Should, obtain etherate：3- vinyl ether hydrocortisones；
B, synthesis methine thing, wish reaction in etherate is occurred completely with methylphenylamine and formaldehyde in organic solvent, obtain secondary
Methyl thing：6- methine hydrocortisones；
C, synthesis 6a- hydrogenated methyl cortisones, methine thing is carried out catalytic hydrogenation in organic solvent, 6a- methyl is obtained
Hydrocortisone.
Further, a kind of 6a- hydrogenated methyls cortisone preparation method, concrete operation step are as follows：
A, synthesis etherate：Be that hydrocortisone is dissolved in organic solvent, triethyl orthoformate is added at 40-70 DEG C,
Under strong acid catalyst react 6～8 hours, TLC confirm reaction end, after react, plus alkali neutralization, recovery organic solvent, then with
Ethanol water is crystallized, dry etherate：3- ether base enol form hydrocortisones, HPLC contents 97.0-99.0%, weight
Yield 100-105%；
B, synthesis methine thing：Above-mentioned etherate to be dissolved in organic solvent, add methylphenylamine and 37% formaldehyde it is water-soluble
Liquid, stirring, adds acid catalyst, is incubated, then is incubated in 50-70 DEG C of continuation reaction 1-1.5
Hour, TLC confirms reaction end, after having reacted, adds appropriate adjusting PH with base 7-8, reduced pressure concentration organic solvent to dry, Ran Houjia
Enter methyl alcohol, stir, be cooled to 0-10 DEG C, then concentrated hydrochloric acid is slowly added dropwise, be incubated after adding little in 20-30 DEG C of continuation reaction 16-18
When, TLC confirms reaction end, after react, the methyl alcohol of reduced pressure concentration about 80%, and cooling, addition is equivalent to 3-4 times of etherate
Running water, stirring and crystallizing 2-3 hour, centrifugation, washing, washing lotion enter purification tank for liquid waste after reclaiming organic solvent with filtrate decompression,
It is dried below 70 DEG C of filter cake, obtains methine thing crude product, HPLC contents 96.0-97.5%, weight yield 100-105%；Crude product Jing C4
Following low carbon alcohol solution recrystallization, obtains methine thing fine work, and HPLC contents more than 99.0% refine weight yield 80-85%, this
Step weight total recovery 82-85%；
C, synthesis 6a- hydrogenated methyl cortisones：It is above-mentioned methine thing to be dissolved in organic solvent, adds palladium carbon catalyst, nitrogen
After gas displacement, it is incubated at 45-65 DEG C, is slowly added into cyclohexene, adds in 0.5-1.0 hours, after adding again at 45-65 DEG C
Insulation reaction 1.5-2 hour, HPLC confirm reaction end, after having reacted, filter palladium charcoal immediately, are cooled to 25-30 DEG C, slowly drip
Plus 6N concentrated acids, dripping off in 0.5-1.0 hours, be then incubated again, HPLC confirms
Reaction end, after having reacted, adds 10% soda bath to be neutralized to the pH6.5-7.5 of solution, and reduced pressure concentration reclaims having for 90-95%
After machine solvent, cool to 10-25 DEG C, add the running water of quite 2 times of thrown methine thing thing, stirring and crystallizing 1.5-2.5
Hour, centrifugation, washing, washing lotion enter purification tank for liquid waste with filtrate, be dried, obtain 6a- hydrogenated methyl cortisones below 100 DEG C of filter cake
Crude product, HPLC contents 98.0-99.0%, weight yield 80-85%；The following low-carbon alcohols recrystallizations of crude product Jing C4, obtain 6a- hydrogenated methyls
Cortisone fine work, HPLC contents more than 99.0% refine weight yield 85-90%, this step weight total recovery 70-75%；Three steps synthesize
Total recovery 60-65% of 6a- hydrogenated methyl cortisones.
Above-mentioned 6a- hydrogenated methyls cortisone preparation method, is further described below：
Organic solvent described in A, etherate synthesis, including dichloromethane, toluene, below C4 low-carbon alcohols, acid catalyst include salt
Acid, sulfuric acid, phosphoric acid, or acetic acid, p-methyl benzenesulfonic acid, oxalic acid；Weak base used by neutralization includes sodium carbonate or pyridine, reaction temperature 20～
70℃；The weight proportion of reactant is, hydrocortisone：Triethyl orthoformate：Acid=1g：0.5～1.0g:0.01～0.05g；
Proportioning between reactant and solvent is, hydrocortisone：Organic solvent=1g：4～8ml；
Described in B, the synthesis of methine thing, organic solvent includes：Toluene, dichloromethane, chloroform, DMF, tetrahydrofuran, dioxy six
Ring, below C4 low-carbon alcohols or their mixture, it is full in wish reaction acid used include hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, to first
Benzene sulfonic acid, oxalic acid；Alkali used by neutralization includes pyridine or triethylamine, it is full in wish 10～40 DEG C of the reaction temperature of reaction, Man Lixi is anti-
The weight proportion for answering thing is, etherate：Methylphenylamine：Formaldehyde：Acid=1g：0.5～1.0ml:2.0～2.6ml:0.01～
0.05g；Proportioning between reactant and solvent is, etherate：Organic solvent=1g：5～15ml, 10-40 DEG C of hydrolysising reacting temperature,
Each material proportion of hydrolysis is etherate：Methyl alcohol：Acid=1g：5～10ml:1.2～1.5g；
Described in the synthesis of C, 6a- hydrogenated methyl cortisone, organic solvent includes：Toluene, dichloromethane, tetrahydrofuran, acetic acid second
Ester, DMF, glacial acetic acid, below C4 low-carbon alcohols；Hydrogenation catalyst is palladium charcoal or active nickel；Reaction temperature is 45-65 DEG C；Turn
The acid of position reaction includes sulfuric acid, hydrochloric acid, and reaction temperature is 10-40 DEG C；Weight proportion between hydrogenation thing is, methine thing：
Hydroborating reagent：Catalyst=1g：1.5～2.5ml：0.1-0.3g, the proportioning between hydrogenation reactant and solvent is：Methine
Thing：Organic solvent=1g：3-5ml, needed for hydrolysis, the proportioning of acid is：Methine thing：Acid=1g：2-4ml.
The mode of priority of the 6a- hydrogenated methyl cortisone preparation methods is：
Described in etherate synthesis, organic solvent is ethanol；Acid catalyst p-methyl benzenesulfonic acid；40～50 DEG C of neutralization reaction temperature,
The weight proportion of reactant is, hydrocortisone：Triethyl orthoformate：Acid=1g：0.8g：0.02g；
Described in the synthesis of methine thing, organic solvent is dichloromethane or ethanol；Man Lixi reactions acid used is to toluene sulphur
Acid, 25～30 DEG C of reaction temperature；In full, the weight proportion of uncommon reactant is, etherate：Methylphenylamine：Formaldehyde：Acid=
1g：0.8ml：2.2ml：0.02g；Proportioning between reactant and solvent is 1g::8～10ml；20-25 DEG C of hydrolysising reacting temperature；First
Alcohol：Acid=1g：8ml：1.25g；
Described in the synthesis of 6a- hydrogenated methyls cortisone, organic solvent is ethanol, and hydrogenation temperature is 55-60 DEG C；Translocation reaction
Acid be hydrochloric acid, reaction temperature is 20-25 DEG C；Methine thing：Hydroborating reagent：Catalyst=1g：2ml：0.2g；Reactant with it is molten
Proportioning between agent is, methine thing：Organic solvent=1g：4ml；Methine thing：Acid=1g：3ml.
The invention has the beneficial effects as follows：As raw material, 3 etherificates of Jing, 6 precedences methylate hydrocortisone with 4AD preparations,
The three-step reactions such as hydrogenation synthesis 6a- hydrogenated methyl cortisones are relative that the biography that the mould de- thing for obtaining makees raw material is processed with Chinese yam saponin
System method, present invention process have raw material sources extensively, and process economicses environmental protection, production operation are easy, and synthetic route is short, and product is received
Many advantages, such as rate is high；6a- hydrogenated methyl cortisones are produced with this law, production cost reduces 40-50% than conventional method；Production
Used in the recyclable recycled of solvent, easily implement industrialized production.
Description of the drawings
Fig. 1 is the synthetic route chart of conventional method 6a- hydrogenated methyl cortisone；
Fig. 2 is the synthetic route chart of 6a- hydrogenated methyls cortisone of the present invention.
Specific embodiment
In order to more easily illustrate the main points of the present invention and spirit, citing below is explained：
Embodiment one：
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g hydrocortisones, 200ml ethanol, 80ml triethyl orthoformates, 2g pair
Toluenesulfonic acid, is incubated in 40-45 degree stirring reaction 6～8 hours, TLC detection reaction ends, after react, addition 3ml pyridines,
Stirring 20-25 minutes neutralize acid, and then the organic solvent of recovered under reduced pressure 90-95%, adds the ethanol water of 500ml 50%,
System is cooled to into -5-0 degree, stirred crystallization 2～3 hours, suction filtration, a small amount of ethanol water washing, washing lotion and filtrate merging, is returned
Solvent is received, drying below 70 degree of filter cake obtains etherate 101.6g, HPLC contents 99.2%, weight yield 101.6%.
The preparation of B, methine thing
In a 1000ml there-necked flask, 100g etherates, 800ml ethanol, 50ml dichloromethane are added, 2g after dissolving, is added
P-methyl benzenesulfonic acid and the solution of 50ml ethanol, then add the formalin of 70mlN- methylanilines and 200ml 37%, rise
Temperature is reacted 1.5～2.0 hours to 25-30 degree insulated and stirred, then continues reaction 1.0-1.5 hours in 50-55 degree, and TLC detections are anti-
Terminal is answered, after having reacted, is added 4ml triethylamines to be neutralized to PH7-8, then reduced pressure concentration, is reclaimed the organic solvent of 90-95%.It is residual
Night adds 800ml methyl alcohol, is cooled to 0-5 degree, and the concentrated hydrochloric acid of 40ml 36% is added dropwise so as to slowly complete molten, is then incubated in 20-25 degree
Reaction 16-18 hours, TLC confirm reaction end, and after having reacted, then recovered under reduced pressure about 650ml methyl alcohol cool down, and add 300ml
Pure water, then system is cooled to into 5-10 degree, stirring and crystallizing 2-3 hour is filtered, and filter cake is washed with a small amount of 50% methanol aqueous solution
Wash, washing lotion and filtrate merge, and purification tank for liquid waste is entered after recycling design, and drying below 70 degree of filter cake obtains methine thing crude product
102.8g, HPLC content 97.2%, crude product obtain methine thing fine work 84.5g with 95% ethyl alcohol recrystallization, HPLC contents 99.2%,
Weight total recovery 84.5%.
C：The preparation of 6a- hydrogenated methyl cortisones
In a 1000ml there-necked flask, 100g methine things, 800ml ethanol are added, after dissolving, add the palladium carbon of 20g 5%,
45-50 degree is incubated after nitrogen displacement 200ml cyclohexene is slowly added dropwise, dripped off within about 0.5 hour, then heat to the continuation of 55-60 degree
Insulated and stirred is reacted 1.5～2 hours, TLC detection reaction ends, after having reacted, emptying, and nitrogen press filtration while hot, 50ml ethanol are washed
Wash, filter cake send producer to reclaim；Washing lotion and filtrate merge, and are cooled to 25-30 degree, and 240ml 6N hydrochloric acid, about 0.5-1.0 is slowly added dropwise
Drip off in hour, be then incubated again and continue translocation reaction 1.5-2.0 hours in 45-50 degree, HPLC confirms reaction end, reacted
Afterwards, add 10% soda bath to be neutralized to PH6.5-7.5, the ethanol of reduced pressure concentration 90-95% is cooled to 20-25 degree, add
200ml running water, then system is cooled to into 5-10 degree, stirring and crystallizing 2-3 hour, filtration, washing, filtrate and washing lotion concentration and recovery
Purification tank for liquid waste is entered after solvent, drying below 100 degree of filter cake obtains 6a- hydrogenated methyl cortisone crude product 82.5g, HPLC contents
98.3%, weight total recovery 82.5%；Above-mentioned 6- hydrogenated methyls cortisone crude product is recrystallized with 80% ethanol water, 6a- is obtained
Hydrogenated methyl cortisone fine work 72.8g, HPLC contents 99.3%, this step weight total recovery 72.8%.
Example two
The preparation of A, etherate
In a 1000ml there-necked flask, add 100g hydrocortisones, 200ml chloroforms, 80ml triethyl orthoformates, 2g dense
Sulfuric acid, is incubated in 40-45 degree stirring reaction 6～8 hours, TLC detection reaction ends, after react, adds 3ml pyridines, stir
20-25 minutes neutralize acid, then the organic solvent of recovered under reduced pressure 90-95%, add the ethanol water of 500ml 50%, by body
System is cooled to -5-0 degree, stirred crystallization 2～3 hours, suction filtration, a small amount of ethanol water washing, washing lotion and filtrate merging, reclaims molten
Agent, drying below 70 degree of filter cake obtain etherate 101.2g, HPLC contents 99.0%, weight yield 101.2%.
The preparation of B, methine thing
In a 1000ml there-necked flask, 100g etherates, 800ml tetrahydrofurans, 50ml chloroforms are added, added after dissolving
Enter the solution of the 2g concentrated sulfuric acids and 50ml tetrahydrofurans, then add 70mlN- methylanilines molten with the formaldehyde of 200ml 37%
Liquid, is warming up to 25-30 degree insulated and stirred and reacts 1.5～2.0 hours, then continues reaction 1.0-1.5 hours, TLC inspections in 50-55 degree
Reaction end is surveyed, after having reacted, is added 6ml pyridines to be neutralized to PH7-8, then reduced pressure concentration, is reclaimed the organic solvent of 90-95%.
Residual night adds 800ml methyl alcohol, is cooled to 0-5 degree, and the concentrated hydrochloric acid of 40ml 36% is added dropwise so as to slowly complete molten, is then incubated in 20-25
Degree reaction 16-18 hours, TLC confirm reaction end, and after having reacted, then recovered under reduced pressure about 650ml methyl alcohol cool down, and adds
300ml pure water, then system is cooled to into 5-10 degree, stirring and crystallizing 2-3 hour is filtered, filter cake with a small amount of 50% methanol-water
Solution is washed, and washing lotion and filtrate merge, and purification tank for liquid waste is entered after recycling design, and drying below 70 degree of filter cake obtains methine thing
Crude product 101.2g, HPLC content 97.5%, crude product obtain methine thing fine work 82.6g, HPLC contents with 95% ethyl alcohol recrystallization
99.4%, weight total recovery 82.6%.
The preparation of C, 6a- hydrogenated methyl cortisone
In a 1000ml there-necked flask, 100g methine things, 800ml chloroforms are added, after dissolving, add the palladium carbon of 20g 5%,
45-50 degree is incubated after nitrogen displacement 200ml cyclohexene is slowly added dropwise, dripped off within about 0.5 hour, then heat to the continuation of 55-60 degree
Insulated and stirred is reacted 1.5～2 hours, TLC detection reaction ends, after having reacted, emptying, and nitrogen press filtration while hot, 50ml chloroforms are washed
Wash, filter cake send producer to reclaim；Washing lotion and filtrate merge, and are cooled to 25-30 degree, and 240ml 6N hydrochloric acid, about 0.5-1.0 is slowly added dropwise
Drip off in hour, be then incubated again and continue translocation reaction 1.5-2.0 hours in 45-50 degree, HPLC confirms reaction end, reacted
Afterwards, 10% soda bath is added to be neutralized to PH6.5-7.5, reduced pressure concentration reclaims the chloroform of 90-95%, is cooled to 20-25 degree, plus
Enter 200ml running water, then system is cooled to into 5-10 degree, stirring and crystallizing 2-3 hour is filtered, and washing, filtrate are concentrated back with washing lotion
Purification tank for liquid waste is entered after receiving solvent, drying below 100 degree of filter cake obtains 6a- hydrogenated methyl cortisone crude product 81.5g, and HPLC contains
Amount 98.5%, weight total recovery 81.5%；Above-mentioned 6a- hydrogenated methyls cortisone crude product is recrystallized with 80% ethanol water, is obtained
6a- hydrogenated methyl cortisone fine work 70.8g, HPLC contents 99.5%, this step weight total recovery 70.8%.
Embodiment three
The preparation of A, etherate
In a 1000ml there-necked flask, 100g hydrocortisones, 200ml toluene, 80ml triethyl orthoformates, 2gHCl are added
With the mixed solution of 20ml ethanol, it is incubated in 40-45 degree stirring reaction 6～8 hours, TLC detection reaction ends, after having reacted,
3ml pyridines, stirring 20-25 minutes is added to neutralize acid, then the organic solvent of recovered under reduced pressure 90-95%, adds 500ml 50%
Ethanol water, system is cooled to into -5-0 degree, stirred crystallization 2～3 hours, suction filtration, a small amount of ethanol water washing, washing lotion
Merge with filtrate, recycling design, drying below 70 degree of filter cake obtain etherate 100.8g, HPLC contents 99.5%, weight yield
100.8%。
The preparation of B, methine thing
In a 1000ml there-necked flask, 100g etherates, 800ml toluene, 50ml chloroforms are added, 2g after dissolving, is added
P-methyl benzenesulfonic acid and the mixed solution of 50ml toluene, then add 70mlN- methylanilines molten with the formaldehyde of 200ml 37%
Liquid, is warming up to 25-30 degree insulated and stirred and reacts 1.5～2.0 hours, then continues reaction 1.0-1.5 hours, TLC inspections in 50-55 degree
Reaction end is surveyed, after having reacted, is added 4ml triethylamines to be neutralized to PH7-8, then reduced pressure concentration, is reclaimed the organic molten of 90-95%
Agent.Residual night adds 800ml methyl alcohol, is cooled to 0-5 degree, and the concentrated hydrochloric acid of 40ml 36% is added dropwise so as to slowly complete molten, be then incubated in
20-25 degree reacts 16-18 hours, and TLC confirms reaction end, and after having reacted, then recovered under reduced pressure about 650ml methyl alcohol cool down, plus
Enter 300ml pure water, then system be cooled to into 5-10 degree, stirring and crystallizing 2-3 hour is filtered, filter cake with a small amount of 50% methyl alcohol
Solution washing, washing lotion and filtrate merge, and purification tank for liquid waste is entered after recycling design, and drying below 70 degree of filter cake obtains methine
Thing crude product 100.8g, HPLC contents 98.5%, crude product obtain methine thing fine work 82.2g, HPLC contents with 95% ethyl alcohol recrystallization
99.6%, weight total recovery 82.2%.
The preparation of C, 6a- hydrogenated methyl cortisone
In a 1000ml there-necked flask, 100g methine things, 800ml ethyl acetate are added, after dissolving, add the palladium of 20g 5%
Carbon, after nitrogen displacement be incubated 45-50 degree 200ml cyclohexene is slowly added dropwise, drip off within about 0.5 hour, then heat to 55-60 degree after
The warm stirring reaction of continuation of insurance 1.5～2 hours, TLC detection reaction ends, after having reacted, emptying, nitrogen press filtration while hot, 50ml acetic acid
Ethyl ester is washed, and filter cake send producer to reclaim；Washing lotion and filtrate merge, and are cooled to 25-30 degree, 240ml 6N hydrochloric acid are slowly added dropwise, about
Drip off in 0.5-1.0 hours, be then incubated again and continue translocation reaction 1.5-2.0 hours in 45-50 degree, HPLC confirms reaction eventually
Point, after having reacted, adds 10% soda bath to be neutralized to PH6.5-7.5, and the ethyl acetate of reduced pressure concentration 90-95% is cooled to
20-25 degree, adds 200ml running water, then system is cooled to 5-10 degree, and stirring and crystallizing 2-3 hour is filtered, washing, filtrate with
Purification tank for liquid waste is entered after washing lotion concentration and recovery solvent, drying below 100 degree of filter cake obtains 6a- hydrogenated methyl cortisone crude products
84.2g, HPLC content 98.5%, weight total recovery 84.2%；Above-mentioned 6- hydrogenated methyls cortisone crude product is water-soluble with 80% ethanol
Liquid is recrystallized, and obtains 6a- hydrogenated methyl cortisone fine work 74.0g, HPLC contents 99.5%, this step weight total recovery 74.0%.
Claims (4)
1. a kind of preparation method of 6a- hydrogenated methyls cortisone, adopts by 4-AD（Abbreviation 4AD）Preparation hydrogenation can
Pine is raw material, and the etherificate of Jing 3,6 precedences methylate, hydrogenate, three-step reaction synthesis 6a- hydrogenated methyl cortisones, i.e.,：
A, synthesis etherate, it is with the hydrocortisone prepared by 4AD, anti-with triethyl orthoformate acid catalysis in organic solvent
Should, obtain etherate：3- ether base enol form hydrocortisones；
B, synthesis methine thing, wish reaction in etherate is occurred completely with methylphenylamine and formaldehyde in organic solvent, obtain secondary
Methyl thing：6- methine hydrocortisones；
C, synthesis 6a- hydrogenated methyl cortisones, methine thing is carried out catalytic hydrogenation in organic solvent, 6a- methyl is obtained
Hydrocortisone.
2. 6a- hydrogenated methyls cortisone preparation method according to claim 1, concrete operation step are as follows：
A, synthesis etherate：Be that hydrocortisone is dissolved in organic solvent, triethyl orthoformate is added at 40-70 DEG C,
Under strong acid catalyst react 6～8 hours, TLC confirm reaction end, after react, plus alkali neutralization, recovery organic solvent, then with
Ethanol water is crystallized, dry etherate：3- ether base enol form hydrocortisones, HPLC contents 97.0-99.0%, weight
Yield 100-105%；
B, synthesis methine thing：Above-mentioned etherate to be dissolved in organic solvent, add methylphenylamine and 37% formaldehyde it is water-soluble
Liquid, stirring, adds acid catalyst, is incubated, then is incubated in 50-70 DEG C of continuation reaction 1-1.5
Hour, TLC confirms reaction end, adds adjusting PH with base 7-8, and reduced pressure concentration organic solvent is subsequently adding methyl alcohol to dry, stirs,
0-10 DEG C is cooled to, then concentrated hydrochloric acid is slowly added dropwise, be incubated after adding, TLC confirms anti-
Answer terminal；The methyl alcohol of rear reduced pressure concentration 80% is reacted, has been cooled down, added the running water equivalent to 3-4 times of etherate, stirring and crystallizing
2-3 hours, centrifugation, washing, washing lotion enter purification tank for liquid waste after reclaiming organic solvent with filtrate decompression, do below 70 DEG C of filter cake
It is dry, obtain methine thing crude product；HPLC contents 96.0-97.5%, weight yield 100-105%；The following low-carbon alcohols of crude product Jing C4 are water-soluble
Liquid is recrystallized, and obtains methine thing fine work, and HPLC contents more than 99.0% refine weight yield 80-85%, this step weight total recovery
82-85%；
C, synthesis 6a- hydrogenated methyl cortisones：Above-mentioned methine thing is dissolved in organic solvent, palladium carbon catalyst, nitrogen is added
After displacement, it is incubated at 45-65 DEG C, is slowly added into cyclohexene, adds in 0.5-1.0 hours, is protected at 45-65 DEG C after adding again
Temperature reaction 1.5-2 hours, HPLC confirm reaction end, filter palladium charcoal immediately, be cooled to 25-30 DEG C, be slowly added dropwise after having reacted
6N concentrated acids, drip off in 0.5-1.0 hours, are then incubated again, and HPLC confirms anti-
Terminal is answered, after having reacted, adds 10% soda bath to be neutralized to the pH6.5-7.5 of solution, reduced pressure concentration reclaims the organic of 90-95%
After solvent, cool to 10-25 DEG C, add the running water of 2 times of methine thing thing, stirring and crystallizing 1.5-2.5 hour to be centrifuged,
Washing, washing lotion enter purification tank for liquid waste with filtrate, be dried, obtain 6a- hydrogenated methyl cortisone crude products below 100 DEG C of filter cake；HPLC
Content 98.0-99.0%, weight yield 80-85%；The following low-carbon alcohols recrystallizations of crude product Jing C4, obtain 6a- hydrogenated methyls cortisone essence
Product, HPLC contents more than 99.0% refine weight yield 85-90%, this step weight total recovery 70-75%；Three steps synthesize 6a- methyl
Total recovery 60-65% of hydrocortisone.
3. 6a- hydrogenated methyls cortisone preparation method according to claim 2, is characterized in that,
Organic solvent described in A, etherate synthesis, including dichloromethane, toluene, below C4 low-carbon alcohols, acid catalyst include salt
Acid, sulfuric acid, phosphoric acid, or acetic acid, p-methyl benzenesulfonic acid, oxalic acid；Weak base used by neutralization includes sodium carbonate or pyridine, reaction temperature 20～
70℃；The weight proportion of reactant is, hydrocortisone：Triethyl orthoformate：Acid=1：0.5～1.0:0.01～0.05；Instead
The proportioning between thing and solvent is answered to be, hydrocortisone：Organic solvent=1g：4～8ml；
Described in B, the synthesis of methine thing, organic solvent includes：Toluene, dichloromethane, chloroform, DMF, tetrahydrofuran, dioxy six
Ring, below C4 low-carbon alcohols or their mixture, it is full in wish reaction acid used include hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, to first
Benzene sulfonic acid, oxalic acid；Alkali used by neutralization includes pyridine or triethylamine, it is full in wish 10～40 DEG C of the reaction temperature of reaction, Man Lixi is anti-
The weight proportion for answering thing is, etherate：Methylphenylamine：Formaldehyde：Acid=1g：0.5～1.0ml:2.0～2.6ml:0.01～
0.05g；Proportioning between reactant and solvent is, etherate：Organic solvent=1g：5～15ml, 10-40 DEG C of hydrolysising reacting temperature,
Each material proportion of hydrolysis is etherate：Methyl alcohol：Acid=1g：5～10ml:1.2～1.5g；
Described in the synthesis of C, 6a- hydrogenated methyl cortisone, organic solvent includes：Toluene, dichloromethane, tetrahydrofuran, acetic acid second
Ester, DMF, glacial acetic acid, below C4 low-carbon alcohols；Hydrogenation catalyst is palladium charcoal or active nickel；Reaction temperature is 45-65 DEG C；Turn
The acid of position reaction includes sulfuric acid, hydrochloric acid, and reaction temperature is 10-40 DEG C；Weight proportion between hydrogenation thing is, methine thing：
Hydroborating reagent：Catalyst=1g：1.5～2.5ml：0.1-0.3g, the proportioning between hydrogenation reactant and solvent is：Methine
Thing：Organic solvent=1g：3-5ml, needed for hydrolysis, the proportioning of acid is：Methine thing：Acid=1g：2-4ml.
4. the 6a- hydrogenated methyl cortisone preparation methods according to Claims 2 or 3, is characterized in that,
Described in etherate synthesis, organic solvent is ethanol；Acid catalyst p-methyl benzenesulfonic acid；40～50 DEG C of neutralization reaction temperature,
The weight proportion of reactant is, hydrocortisone：Triethyl orthoformate：Acid=1g：0.8g：0.02g；
Described in the synthesis of methine thing, organic solvent is dichloromethane or ethanol；Man Lixi reactions acid used is to toluene sulphur
Acid；25～30 DEG C of reaction temperature；In full, the weight proportion of uncommon reactant is, etherate：Methylphenylamine：Formaldehyde：Acid=
1g：0.8ml：2.2ml：0.02g；Proportioning between reactant and solvent is 1g::8～10ml；20-25 DEG C of hydrolysising reacting temperature；First
Alcohol：Acid=1g：8ml：1.25g；
Described in the synthesis of 6a- hydrogenated methyls cortisone, organic solvent is ethanol, and hydrogenation temperature is 55-60 DEG C；Translocation reaction
Acid be hydrochloric acid, reaction temperature is 20-25 DEG C；Methine thing：Hydroborating reagent：Catalyst=1g：2ml：0.2g；Reactant with it is molten
Proportioning between agent is, methine thing：Organic solvent=1g：4ml；Methine thing：Acid=1g：3ml.
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| RU2663484C1 (en) * | 2017-05-18 | 2018-08-06 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | METHOD OF PREPARATION 6α-METHYLHYDROCORTISONE OR ESTERS THEREOF FROM HYDROCORTISONE 21-ACETATE |
| CN107338281A (en) * | 2017-06-26 | 2017-11-10 | 浙江仙琚制药股份有限公司 | The method for preparing methylprednisolone |
| RU2664101C1 (en) * | 2017-06-30 | 2018-08-15 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Method for producing 6-methylenehydrocortisone or esters thereof from hydrocortisone 21-acetate |
| RU2663893C1 (en) * | 2017-07-14 | 2018-08-13 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Method for obtaining 6-dehydro-6-methylhydrocortisone or ester thereof from hydrocortisone 21-acetate |
| RU2663483C1 (en) * | 2017-12-29 | 2018-08-06 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Method of preparing 6-(n-methyl-n-phenyl)aminomethyl-hydrocortisone esters thereof from hydrocortisone 21-acetate |
| CN110655548B (en) * | 2018-06-29 | 2022-05-17 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN110655549B (en) * | 2018-06-29 | 2022-06-14 | 天津药业研究院股份有限公司 | Preparation method of 6 beta-methylprednisolone |
| CN110655548A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methyl steroid compound |
| CN110655549A (en) * | 2018-06-29 | 2020-01-07 | 天津药业研究院有限公司 | Preparation method of 6 beta-methylprednisolone |
| CN109678919A (en) * | 2018-12-27 | 2019-04-26 | 重庆华邦胜凯制药有限公司 | A kind of preparation method of Methylprednisolone succinate impurity |
| CN109485686B (en) * | 2018-12-27 | 2021-08-27 | 重庆华邦胜凯制药有限公司 | Method for improving content of key intermediate 6 beta in methylprednisolone succinate impurity synthesis |
| CN109485686A (en) * | 2018-12-27 | 2019-03-19 | 重庆华邦胜凯制药有限公司 | A method of improving 6 β content of key intermediate in the synthesis of Methylprednisolone succinate impurity |
| CN113583074A (en) * | 2021-06-28 | 2021-11-02 | 佳尔科生物科技南通有限公司 | Novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and precursor thereof |
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