CN102863505B - Process for synthesizing triamcinolone acetonide acetate - Google Patents
Process for synthesizing triamcinolone acetonide acetate Download PDFInfo
- Publication number
- CN102863505B CN102863505B CN201210402342.7A CN201210402342A CN102863505B CN 102863505 B CN102863505 B CN 102863505B CN 201210402342 A CN201210402342 A CN 201210402342A CN 102863505 B CN102863505 B CN 102863505B
- Authority
- CN
- China
- Prior art keywords
- triamcinolone acetonide
- reaction
- add
- acetonide acetate
- reaction system
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 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 60
- 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 36
- 238000000967 suction filtration Methods 0.000 claims description 26
- 238000003756 stirring 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
- 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
- 238000010189 synthetic method Methods 0.000 claims description 20
- 238000010792 warming Methods 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 17
- 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 16
- 239000007789 gas Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- 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
- 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
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 7
- 229960001180 norfloxacin Drugs 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
- 238000004090 dissolution Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 5
- 238000002156 mixing Methods 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
- 150000001875 compounds Chemical class 0.000 description 15
- 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
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 0 C[C@]1([C@@](*)(C[C@]2*)[C@](C)(CCC([C@]3(C)C=C4)=CC4=I)C3=CC1)[C@@]2(*)C(COC(C)=O)=O Chemical compound C[C@]1([C@@](*)(C[C@]2*)[C@](C)(CCC([C@]3(C)C=C4)=CC4=I)C3=CC1)[C@@]2(*)C(COC(C)=O)=O 0.000 description 2
- 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
Landscapes
- 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 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, comparatively lasting, water-sodium retention effect is stronger.Triamcinolone acetonide acetate is generally 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 pharmaceutical factory of Community of Jin Tan County city to produce triamcinolone acetonide acetate bulk drug, not yet has the pertinent literature of triamcinolone acetonide acetate synthesis technique to report.
Summary of the invention
Technical problem to be solved by this invention is, for above-mentioned the deficiencies in the prior art, to provide a kind of synthetic method of triamcinolone acetonide acetate.The method reaction conditions is gentle, is easy to control, and auxiliary material toxicity used is little, dangerous little, pollutes little, is applicable to 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 comprises the following steps:
Step one, with 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I for raw material, under the effect of formic acid and potassium permanganate, obtain oxide compound II through oxidizing reaction;
Step 2, with oxide compound II described in step one for raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material III through Norfloxacin Reaction;
Step 3, with ring shrinking material III described in step 2 for raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, obtain triamcinolone acetonide acetate crude product;
Step 4, purifying is carried out to the crude product of triamcinolone acetonide acetate described in step 3, obtain triamcinolone acetonide acetate.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the process of oxidizing reaction described in step one is:
101, in reactor, 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I and reaction solvent acetone is added, be cooled to-3 DEG C ~ 6 DEG C, then in reactor, formic acid is added, in reactor, potassium permanganate solution is added after stirring 10min ~ 20min, in reactor, reduced liquid is added again after stirring reaction 4min ~ 8min, stirring reaction 5min ~ 15min, filters after the reaction system in reactor being warming up to 35 DEG C ~ 40 DEG C, 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; The sodium sulfite aqueous solution of described reduced liquid to be concentration be 80g/L ~ 120g/L;
102, by filtrate reduced in volume described in 101 to without acetone taste, then add water in the filtrate after concentrating under reduced pressure, be cooled to less than 10 DEG C, standing 1h ~ 2h crystallize out, obtains filter cake after suction filtration;
103, by the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain 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 Norfloxacin Reaction described in step 2 is:
201, in reactor, add oxide compound II, perchloric acid and reaction solvent acetone, stirring reaction is until oxide compound II completely dissolve in reaction system at ambient temperature; Then reaction system is cooled to 5 DEG C ~ 10 DEG C, in the reaction system after cooling, add N-bromo-succinimide, be insulation reaction under the condition of 5 DEG C ~ 10 DEG C in temperature; After question response is complete, in reaction system, add reduced liquid, after stirring 10min ~ 15min, in reaction system, add alkali lye again, regulate reaction system pH >=9, reaction system after adjust ph is warming up to 50 DEG C ~ 55 DEG C, after insulation 2h ~ 3h, is cooled to 25 DEG C ~ 30 DEG C; In reaction system, add acetic acid again regulates pH value of reaction system to be 7, is evaporated to the reaction system after adjust ph without acetone taste, adds water, be cooled to less than 10 DEG C, leaves standstill 1h ~ 2h crystallize out, is dried by solid after suction filtration; The sodium sulfite aqueous solution of described reduced liquid to be concentration be 80g/L ~ 120g/L;
202, dissolved by the solid trichloromethane after drying in 201, filter after being warming up to 35 DEG C ~ 38 DEG C, in the filtrate after filtering, add methyl alcohol, be concentrated under the condition of 35 DEG C ~ 45 DEG C in temperature, repeats to add methyl alcohol and concentration process 1 ~ 3 time, obtain enriched material; The once used amount of described methyl alcohol is: the solid 5mL ~ 7mL methyl alcohol after every gram of oven dry;
203, enriched material described in 202 is cooled to 0 DEG C, leaves standstill crystallization 1h ~ 2h, suction filtration, with methyl alcohol drip washing filter cake, dry and obtain ring shrinking material III.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the bromo-succinimide of N-described in 201 divides four times to add in reaction system, interval 20min ~ 30min between adjacent twice.
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, the potassium hydroxide solution of described alkali lye to be concentration be 80g/L ~ 120g/L.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the process of fluoride reaction described in step 3 is: in reactor, add dimethyl formamide and pass into HF gas, tail gas ammonia absorption, be cooled to less than-10 DEG C, in reactor, add ring shrinking material III, treat that temperature rises to 0 DEG C, hold over night, suction filtration, filter cake washes 1h ~ 2h with water, obtains triamcinolone acetonide acetate crude product after oven dry.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, 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.
The synthetic method of above-mentioned a kind of triamcinolone acetonide acetate, the method of purifying described in step 4 is: by triamcinolone acetonide acetate crude product trichloromethane and dissolve with methanol, then in solution, add gac, be warming up to 35 DEG C ~ 38 DEG C, backflow 1h ~ 2h concentrating under reduced pressure, add concentrating under reduced pressure after acetic acid ethyl dissolution again, be cooled to 0 DEG C, suction filtration after standing 2h, with ethyl acetate drip washing filter cake, then be vacuum-drying under the condition of 40 DEG C ~ 50 DEG C in temperature by the filter cake after 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 is 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 auxiliary material toxicity used is little, dangerous little, pollutes little, is applicable to suitability for industrialized production.
2, the triamcinolone acetonide acetate adopting method of the present invention to synthesize detects through HPLC, and purity can reach 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 one, be raw material with 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate, 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 DEG C, then in reactor, 6mL formic acid is added, in reactor, 150mL potassium permanganate solution is added after stirring 15min, in reactor, 100mL reduced liquid (concentration is the sodium sulfite aqueous solution of 100g/L) is added again after stirring reaction 6min, stirring reaction 10min, filters after the reaction system in reactor is warming up to 38 DEG C, 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, by filtrate reduced in volume described in 101 to without acetone taste, then add water in the filtrate after concentrating under reduced pressure, be cooled to less than 10 DEG C, standing 2h crystallize out, obtains filter cake after suction filtration;
103, by the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain 19.3g oxide compound, yield is 96.5%;
Step 2, with oxide compound described in step one for raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material through Norfloxacin Reaction, detailed process is;
201, in reactor, add 18g oxide compound, 450mL reaction solvent acetone and 3.1mL perchloric acid, stirring reaction is until oxide compound completely dissolve in reaction system at ambient temperature; Then reaction system is cooled to 8 DEG C, in the reaction system after cooling, add 14.8g N-bromo-succinimide, be insulation reaction under the condition of 8 DEG C in temperature, TLC monitors reaction; After question response is complete, 100mL reduced liquid (concentration is the sodium sulfite aqueous solution of 100g/L) is added in reaction system, stir 12min, alkali lye (concentration is the potassium hydroxide aqueous solution of 100g/L) is added again in reaction system, reaction system pH is regulated to be 9, reaction system after adjust ph is warming up to 52 DEG C, after insulation 3h, is cooled to 30 DEG C; In reaction system, add acetic acid again regulates pH value of reaction system to be 7, is evaporated to the reaction system after adjust ph without acetone taste, adds water, be cooled to less than 10 DEG C, leaves standstill 2h crystallize out, is dried by solid after suction filtration; Described N-bromo-succinimide divides four times to add in reaction system, interval 30min between adjacent twice;
202, dissolved by the solid 144mL trichloromethane after drying in 201, filter after being warming up to 37 DEG C, in the filtrate after filtering, add methyl alcohol, be concentrated under the condition of 40 DEG C in temperature, repeats 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 of oven dry;
203, enriched material described in 202 is cooled to 0 DEG C, leaves standstill crystallization 2h, suction filtration, with methyl alcohol drip washing filter cake, dry and obtain 18g ring shrinking material, yield is 100%;
Step 3, with ring shrinking material described in step 2 for raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, detailed process is: in reactor, add 55.8g dimethyl formamide and pass into HF gas, tail gas ammonia absorption, be cooled to less than-10 DEG C, in reactor, add 18g ring shrinking material, treat that temperature rises to 0 DEG C, hold over night, suction filtration, filter cake washes 2h with water, obtains 15.5g triamcinolone acetonide acetate crude product after oven dry, and yield is 86.1%; The Ventilation Rate of described HF gas is 25mL/min;
Step 4, purifying is carried out to the crude product of triamcinolone acetonide acetate described in step 3: by 15.5g triamcinolone acetonide acetate crude product 248mL trichloromethane and 15.5mL dissolve with methanol, then in solution, 3.1g gac is added, be warming up to 36 DEG C of backflow 2h concentrating under reduced pressure, add concentrating under reduced pressure after 77.5mL acetic acid ethyl dissolution again, be cooled to 0 DEG C, suction filtration after standing 2h, with ethyl acetate drip washing filter cake, be vacuum-drying under the condition of 45 DEG C in temperature, obtain 14g triamcinolone acetonide acetate, yield is 90.3%, white crystalline powder, and fusing point is 275 DEG C ~ 277 DEG C.
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 to detect triamcinolone acetonide acetate prepared by the present embodiment, quality product purity reaches more than 99%.
Embodiment 2
Step one, be raw material with 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate, 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 DEG C, then in reactor, 5.7mL formic acid is added, in reactor, 190mL potassium permanganate solution is added after stirring 10min, in reactor, 96mL reduced liquid (concentration is the sodium sulfite aqueous solution of 80g/L) is added again after stirring reaction 4min, stirring reaction 5min, filters after the reaction system in reactor is warming up to 35 DEG C, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, wherein the concentration 50g/L of potassium permanganate, and the volume ratio of acetone and water is 1: 12;
102, by filtrate reduced in volume described in 101 to without acetone taste, then add water in the filtrate after concentrating under reduced pressure, be cooled to less than 10 DEG C, standing 1.5h crystallize out, obtains filter cake after suction filtration;
103, by the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain 19.1g oxide compound, yield is 95.5%;
Step 2, with oxide compound described in step one for raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material through Norfloxacin Reaction, detailed process is;
201, in reactor, add 18g oxide compound, 400mL reaction solvent acetone and 3.2mL perchloric acid, stirring reaction is until oxide compound completely dissolve in reaction system at ambient temperature; Then reaction system is cooled to 5 DEG C, in the reaction system after cooling, add 14.4g N-bromo-succinimide, be insulation reaction under the condition of 5 DEG C in temperature, TLC monitors reaction; After question response is complete, 106mL reduced liquid (concentration is the sodium sulfite aqueous solution of 80g/L) is added in reaction system, in reaction system, alkali lye (concentration is 120g/L potassium hydroxide aqueous solution) is added again after stirring 15min, reaction system pH is regulated to be 12, reaction system is warming up to 50 DEG C, after insulation 2h, is cooled to 25 DEG C; In reaction system, add acetic acid again regulates pH value of reaction system to be 7, and be evaporated to the reaction system after adjust ph without acetone taste, add water 54mL, is cooled to less than 10 DEG C, leaves standstill 1h crystallize out, is dried by solid after suction filtration; Described N-bromo-succinimide divides four times to add in reaction system, interval 20min between adjacent twice;
202, dissolved by the solid 108mL trichloromethane after drying in 201, filter after being warming up to 35 DEG C, in the filtrate after filtering, add methyl alcohol, be concentrated under the condition of 35 DEG C in temperature, repeats 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 of oven dry;
203, enriched material described in 202 is cooled to 0 DEG C, leaves standstill crystallization 1.5h, suction filtration, with methyl alcohol drip washing filter cake, dry and obtain 18.4g ring shrinking material, yield is 102.2%;
Step 3, with ring shrinking material described in step 2 for raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, detailed process is: in reactor, add 51.8g dimethyl formamide and pass into HF gas, tail gas ammonia absorption, be cooled to less than-10 DEG C, in reactor, add 18g ring shrinking material, treat that temperature rises to 0 DEG C, hold over night, suction filtration, filter cake washes 1h with water, obtains 15.3g triamcinolone acetonide acetate crude product after oven dry, and yield is 85.0%; The Ventilation Rate of described HF gas is 20mL/min;
Step 4, purifying is carried out to the crude product of triamcinolone acetonide acetate described in step 3: by 15.0g triamcinolone acetonide acetate crude product 225mL trichloromethane and 22.5mL dissolve with methanol, then in solution, 2.25g gac is added, be warming up to 38 DEG C of backflow 1h concentrating under reduced pressure, add concentrating under reduced pressure after 75mL acetic acid ethyl dissolution again, be cooled to 0 DEG C, suction filtration after standing 2h, filter cake ethyl acetate drip washing, be vacuum-drying under the condition of 50 DEG C in temperature, obtain 13.5g triamcinolone acetonide acetate, yield is 90.0%, white crystalline powder, and fusing point is 274 DEG C ~ 279 DEG C.
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 to detect triamcinolone acetonide acetate prepared by the present embodiment, quality product purity reaches more than 99%.
Embodiment 3
Step one, be raw material with 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate, 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 DEG C, then in reactor, 6.1mL formic acid is added, in reactor, 148mL potassium permanganate solution is added after stirring 20min, in reactor, 110mL reduced liquid (concentration is the sodium sulfite aqueous solution of 120g/L) is added again after stirring reaction 8min, stirring reaction 15min, filters after the reaction system in reactor is warming up to 40 DEG C, obtains filter cake and filtrate; Described potassium permanganate solution is the mixing solutions of potassium permanganate, acetone and water, wherein the concentration 70g/L of potassium permanganate, and the volume ratio of acetone and water is 1: 16;
102, by filtrate reduced in volume described in 101 to without acetone taste, then add water in the filtrate after concentrating under reduced pressure, be cooled to less than 10 DEG C, standing 1h crystallize out, obtains filter cake after suction filtration;
103, by the acetone drip washing of filter cake described in 101, then with 102 in filter cake together dry, obtain 19.2g oxide compound, yield is 96.0%;
Step 2, with oxide compound described in step one for raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material through Norfloxacin Reaction, detailed process is;
201, in reactor, add 18g oxide compound, 500mL reaction solvent acetone and 3.3mL perchloric acid, stirring reaction is until oxide compound completely dissolve in reaction system at ambient temperature; Then reaction system is cooled to 10 DEG C, in the reaction system after cooling, add 15.2g N-bromo-succinimide, be insulation reaction under the condition of 10 DEG C in temperature, TLC monitors reaction; After question response is complete, 95mL reduced liquid (concentration is the sodium sulfite aqueous solution of 120g/L) is added in reaction system, in reaction system, alkali lye (concentration is 120g/L potassium hydroxide aqueous solution) is added again after stirring 10min, reaction system pH is regulated to be 10, reaction system is warming up to 55 DEG C, after insulation 2.5h, is cooled to 28 DEG C; In reaction system, add acetic acid again regulates pH value of reaction system to be 7, is evaporated to the reaction system after adjust ph without acetone taste, adds water, be cooled to less than 10 DEG C, leaves standstill 1.5h crystallize out, is dried by solid after suction filtration; Described N-bromo-succinimide divides four times to add in reaction system, interval 25min between adjacent twice;
202, dissolved by the solid 180mL trichloromethane after drying in 201, filter after being warming up to 38 DEG C, in the filtrate after filtering, add methyl alcohol, be concentrated under the condition of 45 DEG C in temperature, repeats 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 of oven dry;
203, enriched material described in 202 is cooled to 0 DEG C, leaves standstill crystallization 1h, suction filtration, with methyl alcohol drip washing filter cake, dry and obtain 17.9g ring shrinking material, yield is 99.4%;
Step 3, with ring shrinking material described in step 2 for raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, detailed process is: in reactor, add 69.2g dimethyl formamide and pass into HF gas, tail gas ammonia absorption, be cooled to less than-10 DEG C, in reactor, add 18g ring shrinking material, treat that temperature rises to 0 DEG C, hold over night, suction filtration, filter cake washes 1.5h with water, obtains 15.6g triamcinolone acetonide acetate crude product after oven dry, and yield is 86.1%; The Ventilation Rate of described HF gas is 30mL/min;
Step 4, purifying is carried out to the crude product of triamcinolone acetonide acetate described in step 3: by 15.6g triamcinolone acetonide acetate crude product 280mL trichloromethane and 14mL dissolve with methanol, then in solution, 3.9g gac is added, be warming up to 35 DEG C of backflow 1.5h concentrating under reduced pressure, add concentrating under reduced pressure after 93.6mL acetic acid ethyl dissolution again, be cooled to 0 DEG C, suction filtration after standing 2h, filter cake ethyl acetate drip washing, be vacuum-drying under the condition of 40 DEG C in temperature, obtain 14.0g triamcinolone acetonide acetate, yield is 89.7%, white crystalline powder, and fusing point is 274 DEG C ~ 276 DEG C.
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 to detect triamcinolone acetonide acetate prepared by the present embodiment, quality product purity reaches more than 99%.
The above; it is only preferred embodiment of the present invention; not the present invention is imposed any restrictions, every above embodiment is done according to the technology of the present invention essence any simple modification, change and equivalent structure transformation, all still belong in the protection domain of technical solution of the present invention.
Claims (7)
1. a synthetic method for triamcinolone acetonide acetate, is characterized in that, the method comprises the following steps:
Step one, with 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I for raw material, under the effect of formic acid and potassium permanganate, obtain oxide compound II through oxidizing reaction;
Step 2, with oxide compound II described in step one for raw material, under the effect of perchloric acid and N-bromo-succinimide, obtain ring shrinking material III through Norfloxacin Reaction;
The process of described Norfloxacin Reaction is:
201, in reactor, add oxide compound II, perchloric acid and reaction solvent acetone, stirring reaction is until oxide compound II completely dissolve in reaction system at ambient temperature; Then reaction system is cooled to 5 DEG C ~ 10 DEG C, in the reaction system after cooling, add N-bromo-succinimide, be insulation reaction under the condition of 5 DEG C ~ 10 DEG C in temperature; After question response is complete, in reaction system, add reduced liquid, after stirring 10min ~ 15min, in reaction system, add alkali lye again, regulate reaction system pH >=9, reaction system after adjust ph is warming up to 50 DEG C ~ 55 DEG C, after insulation 2h ~ 3h, is cooled to 25 DEG C ~ 30 DEG C; In reaction system, add acetic acid again regulates pH value of reaction system to be 7, is evaporated to the reaction system after adjust ph without acetone taste, adds water, be cooled to less than 10 DEG C, leaves standstill 1h ~ 2h crystallize out, is dried by solid after suction filtration; The sodium sulfite aqueous solution of described reduced liquid to be concentration be 80g/L ~ 120g/L;
202, dissolved by the solid trichloromethane after drying in 201, filter after being warming up to 35 DEG C ~ 38 DEG C, in the filtrate after filtering, add methyl alcohol, be concentrated under the condition of 35 DEG C ~ 45 DEG C in temperature, repeats to add methyl alcohol and concentration process 1 ~ 3 time, obtain enriched material; The once used amount of described methyl alcohol is: the solid 5mL ~ 7mL methyl alcohol after every gram of oven dry;
203, enriched material described in 202 is cooled to 0 DEG C, leaves standstill crystallization 1h ~ 2h, suction filtration, with methyl alcohol drip washing filter cake, dry and obtain ring shrinking material III;
Step 3, with ring shrinking material III described in step 2 for raw material, under the effect of hydrogen fluoride and dimethyl formamide, carry out fluoride reaction, obtain triamcinolone acetonide acetate crude product;
The process of described fluoride reaction is: in reactor, add dimethyl formamide and pass into HF gas, tail gas ammonia absorption, be cooled to less than-10 DEG C, ring shrinking material III is added in reactor, treat that temperature rises to 0 DEG C, hold over night, suction filtration, filter cake washes 1h ~ 2h with water, obtains triamcinolone acetonide acetate crude product after oven dry;
Step 4, purifying is carried out to the crude product of triamcinolone acetonide acetate described in step 3, obtain triamcinolone acetonide acetate;
The consumption of dimethyl formamide described in step 3 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.
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 step one is:
101, in reactor, 21-hydroxy-1,4,9(11),16-pregnatetraene-3,20-dione-21-acetate I and reaction solvent acetone is added, be cooled to-3 DEG C ~ 6 DEG C, then in reactor, formic acid is added, in reactor, potassium permanganate solution is added after stirring 10min ~ 20min, in reactor, reduced liquid is added again after stirring reaction 4min ~ 8min, stirring reaction 5min ~ 15min, filters after the reaction system in reactor being warming up to 35 DEG C ~ 40 DEG C, 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; The sodium sulfite aqueous solution of described reduced liquid to be concentration be 80g/L ~ 120g/L;
102, by filtrate reduced in volume described in 101 to without acetone taste, then add water in the filtrate after concentrating under reduced pressure, be cooled to less than 10 DEG C, standing 1h ~ 2h crystallize out, suction filtration;
103, by the acetone drip washing of filter cake described in 101, then with 102 in filter cake after suction filtration together dry, obtain 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 bromo-succinimide of N-described in 201 divides four times to add in reaction system, interval 20min ~ 30min between adjacent twice.
5. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 1, 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, the potassium hydroxide solution of described alkali lye to be concentration be 80g/L ~ 120g/L.
6. 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 step 4 is: by triamcinolone acetonide acetate crude product trichloromethane and dissolve with methanol, then in solution, gac is added, be warming up to 35 DEG C ~ 38 DEG C, backflow 1h ~ 2h concentrating under reduced pressure, add concentrating under reduced pressure after acetic acid ethyl dissolution again, be cooled to 0 DEG C, suction filtration after standing 2h, with ethyl acetate drip washing filter cake, be then vacuum-drying under the condition of 40 DEG C ~ 50 DEG C in temperature by the filter cake after drip washing, obtain triamcinolone acetonide acetate.
7. the synthetic method of a kind of triamcinolone acetonide acetate according to claim 6, 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210402342.7A CN102863505B (en) | 2012-10-22 | 2012-10-22 | Process for synthesizing triamcinolone acetonide acetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210402342.7A CN102863505B (en) | 2012-10-22 | 2012-10-22 | Process for synthesizing triamcinolone acetonide acetate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102863505A CN102863505A (en) | 2013-01-09 |
| CN102863505B true CN102863505B (en) | 2015-03-04 |
Family
ID=47442661
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210402342.7A Active CN102863505B (en) | 2012-10-22 | 2012-10-22 | Process for synthesizing triamcinolone acetonide acetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102863505B (en) |
Families Citing this family (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 |
| 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 |
| CN106518952B (en) * | 2016-09-20 | 2018-07-13 | 中国科学院上海药物研究所 | Triamcinolone acetonide acetate crystal form B, preparation method, the pharmaceutical composition and purposes for including the 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 |
| 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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2998433A (en) * | 1960-07-22 | 1961-08-29 | American Cyanamid Co | 2alpha-halo-4, 9(11), 16-pregnatriene-3, 20-diones |
| US3035050A (en) * | 1960-08-19 | 1962-05-15 | Olin Mathieson | 1-dehydrogenation of 11beta-hydroxy steroids by 2, 3-dibromo-5, 6-dicyanoquinone |
| US3549498A (en) * | 1968-04-02 | 1970-12-22 | Squibb & Sons Inc | 11alpha-substituted steroids and process |
| US4036831A (en) * | 1975-10-28 | 1977-07-19 | Steroid Development Company Establishment | Trimethyl siloxane steroid intermediates |
| JPS5463066A (en) * | 1977-10-28 | 1979-05-21 | Toukawa Tetsuo | Manufacture of steroid compounds |
-
2012
- 2012-10-22 CN CN201210402342.7A patent/CN102863505B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN102863505A (en) | 2013-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102863505B (en) | Process for synthesizing triamcinolone acetonide acetate | |
| CN103724261B (en) | A kind of industrialized process for preparing of hydroxychloroquine sulfate quinoline | |
| CN101631878A (en) | Process for the preparation of sucralose by the chlorination of sugar with triphosgene (BTC) | |
| WO2023279276A1 (en) | Method for purifying sucralose-6-ester | |
| CN105294534A (en) | Industrial method for preparing apremilast and intermediate thereof | |
| CN103012312B (en) | Method for recycling industrial wastewater of aminothiazoly loximate | |
| CN102603843B (en) | Preparation method of dexamethasone intermediate | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN104086545A (en) | Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride | |
| CN102174007B (en) | Industrial preparation method of [2-(2-cyano-pyrrolidine-1-yl)-2-oxo-ethyl]-tert-butyl carbamate | |
| CN102146052B (en) | Method for preparing tryptophan | |
| JP2010184902A (en) | Purification method and recovery method for ionic liquid | |
| CN109575017A (en) | A kind of preparation method of Olprinone HCl compound | |
| CN105585539B (en) | The method of one pot process cefotaxime side chain acetoacetic ester | |
| CN105037277B (en) | One kind 3, the synthetic method of 4 dihydropyrimidinonesands/thioketones heterocyclic compounds | |
| CN106905406A (en) | A kind of preparation technology of Triamcinolone acetonide | |
| CN105949184A (en) | Refinement method of arotinolol hydrochloride | |
| CN102382044A (en) | Purification method for 2,3-dimethylpyridine | |
| CN102432575A (en) | Method for extracting high-purity hesperetin from immature bitter orange | |
| CN104447724B (en) | A kind of process for purification of Raltitrexed | |
| CN102382045A (en) | Purification of 2,3-dimethyl pyridine | |
| CN104529812B (en) | A kind of preparation method of prilocaine hydrochloride | |
| CN101417921A (en) | A kind of crystal refining method of naphthalene | |
| CN104529846A (en) | Method for increasing yield of produced methomyl | |
| CN103951669A (en) | Synthesis method of Anagliptin key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Process for synthesizing triamcinolone acetonide acetate Effective date of registration: 20170904 Granted publication date: 20150304 Pledgee: Qishan County Rural Credit Cooperative Association Pledgor: Baoji Kangle Biotechnology Co.,Ltd. Registration number: 2017990000816 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20200828 Granted publication date: 20150304 Pledgee: Qishan County Rural Credit Cooperative Association Pledgor: BAOJI KANGLE BIOTECHNOLOGY Co.,Ltd. Registration number: 2017990000816 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A synthetic method of triamcinolone acetonide acetate Effective date of registration: 20200901 Granted publication date: 20150304 Pledgee: Shaanxi Qishan Rural Commercial Bank Co.,Ltd. Pledgor: BAOJI KANGLE BIOTECHNOLOGY Co.,Ltd. Registration number: Y2020980005601 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210901 Granted publication date: 20150304 Pledgee: Shaanxi Qishan Rural Commercial Bank Co.,Ltd. Pledgor: BAOJI KANGLE BIOTECHNOLOGY Co.,Ltd. Registration number: Y2020980005601 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A synthetic method of triamcinolone acetonide acetate Effective date of registration: 20210902 Granted publication date: 20150304 Pledgee: Shaanxi Qishan Rural Commercial Bank Co.,Ltd. Pledgor: BAOJI KANGLE BIOTECHNOLOGY Co.,Ltd. Registration number: Y2021980008819 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230828 Granted publication date: 20150304 Pledgee: Shaanxi Qishan Rural Commercial Bank Co.,Ltd. Pledgor: BAOJI KANGLE BIOTECHNOLOGY Co.,Ltd. Registration number: Y2021980008819 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Synthesis Method of Triamcinolone Acetate Effective date of registration: 20230831 Granted publication date: 20150304 Pledgee: Shaanxi Qishan Rural Commercial Bank Co.,Ltd. Pledgor: BAOJI KANGLE BIOTECHNOLOGY Co.,Ltd. Registration number: Y2023980054923 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |