CN102863505A - Process for synthesizing triamcinolone acetonide acetate - Google Patents
Process for synthesizing triamcinolone acetonide acetate Download PDFInfo
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- VOBDXTSTTMAKHK-VHDCPBDGSA-N 3870-07-3 Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O VOBDXTSTTMAKHK-VHDCPBDGSA-N 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 29
- 230000008569 process Effects 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 108
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000463 material Substances 0.000 claims abstract description 38
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 28
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 26
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000012043 crude product Substances 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000019253 formic acid Nutrition 0.000 claims abstract description 13
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 96
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 70
- 239000012065 filter cake Substances 0.000 claims description 37
- 238000003756 stirring Methods 0.000 claims description 25
- 238000000967 suction filtration Methods 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 24
- 238000010189 synthetic method Methods 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 20
- 238000010792 warming Methods 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 229960001701 chloroform Drugs 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- 230000001143 conditioned effect Effects 0.000 claims description 10
- 239000000796 flavoring agent Substances 0.000 claims description 10
- 235000019634 flavors Nutrition 0.000 claims description 10
- 238000009413 insulation Methods 0.000 claims description 10
- 235000010265 sodium sulphite Nutrition 0.000 claims description 10
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 230000006837 decompression Effects 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000009423 ventilation Methods 0.000 claims description 5
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 5
- 230000001988 toxicity Effects 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- -1 acetic acid tetraene Chemical class 0.000 abstract 1
- 238000001514 detection method Methods 0.000 abstract 1
- 238000003682 fluorination reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound 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 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
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- 238000005516 engineering process Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010041277 Sodium retention Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 208000004760 Tenosynovitis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- Steroid Compounds (AREA)
Abstract
The invention discloses a process for synthesizing triamcinolone acetonide acetate. The process comprises the steps of firstly, taking an acetic acid tetraene material as a raw material, and obtaining an oxide through an oxidation reaction under the effect of methanoic acid and potassium permanganate; secondly, taking the oxide as a raw material, and obtaining a ring-reducing material through a ring-reducing reaction under the effect of perchloric acid and N-bromosuccinimide; thirdly, taking the ring-reducing material as a raw material, and conducting a fluorination reaction under the effect of fluorine hydride and dimethylformamide to obtain a triamcinolone acetonide acetate crude product; and fourthly, purifying the triamcinolone acetonide acetate crude product to obtain the triamcinolone acetonide acetate. The process is mild in reaction condition, easy to control, low in toxicity and dangerousness of used auxiliary materials, low in pollution and applicable to industrial production, the triamcinolone acetonide acetate which is synthesized by the process is subjected to high performance liquid chromatography (HPLC) detection, the purity can exceed 99%, and the yield is high.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, be specifically related to a kind of synthetic method of triamcinolone acetonide acetate.
Background technology
Triamcinolone acetonide acetate is a kind of common tetter medication, and its effect is similar to hydrocortisone, and anti-inflammatory intensity is 5～20 times of hydrocortisone, and anti-inflammatory action and anti-allergic effects by force, more lasting, the water-sodium retention effect is stronger.Triamcinolone acetonide acetate generally is divided into injection liquid and ointment clinically, is applicable to various tetter, allergic rhinitis, arthrodynia, bronchial asthma, scapulohumeral periarthritis, tenosynovitis, synovitis, acute sprain, rheumatoid arthritis etc.At present, domestic only have Beijing dawn medicine company limited liability company, Zhejiang Province XianJu Pharmacy stock Co., Ltd, Xiangyang Pharmaceutical Factory and Community of Jin Tan County city pharmaceutical factory to produce the triamcinolone acetonide acetate bulk drug, and the pertinent literature report of triamcinolone acetonide acetate synthesis technique is not yet arranged.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of synthetic method of triamcinolone acetonide acetate for above-mentioned the deficiencies in the prior art.The method reaction conditions is gentle, is easy to control, and used auxiliary material toxicity is little, dangerous little, pollutes little, suitable suitability for industrialized production.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of synthetic method of triamcinolone acetonide acetate is characterized in that the method may further comprise the steps:
Step 1, take the 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I as raw material, under the effect of formic acid and potassium permanganate, obtain the oxide compound II through oxidizing reaction;
Step 2, take the II of oxide compound described in the step 1 as raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain the ring shrinking material III through contracting ring reaction;
Step 3, take the III of ring shrinking material described in the step 2 as raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, obtain the triamcinolone acetonide acetate crude product;
Step 4, the crude product of triamcinolone acetonide acetate described in the step 3 is carried out purifying, obtain triamcinolone acetonide acetate.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the process of oxidizing reaction described in the step 1 is:
101, in reactor, add 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I and reaction solvent acetone, be cooled to-3 ℃～6 ℃, then in reactor, add formic acid, stir in the backward reactor of 10min～20min and add potassium permanganate solution, in reactor, add reduced liquid again behind stirring reaction 4min～8min, stirring reaction 5min～15min filters after the reaction system in the reactor is warming up to 35 ℃～40 ℃, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, and wherein the concentration of potassium permanganate is 50g/L～70g/L, and the volume ratio of acetone and water is 1: 12～16; Described reduced liquid is that concentration is the sodium sulfite aqueous solution of 80g/L～120g/L;
102, filtrate decompression described in 101 is concentrated into without acetone flavor, then adds water in the filtrate behind the concentrating under reduced pressure, be cooled to below 10 ℃, leave standstill 1h～2h crystallize out, obtain filter cake behind the suction filtration;
103, with the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain the oxide compound II.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the consumption of formic acid described in 101 is 2.8～3.0 times of molar equivalents of 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I, the consumption of described potassium permanganate is 1.1～1.2 times of molar equivalents of 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I, and the consumption of described S-WAT is 1.1～1.9 times of molar equivalents of 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the process of the ring of contracting described in step 2 reaction is:
201, add oxide compound II, perchloric acid and reaction solvent acetone in reactor, stirring reaction is until oxide compound II completely dissolve in the reaction system at ambient temperature; Then reaction system being cooled to 5 ℃～10 ℃, adding the N-bromo-succinimide in the reaction system after the cooling, is insulation reaction under 5 ℃～10 ℃ the condition in temperature; After question response is complete, in reaction system, add reduced liquid, in reaction system, add alkali lye again, conditioned reaction system pH 〉=9 behind stirring 10min～15min, reaction system after the adjusting pH value is warming up to 50 ℃～55 ℃, is cooled to 25 ℃～30 ℃ behind insulation 2h～3h; Adding acetic acid conditioned reaction system pH in the reaction system again is 7, is evaporated to without acetone and distinguishes the flavor of regulating reaction system after the pH value, adds water, is cooled to below 10 ℃, leaves standstill 1h～2h crystallize out, behind the suction filtration solid is dried; Described reduced liquid is that concentration is the sodium sulfite aqueous solution of 80g/L～120g/L;
202, the solid after the oven dry in 201 being dissolved with trichloromethane, filter after being warming up to 35 ℃～38 ℃, add methyl alcohol in the filtrate after filter, is concentrated under 35 ℃～45 ℃ the condition in temperature, repeats to add methyl alcohol and concentration process 1～3 time, obtains enriched material; The once used amount of described methyl alcohol is: the solid 5mL～7mL methyl alcohol after every gram oven dry;
203, enriched material described in 202 is cooled to 0 ℃, leaves standstill crystallization 1h～2h, suction filtration, with methyl alcohol drip washing filter cake, oven dry obtains the ring shrinking material III.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the bromo-succinimide of N-described in 201 are divided and are added in the reaction system interval 20min～30min between adjacent twice for four times.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the consumption of perchloric acid described in 201 is 1.2～1.3 times of molar equivalents of oxide compound II, the consumption of described N-bromo-succinimide is 1.8～1.9 times of molar equivalents of oxide compound II, the consumption of described S-WAT is 1.5～2.0 times of molar equivalents of oxide compound II, and described alkali lye is that concentration is the potassium hydroxide solution of 80g/L～120g/L.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the process of fluoride reaction described in the step 3 is: add dimethyl formamide and pass into HF gas in reactor, the tail gas ammonia absorption, be cooled to below-10 ℃, in reactor, add the ring shrinking material III, treat that temperature rises to 0 ℃, hold over night, suction filtration, filter cake washes 1h～2h with water, obtains the triamcinolone acetonide acetate crude product after the oven dry.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the consumption of described dimethyl formamide are 18～24 times of molar equivalents of ring shrinking material III, and the Ventilation Rate of described HF gas is 20mL/min～30mL/min.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the method of purifying described in the step 4 is: with triamcinolone acetonide acetate crude product trichloromethane and dissolve with methanol, then in solution, add gac, be warming up to 35 ℃～38 ℃, backflow 1h～2h concentrating under reduced pressure, add again concentrating under reduced pressure behind the acetic acid ethyl dissolution, be cooled to 0 ℃, leave standstill suction filtration behind the 2h, with ethyl acetate drip washing filter cake, then be vacuum-drying under 40 ℃～50 ℃ the condition in temperature with the filter cake after the drip washing, obtain triamcinolone acetonide acetate.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the volume ratio of described trichloromethane and methyl alcohol are 10～20: 1, and the add-on of described gac is 0.15～0.25 times of triamcinolone acetonide acetate crude product quality.
The present invention compared with prior art has the following advantages:
1, method reaction conditions of the present invention is gentle, is easy to control, and used auxiliary material toxicity is little, dangerous little, pollutes little, suitable suitability for industrialized production.
2, adopt the synthetic triamcinolone acetonide acetate of method of the present invention to detect through HPLC, purity is more than 99%, and yield is higher.
Below by embodiment, technical scheme of the present invention is described in further detail.
Embodiment
Embodiment 1
Step 1, take 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate as raw material, under the effect of formic acid and potassium permanganate, obtain oxide compound through oxidizing reaction, detailed process is:
101, in reactor, add 20g 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate and 640mL reaction solvent acetone, be cooled to 0 ℃, then in reactor, add 6mL formic acid, stir and add the 150mL potassium permanganate solution in the backward reactor of 15min, in reactor, add 100mL reduced liquid (concentration is the sodium sulfite aqueous solution of 100g/L) again behind the stirring reaction 6min, stirring reaction 10min filters after the reaction system in the reactor is warming up to 38 ℃, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, and wherein the concentration of potassium permanganate is 65g/L, and the volume ratio of acetone and water is 1: 14;
102, filtrate decompression described in 101 is concentrated into without acetone flavor, then adds water in the filtrate behind the concentrating under reduced pressure, be cooled to below 10 ℃, leave standstill the 2h crystallize out, obtain filter cake behind the suction filtration;
103, with the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain the 19.3g oxide compound, yield is 96.5%;
Step 2, take oxide compound described in the step 1 as raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material through contracting ring reaction, detailed process is;
201, add 18g oxide compound, 450mL reaction solvent acetone and 3.1mL perchloric acid in reactor, stirring reaction is until oxide compound completely dissolve in the reaction system at ambient temperature; Then reaction system being cooled to 8 ℃, adding 14.8g N-bromo-succinimide in the reaction system after the cooling, is insulation reaction under 8 ℃ the condition in temperature, the TLC monitoring reaction; After question response is complete, in reaction system, add 100mL reduced liquid (concentration is the sodium sulfite aqueous solution of 100g/L), stir 12min, in reaction system, add alkali lye (concentration is the potassium hydroxide aqueous solution of 100g/L) again, conditioned reaction system pH is 9, reaction system after the adjusting pH value is warming up to 52 ℃, is cooled to 30 ℃ behind the insulation 3h; Adding acetic acid conditioned reaction system pH in the reaction system again is 7, is evaporated to without acetone and distinguishes the flavor of regulating reaction system after the pH value, adds water, is cooled to below 10 ℃, leaves standstill the 2h crystallize out, behind the suction filtration solid is dried; Described N-bromo-succinimide divides and adds in the reaction system interval 30min between adjacent twice for four times;
202, with the solid after the oven dry in 201 with the dissolving of 144mL trichloromethane, filter after being warming up to 37 ℃, add methyl alcohol in the filtrate after filter, be concentrated under 40 ℃ the condition in temperature, repeat to add methyl alcohol and concentration process 1 time, obtain enriched material; The consumption of described methyl alcohol is: the solid 7mL methyl alcohol after every gram oven dry;
203, enriched material described in 202 is cooled to 0 ℃, leaves standstill crystallization 2h, suction filtration, with methyl alcohol drip washing filter cake, oven dry obtains the 18g ring shrinking material, and yield is 100%;
Step 3, take ring shrinking material described in the step 2 as raw material, carry out fluoride reaction under the effect of hydrogen fluoride and dimethyl formamide, detailed process is: add the 55.8g dimethyl formamide and pass into HF gas, the tail gas ammonia absorption in reactor, be cooled to below-10 ℃, in reactor, add the 18g ring shrinking material, treat that temperature rises to 0 ℃, hold over night, suction filtration, filter cake washes 2h with water, obtains 15.5g triamcinolone acetonide acetate crude product after the oven dry, and yield is 86.1%; The Ventilation Rate of described HF gas is 25mL/min;
Step 4, the crude product of triamcinolone acetonide acetate described in the step 3 is carried out purifying: with 15.5g triamcinolone acetonide acetate crude product with 248mL trichloromethane and 15.5mL dissolve with methanol, then in solution, add the 3.1g gac, be warming up to 36 ℃ of backflow 2h concentrating under reduced pressure, add again concentrating under reduced pressure behind the 77.5mL acetic acid ethyl dissolution, be cooled to 0 ℃, leave standstill suction filtration behind the 2h, with ethyl acetate drip washing filter cake, be vacuum-drying under 45 ℃ the condition in temperature, obtain the 14g triamcinolone acetonide acetate, yield is 90.3%, and white crystalline powder, fusing point are 275 ℃～277 ℃.
1H-NMR(CD
3Cl,300MHz)δ：6.95(d,1H,H-2),6.40(d,1H,H-1),6.12(s,1H,H-4),5.24(s,2H,-COCH
2O-),4.10(t,1H,H-16),3.68(d,1H,-OH),3.43(m,1H,H-11),2.21(s,3H,-COCH
3);IR(KBr,ν/cm
-1):3340,2950,1750,1730,1660,1603,1378,1240,1082,1059,903,885,847。
Adopt HPLC that the triamcinolone acetonide acetate of present embodiment preparation is detected, quality product purity reaches more than 99%.
Embodiment 2
Step 1, take 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate as raw material, under the effect of formic acid and potassium permanganate, obtain oxide compound through oxidizing reaction, detailed process is:
101, in reactor, add 20g 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate and 600mL reaction solvent acetone, be cooled to-3 ℃, then in reactor, add 5.7mL formic acid, stir and add the 190mL potassium permanganate solution in the backward reactor of 10min, in reactor, add 96mL reduced liquid (concentration is the sodium sulfite aqueous solution of 80g/L) again behind the stirring reaction 4min, stirring reaction 5min filters after the reaction system in the reactor is warming up to 35 ℃, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, the concentration 50g/L of potassium permanganate wherein, and the volume ratio of acetone and water is 1: 12;
102, filtrate decompression described in 101 is concentrated into without acetone flavor, then adds water in the filtrate behind the concentrating under reduced pressure, be cooled to below 10 ℃, leave standstill the 1.5h crystallize out, obtain filter cake behind the suction filtration;
103, with the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain the 19.1g oxide compound, yield is 95.5%;
Step 2, take oxide compound described in the step 1 as raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material through contracting ring reaction, detailed process is;
201, add 18g oxide compound, 400mL reaction solvent acetone and 3.2mL perchloric acid in reactor, stirring reaction is until oxide compound completely dissolve in the reaction system at ambient temperature; Then reaction system being cooled to 5 ℃, adding 14.4g N-bromo-succinimide in the reaction system after the cooling, is insulation reaction under 5 ℃ the condition in temperature, the TLC monitoring reaction; After question response is complete, in reaction system, add 106mL reduced liquid (concentration is the sodium sulfite aqueous solution of 80g/L), in reaction system, add alkali lye (concentration is the 120g/L potassium hydroxide aqueous solution) again after stirring 15min, conditioned reaction system pH is 12, reaction system is warming up to 50 ℃, is cooled to 25 ℃ behind the insulation 2h; Adding acetic acid conditioned reaction system pH in the reaction system again is 7, is evaporated to without acetone and distinguishes the flavor of regulating reaction system after the pH value, adds water 54mL, is cooled to below 10 ℃, leaves standstill the 1h crystallize out, behind the suction filtration solid is dried; Described N-bromo-succinimide divides and adds in the reaction system interval 20min between adjacent twice for four times;
202, with the solid after the oven dry in 201 with the dissolving of 108mL trichloromethane, filter after being warming up to 35 ℃, add methyl alcohol in the filtrate after filter, be concentrated under 35 ℃ the condition in temperature, repeat to add methyl alcohol and concentration process 2 times, obtain enriched material; The once used amount of described methyl alcohol is: the solid 5mL methyl alcohol after every gram oven dry;
203, enriched material described in 202 is cooled to 0 ℃, leaves standstill crystallization 1.5h, suction filtration, with methyl alcohol drip washing filter cake, oven dry obtains the 18.4g ring shrinking material, and yield is 102.2%;
Step 3, take ring shrinking material described in the step 2 as raw material, carry out fluoride reaction under the effect of hydrogen fluoride and dimethyl formamide, detailed process is: add the 51.8g dimethyl formamide and pass into HF gas, the tail gas ammonia absorption in reactor, be cooled to below-10 ℃, in reactor, add the 18g ring shrinking material, treat that temperature rises to 0 ℃, hold over night, suction filtration, filter cake washes 1h with water, obtains 15.3g triamcinolone acetonide acetate crude product after the oven dry, and yield is 85.0%; The Ventilation Rate of described HF gas is 20mL/min;
Step 4, the crude product of triamcinolone acetonide acetate described in the step 3 is carried out purifying: with 15.0g triamcinolone acetonide acetate crude product with 225mL trichloromethane and 22.5mL dissolve with methanol, then in solution, add the 2.25g gac, be warming up to 38 ℃ of backflow 1h concentrating under reduced pressure, add again concentrating under reduced pressure behind the 75mL acetic acid ethyl dissolution, be cooled to 0 ℃, leave standstill suction filtration behind the 2h, filter cake ethyl acetate drip washing, be vacuum-drying under 50 ℃ the condition in temperature, obtain the 13.5g triamcinolone acetonide acetate, yield is 90.0%, and white crystalline powder, fusing point are 274 ℃～279 ℃.
1H-NMR(CD
3OCl,300MHz)δ：7.07(d,1H,H-2),6.44(d,1H,H-1),6.09(s,1H,H-4),5.14(s,2H,-COCH
2O-),4.08(t,1H,H-16),3.68(d,1H,-OH),3.45(m,1H,H-11),2.31(s,3H,-COCH
3);IR(KBr,ν/cm
-1):3341,2938,1753,1734,1660,1600,1380,1238,1081,1053,900,889,841。
Adopt HPLC that the triamcinolone acetonide acetate of present embodiment preparation is detected, quality product purity reaches more than 99%.
Embodiment 3
Step 1, take 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate as raw material, under the effect of formic acid and potassium permanganate, obtain oxide compound through oxidizing reaction:
101, in reactor, add 20g 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate and 680mL reaction solvent acetone, be cooled to 6 ℃, then in reactor, add 6.1mL formic acid, stir and add the 148mL potassium permanganate solution in the backward reactor of 20min, in reactor, add 110mL reduced liquid (concentration is the sodium sulfite aqueous solution of 120g/L) again behind the stirring reaction 8min, stirring reaction 15min filters after the reaction system in the reactor is warming up to 40 ℃, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, the concentration 70g/L of potassium permanganate wherein, and the volume ratio of acetone and water is 1: 16;
102, filtrate decompression described in 101 is concentrated into without acetone flavor, then adds water in the filtrate behind the concentrating under reduced pressure, be cooled to below 10 ℃, leave standstill the 1h crystallize out, obtain filter cake behind the suction filtration;
103, with the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain the 19.2g oxide compound, yield is 96.0%;
Step 2, take oxide compound described in the step 1 as raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material through contracting ring reaction, detailed process is;
201, add 18g oxide compound, 500mL reaction solvent acetone and 3.3mL perchloric acid in reactor, stirring reaction is until oxide compound completely dissolve in the reaction system at ambient temperature; Then reaction system being cooled to 10 ℃, adding 15.2g N-bromo-succinimide in the reaction system after the cooling, is insulation reaction under 10 ℃ the condition in temperature, the TLC monitoring reaction; After question response is complete, in reaction system, add 95mL reduced liquid (concentration is the sodium sulfite aqueous solution of 120g/L), in reaction system, add alkali lye (concentration is the 120g/L potassium hydroxide aqueous solution) again after stirring 10min, conditioned reaction system pH is 10, reaction system is warming up to 55 ℃, is cooled to 28 ℃ behind the insulation 2.5h; Adding acetic acid conditioned reaction system pH in the reaction system again is 7, is evaporated to without acetone and distinguishes the flavor of regulating reaction system after the pH value, adds water, is cooled to below 10 ℃, leaves standstill the 1.5h crystallize out, behind the suction filtration solid is dried; Described N-bromo-succinimide divides and adds in the reaction system interval 25min between adjacent twice for four times;
202, with the solid after the oven dry in 201 with the dissolving of 180mL trichloromethane, filter after being warming up to 38 ℃, add methyl alcohol in the filtrate after filter, be concentrated under 45 ℃ the condition in temperature, repeat to add methyl alcohol and concentration process 3 times, obtain enriched material; The once used amount of described methyl alcohol is: the solid 6mL methyl alcohol after every gram oven dry;
203, enriched material described in 202 is cooled to 0 ℃, leaves standstill crystallization 1h, suction filtration, with methyl alcohol drip washing filter cake, oven dry obtains the 17.9g ring shrinking material, and yield is 99.4%;
Step 3, take ring shrinking material described in the step 2 as raw material, carry out fluoride reaction under the effect of hydrogen fluoride and dimethyl formamide, detailed process is: add the 69.2g dimethyl formamide and pass into HF gas, the tail gas ammonia absorption in reactor, be cooled to below-10 ℃, in reactor, add the 18g ring shrinking material, treat that temperature rises to 0 ℃, hold over night, suction filtration, filter cake washes 1.5h with water, obtains 15.6g triamcinolone acetonide acetate crude product after the oven dry, and yield is 86.1%; The Ventilation Rate of described HF gas is 30mL/min;
Step 4, the crude product of triamcinolone acetonide acetate described in the step 3 is carried out purifying: with 15.6g triamcinolone acetonide acetate crude product with 280mL trichloromethane and 14mL dissolve with methanol, then in solution, add the 3.9g gac, be warming up to 35 ℃ of backflow 1.5h concentrating under reduced pressure, add again concentrating under reduced pressure behind the 93.6mL acetic acid ethyl dissolution, be cooled to 0 ℃, leave standstill suction filtration behind the 2h, filter cake ethyl acetate drip washing, be vacuum-drying under 40 ℃ the condition in temperature, obtain the 14.0g triamcinolone acetonide acetate, yield is 89.7%, and white crystalline powder, fusing point are 274 ℃～276 ℃.
1H-NMR(CD
3Cl,300MHz)δ：6.91(d,1H,H-2),6.28(d,1H,H-1),6.02(s,1H,H-4),5.14(s,2H,-COCH
2O-),4.06(t,1H,H-16),3.59(d,1H,-OH),3.43(m,1H,H-11),2.14(s,3H,-COCH
3);IR(KBr,ν/cm
-1):3347,2950,1754,1734,1668,1593,1375,1238,1078,1060,900,881,844。
Adopt HPLC that the triamcinolone acetonide acetate of present embodiment preparation is detected, quality product purity reaches more than 99%.
The above; it only is preferred embodiment of the present invention; be not that the present invention is imposed any restrictions, every according to the technology of the present invention essence to any simple modification, change and equivalent structure transformation that above embodiment does, all still belong in the protection domain of technical solution of the present invention.
Claims (10)
1. the synthetic method of a triamcinolone acetonide acetate is characterized in that, the method may further comprise the steps:
Step 1, take the 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I as raw material, under the effect of formic acid and potassium permanganate, obtain the oxide compound II through oxidizing reaction;
Step 2, take the II of oxide compound described in the step 1 as raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain the ring shrinking material III through contracting ring reaction;
Step 3, take the III of ring shrinking material described in the step 2 as raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, obtain the triamcinolone acetonide acetate crude product;
Step 4, the crude product of triamcinolone acetonide acetate described in the step 3 is carried out purifying, obtain triamcinolone acetonide acetate.
2. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 1 is characterized in that, the process of oxidizing reaction described in the step 1 is:
101, in reactor, add 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I and reaction solvent acetone, be cooled to-3 ℃～6 ℃, then in reactor, add formic acid, stir in the backward reactor of 10min～20min and add potassium permanganate solution, in reactor, add reduced liquid again behind stirring reaction 4min～8min, stirring reaction 5min～15min filters after the reaction system in the reactor is warming up to 35 ℃～40 ℃, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, and wherein the concentration of potassium permanganate is 50g/L～70g/L, and the volume ratio of acetone and water is 1: 12～16; Described reduced liquid is that concentration is the sodium sulfite aqueous solution of 80g/L～120g/L;
102, filtrate decompression described in 101 is concentrated into without acetone flavor, then adds water in the filtrate behind the concentrating under reduced pressure, be cooled to below 10 ℃, leave standstill 1h～2h crystallize out, obtain filter cake behind the suction filtration;
103, with the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain the oxide compound II.
3. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 2, it is characterized in that, the consumption of formic acid described in 101 is 2.8～3.0 times of molar equivalents of 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I, the consumption of described potassium permanganate is 1.1～1.2 times of molar equivalents of 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I, and the consumption of described S-WAT is 1.1～1.9 times of molar equivalents of 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I.
4. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 1 is characterized in that, the process of the ring of contracting described in step 2 reaction is:
201, add oxide compound II, perchloric acid and reaction solvent acetone in reactor, stirring reaction is until oxide compound II completely dissolve in the reaction system at ambient temperature; Then reaction system being cooled to 5 ℃～10 ℃, adding the N-bromo-succinimide in the reaction system after the cooling, is insulation reaction under 5 ℃～10 ℃ the condition in temperature; After question response is complete, in reaction system, add reduced liquid, in reaction system, add alkali lye again, conditioned reaction system pH 〉=9 behind stirring 10min～15min, reaction system after the adjusting pH value is warming up to 50 ℃～55 ℃, is cooled to 25 ℃～30 ℃ behind insulation 2h～3h; Adding acetic acid conditioned reaction system pH in the reaction system again is 7, is evaporated to without acetone and distinguishes the flavor of regulating reaction system after the pH value, adds water, is cooled to below 10 ℃, leaves standstill 1h～2h crystallize out, behind the suction filtration solid is dried; Described reduced liquid is that concentration is the sodium sulfite aqueous solution of 80g/L～120g/L;
202, the solid after the oven dry in 201 being dissolved with trichloromethane, filter after being warming up to 35 ℃～38 ℃, add methyl alcohol in the filtrate after filter, is concentrated under 35 ℃～45 ℃ the condition in temperature, repeats to add methyl alcohol and concentration process 1～3 time, obtains enriched material; The once used amount of described methyl alcohol is: the solid 5mL～7mL methyl alcohol after every gram oven dry;
203, enriched material described in 202 is cooled to 0 ℃, leaves standstill crystallization 1h～2h, suction filtration, with methyl alcohol drip washing filter cake, oven dry obtains the ring shrinking material III.
5. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 4 is characterized in that, the bromo-succinimide of N-described in 201 divides and adds in the reaction system interval 20min～30min between adjacent twice for four times.
6. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 4, it is characterized in that, the consumption of perchloric acid described in 201 is 1.2～1.3 times of molar equivalents of oxide compound II, the consumption of described N-bromo-succinimide is 1.8～1.9 times of molar equivalents of oxide compound II, the consumption of described S-WAT is 1.5～2.0 times of molar equivalents of oxide compound II, and described alkali lye is that concentration is the potassium hydroxide solution of 80g/L～120g/L.
7. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 1, it is characterized in that, the process of fluoride reaction described in the step 3 is: add dimethyl formamide and pass into HF gas in reactor, the tail gas ammonia absorption is cooled to below-10 ℃, in reactor, add the ring shrinking material III, treat that temperature rises to 0 ℃, hold over night, suction filtration, filter cake washes 1h～2h with water, obtains the triamcinolone acetonide acetate crude product after the oven dry.
8. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 7 is characterized in that, the consumption of described dimethyl formamide is 18～24 times of molar equivalents of ring shrinking material III, and the Ventilation Rate of described HF gas is 20mL/min～30mL/min.
9. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 1, it is characterized in that, the method of purifying described in the step 4 is: with triamcinolone acetonide acetate crude product trichloromethane and dissolve with methanol, then in solution, add gac, be warming up to 35 ℃～38 ℃, backflow 1h～2h concentrating under reduced pressure, add again concentrating under reduced pressure behind the acetic acid ethyl dissolution, be cooled to 0 ℃, leave standstill suction filtration behind the 2h, with ethyl acetate drip washing filter cake, then be vacuum-drying under 40 ℃～50 ℃ the condition in temperature with the filter cake after the drip washing, obtain triamcinolone acetonide acetate.
10. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 9 is characterized in that, the volume ratio of described trichloromethane and methyl alcohol is 10～20: 1, and the add-on of described gac is 0.15～0.25 times of triamcinolone acetonide acetate crude product quality.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104231031A (en) * | 2014-09-10 | 2014-12-24 | 江西赣亮医药原料有限公司 | Preparation method of triamcinolone acetonide |
| CN105543319A (en) * | 2015-12-30 | 2016-05-04 | 苏州汉酶生物技术有限公司 | Method for preparing steroidanti-inflammatory drugintermediatetetraene acetate using enzyme process |
| CN106518952A (en) * | 2016-09-20 | 2017-03-22 | 中国科学院上海药物研究所 | Triamcinolone acetonide acetate crystal form B, preparation method of triamcinolone acetonide acetate crystal form B, medicinal composition containing crystal form B and application of crystal form B |
| CN107778345A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of triamcinolone acetonide acetate |
| CN113666985A (en) * | 2021-10-22 | 2021-11-19 | 山东谷雨春生物科技有限公司 | Preparation method of triamcinolone acetonide |
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| CN104231031A (en) * | 2014-09-10 | 2014-12-24 | 江西赣亮医药原料有限公司 | Preparation method of triamcinolone acetonide |
| CN105543319A (en) * | 2015-12-30 | 2016-05-04 | 苏州汉酶生物技术有限公司 | Method for preparing steroidanti-inflammatory drugintermediatetetraene acetate using enzyme process |
| CN107778345A (en) * | 2016-08-30 | 2018-03-09 | 天津太平洋制药有限公司 | A kind of preparation method of triamcinolone acetonide acetate |
| CN106518952A (en) * | 2016-09-20 | 2017-03-22 | 中国科学院上海药物研究所 | Triamcinolone acetonide acetate crystal form B, preparation method of triamcinolone acetonide acetate crystal form B, medicinal composition containing crystal form B and application of crystal form B |
| CN113666985A (en) * | 2021-10-22 | 2021-11-19 | 山东谷雨春生物科技有限公司 | Preparation method of triamcinolone acetonide |
| CN115322243A (en) * | 2022-09-20 | 2022-11-11 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
| CN115322243B (en) * | 2022-09-20 | 2023-10-03 | 山东赛托生物科技股份有限公司 | Method for preparing triamcinolone acetonide key intermediate by one-pot method |
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