CN114395008A - Method for acylation of 21-position of steroid bulk drug - Google Patents
Method for acylation of 21-position of steroid bulk drug Download PDFInfo
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- CN114395008A CN114395008A CN202111541723.9A CN202111541723A CN114395008A CN 114395008 A CN114395008 A CN 114395008A CN 202111541723 A CN202111541723 A CN 202111541723A CN 114395008 A CN114395008 A CN 114395008A
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- Prior art keywords
- steroid
- acylation
- reaction
- acetone
- bulk
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- 229940079593 drug Drugs 0.000 title claims abstract description 42
- 239000003814 drug Substances 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 39
- 238000005917 acylation reaction Methods 0.000 title claims abstract description 37
- 230000010933 acylation Effects 0.000 title claims abstract description 25
- 125000002345 steroid group Chemical group 0.000 title 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 52
- 150000003431 steroids Chemical class 0.000 claims abstract description 50
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims abstract description 13
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims abstract description 6
- 150000008041 alkali metal carbonates Chemical group 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 26
- 238000010791 quenching Methods 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 230000000171 quenching effect Effects 0.000 claims description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 229940088679 drug related substance Drugs 0.000 claims description 11
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 10
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 claims description 9
- 229960001102 betamethasone dipropionate Drugs 0.000 claims description 9
- CIWBQSYVNNPZIQ-XYWKZLDCSA-N betamethasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-XYWKZLDCSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 229960002800 prednisolone acetate Drugs 0.000 claims description 9
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 claims description 8
- 229960003957 dexamethasone Drugs 0.000 claims description 8
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 8
- 229960003657 dexamethasone acetate Drugs 0.000 claims description 8
- 229960005205 prednisolone Drugs 0.000 claims description 8
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[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 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- ITYMTTQVNYAJAA-XGQKBEPLSA-N [(8s,9r,10s,11s,13s,14s,16s,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CC)[C@@]1(C)C[C@@H]2O ITYMTTQVNYAJAA-XGQKBEPLSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 15
- 239000002904 solvent Substances 0.000 abstract description 14
- 230000008569 process Effects 0.000 abstract description 13
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 abstract description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002351 wastewater Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000004821 distillation Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 231100000086 high toxicity Toxicity 0.000 abstract description 3
- 238000010438 heat treatment Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 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 8
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 6
- 229960001067 hydrocortisone acetate Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 230000021736 acetylation Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229960000890 hydrocortisone Drugs 0.000 description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000004065 wastewater treatment Methods 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000002633 shock therapy Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a method for acylating steroid bulk drugs at the 21-position, which comprises the following steps: performing acylation reaction on the steroid bulk drug and an acylation reagent in an organic solvent under the action of a catalyst to obtain 21-bit acylate of the steroid bulk drug; the catalyst is alkali metal carbonate; the acylation reagent is one or two of acetic anhydride and propionic anhydride; the organic solvent is any one or two of acetone and tetrahydrofuran. The invention adopts acetone or tetrahydrofuran without ammonia nitrogen to replace solvents such as pyridine, dimethyl formamide, dimethyl sulfoxide and the like with high toxicity and high ammonia nitrogen, avoids the generation of high ammonia nitrogen wastewater in the whole synthesis process, reduces the environmental pollution and reduces the harm to operators. In addition, the solvent acetone or tetrahydrofuran can be recycled by distillation, so that the production cost is greatly saved, the concept of green development is met, and the method is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for acylation of 21-position of steroid bulk drugs.
Background
In clinical work, hormones have stronger anti-inflammatory and anti-allergic reaction effects and are widely applied to treatment of bronchial asthma, in recent years, the incidence rate of asthma is on the rise worldwide, and in the conventional treatment of bronchial asthma, when antibiotics, bronchodilators, cough relieving and phlegm reducing and other symptomatic treatments cannot achieve satisfactory curative effects, the hormone shock therapy is applied as early as possible without absolute contraindications.
The 21-bit acylate of steroid bulk drugs, such as dexamethasone acetate, prednisolone acetate, betamethasone dipropionate and the like, is an important glucocorticoid drug of adrenal gland, has the functions of regulating biosynthesis and metabolism of sugar, fat and protein, and also has the functions of suppressing immune response, resisting inflammation, resisting toxicity and resisting shock. The compound is mainly prepared by the reaction of steroid bulk drugs and acylating agents, for example, dexamethasone, prednisolone and acetic anhydride are respectively prepared by the reaction of dexamethasone and prednisolone, and betamethasone-17-propionate is prepared by the reaction of propionic anhydride and betamethasone dipropionate.
At present, pyridine is mostly adopted as a solvent and a catalyst to react in the traditional acylation process, and the pyridine is commonly called as 'nitrobenzene', is expensive, is not beneficial to recovery, seriously pollutes the environment, and is a technical difficulty for research personnel to find a green solvent to replace the pyridine.
The following patent applications disclose several representative acetylation processes for pyridine removal:
chinese patent No. CN1603333, using C3-C5 fatty ketone as solvent, adding a certain amount of acetate, and synthesizing hydrocortisone acetate from hydrocortisone, acetic acid and acetic anhydride. Although pyridine is replaced by a low-toxicity solvent of aliphatic ketone, the method has the advantages of complex synthesis process, low product yield, poor quality, large solvent consumption, high cost, incapability of recycling and the like, and is not suitable for expanded production;
the invention of Chinese patent CN101781349A, dipolar aprotic solvent is used, organic amine is added as catalyst (triethylamine, etc.), and hydrocortisone acetate is prepared. Although the method can also replace pyridine, the organic amine contains too high ammonia nitrogen, the subsequent wastewater treatment cost is higher, the method is not economical, and the yield is too much different from the theoretical yield, so that the method is not suitable for industrial production;
the Chinese invention patent CN104710494A adopts an acetylation reaction in a dipolar aprotic solvent to prepare hydrocortisone acetate and prednisolone acetate, wherein the dipolar aprotic solvent represents that the solvent is dimethylformamide, and the solvent enters wastewater after the reaction to generate a large amount of wastewater containing ammonia nitrogen, so that the wastewater treatment cost is high, and the method still has a great disadvantage in environmental protection;
in the production process for preparing hydrocortisone acetate, the invention patent CN201510023771.7 adopts dipolar aprotic as a solvent, namely dimethylformamide or a system of dimethyl sulfoxide, acetic acid and potassium acetate, and the process still can generate high ammonia nitrogen wastewater.
Therefore, in order to solve the above problems, a new method for acylating the 21-position of a steroid drug substance has been developed, which is a technical problem that needs to be solved by those skilled in the art.
Disclosure of Invention
The invention aims to provide a method for acylating steroid bulk drugs at the 21-position, which replaces toxic and harmful pyridine with acetone or tetrahydrofuran, and improves the yield and quality of the prepared 21-position acylate of the steroid bulk drugs.
The method for acylating the 21-position of the steroid bulk drug provided by the invention comprises the following steps:
performing acylation reaction on the steroid bulk drug and an acylation reagent in an organic solvent under the action of a catalyst to obtain 21-bit acylate of the steroid bulk drug;
the catalyst is alkali metal carbonate;
the acylation reagent is one or two of acetic anhydride and propionic anhydride;
the organic solvent is any one or two of acetone and tetrahydrofuran;
the structural formula of the steroid bulk drug is as follows:
wherein the content of the first and second substances,R1is H or alkene, R2Is H or F, R3Is H or F or alkene, R4Is OH or a ketone, R5Is alpha methyl or beta methyl, R6Is OH or an ester group.
The invention adopts acetone or tetrahydrofuran without ammonia nitrogen to replace solvents such as pyridine, dimethyl formamide, dimethyl sulfoxide and the like with high toxicity and high ammonia nitrogen, avoids the generation of high ammonia nitrogen wastewater in the whole synthesis process, reduces the environmental pollution and reduces the harm to operators. In addition, the solvent acetone or tetrahydrofuran can be recycled by distillation, so that the production cost is greatly saved, the concept of green development is met, and the method is suitable for large-scale industrial production; the catalyst of the acylation reaction adopts non-acidic catalyst alkali carbonate, so that the corrosivity and side reaction of the acidic catalyst are effectively avoided, and the prepared acylate product has good quality and light color; the acylation reagent adopts acid anhydride with medium activity, so that side reaction caused by strong reaction activity of acyl chloride is avoided, and influence of acylation reagents with low activity such as carboxylic acid on conversion efficiency is also avoided. The yield of the 21-bit acylate of the steroid bulk drug prepared by the invention can reach 106 percent at most, and the HPLC purity can reach 99.6 percent, so that the quality and the yield of the product are obviously improved compared with the acetylation process for removing pyridine in the prior art by the acylation process of the invention.
Preferably, in the technical scheme, the mass ratio of the steroid bulk drug, the organic solvent, the acylating reagent and the catalyst is 1: (5-10): (0.4-2.0): (0.3-2).
Specifically, in order to improve the utilization rate of reactants and the conversion rate of products, in the invention, the mass ratio of the steroid bulk drug, the organic solvent, the acylating reagent and the catalyst is 1: (5-10): (0.4-2.0): (0.3-2), and can be specifically adjusted according to the types of the steroid bulk drugs.
Preferably, the alkali metal carbonate is one or more of sodium carbonate, potassium carbonate and sodium bicarbonate.
The alkali metal carbonate used in the invention is one or more of sodium carbonate, potassium carbonate and sodium bicarbonate, and the reaction capability of attacking 21-site protons of steroid bulk drugs is enhanced by enhancing the positive charge of carbon atoms on acyl groups of acylation reagent anhydride.
Preferably, in the technical scheme, the acylation reaction is carried out at the temperature of 35-40 ℃ for 3-5 h.
The present invention has no specific limitation on the acylation reaction conditions, and the reaction temperature can be controlled to be 35-40 ℃ and the reaction time can be controlled to be 3-5 h.
Preferably, in the technical scheme, after the acylation reaction is completed, quenching, concentrating, washing, filtering and drying are sequentially performed to obtain 21-bit acylate of the steroid bulk drug.
After the acylation reaction is finished, TLC is used for detecting the reaction is complete, a quenching agent is used for stopping the reaction, and the condensation, the water washing, the filtration and the drying are sequentially carried out, so that the 21-bit acylate of the steroid bulk drug can be obtained.
Preferably, in the present technical solution, the quenching agent used in the quenching is one or both of an aqueous solution of ammonium chloride and water;
preferably, the dosage of the quenching agent is 0.8-1.2 times of that of the steroid bulk drug.
Since the acylation reaction is not completely completed in a usual case, the reaction proceeds slowly after a certain time, and at this time, the reaction is considered to be completed, and a quencher may be added for completely terminating the reaction. For the anhydrous reaction of acid and alkali, aqueous solution of ammonium chloride and water can be selected as the quenching agent, and water is preferred, wherein the dosage of the quenching agent is 0.8-1.2 times of that of the steroid bulk drug, and is preferably 1 time.
Preferably, in the technical scheme, during water washing, the dosage of water is controlled to be 8-12 times of that of the steroid bulk drug, and the temperature is controlled to be 0-5 ℃.
And finally, after decompression and concentration, the mixture can be added into water with the temperature of 0-5 ℃ which is 8-12 times that of the mixture, fully stirred, filtered and dried, and the 21-bit acylate of the steroid bulk drug can be obtained.
The 21-bit acylate of the steroid bulk drug of the invention refers to dexamethasone acetate, prednisolone acetate, betamethasone dipropionate, hydrocortisone, cortisone, prednisone, betamethasone and the like, but is not limited thereto.
Preferably, the technical scheme is that the steroid bulk drug dexamethasone and sodium carbonate are added into acetone, the temperature is raised to 30-35 ℃, acetic anhydride is added, the reaction is carried out for 3-5 hours at 35-40 ℃, and after the reaction is finished, quenching, concentration, water washing, filtering and drying are carried out in sequence to obtain dexamethasone acetate;
preferably, the mass ratio of the dexamethasone to the acetone to the acetic anhydride to the sodium carbonate is 1: (5-10): (0.4-2.0): (0.3-2);
preferably, the yield of the dexamethasone acetate is 100-110%, and the HPLC purity is 99.0-99.9%.
Preferably, the steroid bulk drug prednisolone and potassium carbonate are added into tetrahydrofuran, the temperature is raised to 30-35 ℃, acetic anhydride is added, the mixture reacts for 3-5 hours at the temperature of 35-40 ℃, and after the reaction is finished, the mixture is sequentially quenched, concentrated, washed, filtered and dried to obtain prednisolone acetate;
preferably, the mass ratio of prednisolone to tetrahydrofuran to acetic anhydride to potassium carbonate is 1: (5-10): (0.4-2.0): (0.3-2);
preferably, the yield of the prednisolone acetate is 100-110%, and the HPLC purity is 99.0-99.9%.
Preferably, the technical scheme is that steroid bulk drug betamethasone-17-propionate and sodium carbonate are added into acetone, the temperature is raised to 30-35 ℃, propionic anhydride is added, the mixture reacts for 3-5 hours at the temperature of 35-40 ℃, and after the reaction is finished, quenching, concentrating, washing, filtering and drying are sequentially carried out to obtain betamethasone dipropionate;
preferably, the mass ratio of the betamethasone-17-propionate, the acetone, the propionic anhydride and the sodium carbonate is 1: (5-10): (0.4-2.0): (0.3-2);
preferably, the yield of betamethasone dipropionate is 100-110%, and the HPLC purity is 99.0-99.9%.
Compared with the prior art, the method for acylating the 21-position of the steroid bulk drug has the following advantages:
1. the invention adopts acetone or tetrahydrofuran without ammonia nitrogen to replace solvents such as pyridine, dimethyl formamide, dimethyl sulfoxide and the like with high toxicity and high ammonia nitrogen, avoids the generation of high ammonia nitrogen wastewater in the whole synthesis process, reduces the environmental pollution and reduces the harm to operators. In addition, the solvent acetone or tetrahydrofuran can be recycled by distillation, so that the production cost is greatly saved, the concept of green development is met, and the method is suitable for large-scale industrial production;
2. the yield of the steroid bulk drug 21-bit acylate prepared by the invention can reach 106% at most, and the HPLC purity can reach 99.6%. Compared with the acetylation process for removing pyridine in the prior art, the acylation process provided by the invention has the advantages that the product quality and yield are obviously improved.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms also include the plural forms unless the context clearly dictates otherwise, and further, it is understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of the stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Adding 10g of dexamethasone, 5g of sodium carbonate and 80ml of acetone into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 9g of acetic anhydride, continuing heating to 38 ℃, carrying out heat preservation reaction for 3 hours, carrying out TLC detection reaction completely, adding 10g of water to quench the reaction, carrying out reduced pressure concentration, pouring into 100g of 5 ℃ water, stirring uniformly, filtering and drying to obtain 10.4g of dexamethasone acetate.
Yield 104% and HPLC purity 99.3%.
Example 2
Adding 10g of dexamethasone, 7g of potassium carbonate and 100ml of tetrahydrofuran into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 12g of acetic anhydride, continuing heating to 38 ℃, carrying out heat preservation reaction for 3 hours, carrying out TLC detection reaction completely, adding 10g of water to quench the reaction, carrying out reduced pressure concentration, pouring into 100g of water with the temperature of 5 ℃, stirring uniformly, filtering and drying to obtain 10.3g of dexamethasone acetate.
The yield was 103% and the HPLC purity was 99.4%.
Example 3
Adding 10g of prednisolone, 12g of potassium carbonate and 60ml of acetone into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 13g of acetic anhydride, continuously heating to 38 ℃, carrying out heat preservation reaction for 4 hours, carrying out TLC detection reaction completely, adding 10g of water for quenching reaction, carrying out reduced pressure concentration, pouring into 100g of water with the temperature of 5 ℃, stirring uniformly, filtering and drying to obtain 10.6g of prednisolone acetate.
Yield 106% and HPLC purity 99.2%.
Example 4
Adding 10g of prednisolone, 15g of sodium bicarbonate and 70ml of tetrahydrofuran into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 16g of acetic anhydride, continuously heating to 38 ℃, carrying out heat preservation reaction for 4 hours, carrying out TLC detection reaction completely, adding 10g of water for quenching reaction, carrying out reduced pressure concentration, pouring into 100g of water with the temperature of 3 ℃, stirring uniformly, filtering and drying to obtain 10.4g of prednisolone acetate.
Yield 104% and HPLC purity 99.4%.
Example 5
Adding 10g betamethasone-17-propionate, 10g sodium carbonate and 80ml acetone into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 17g propionic anhydride, continuously heating to 38 ℃, keeping the temperature and reacting for 5 hours, detecting by TLC (thin layer chromatography) to completely react, adding 10g water to quench and react, decompressing and concentrating, pouring into 100g water of 5 ℃, stirring uniformly, filtering and drying to obtain 10.3g betamethasone dipropionate.
The yield was 103% and the HPLC purity was 99.1%.
Example 6
Adding 10g of betamethasone-17-propionate, 18g of sodium bicarbonate and 100ml of tetrahydrofuran into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 19g of propionic anhydride, continuously heating to 38 ℃, keeping the temperature for reaction for 5 hours, detecting by TLC (thin layer chromatography), completely reacting, adding 10g of water, quenching and reacting, decompressing and concentrating, pouring into 100g of water with the temperature of 3 ℃, uniformly stirring, filtering and drying to obtain 10.5g of betamethasone dipropionate.
The yield was 105% and the HPLC purity was 99.0%.
Example 7
Adding 10g of hydrocortisone, 3g of sodium bicarbonate and 50ml of tetrahydrofuran into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 4g of propionic anhydride, continuously heating to 35 ℃, carrying out heat preservation reaction for 3 hours, detecting by TLC to completely react, adding 8g of water to quench and react, carrying out reduced pressure concentration, pouring into 80g of water with the temperature of 0 ℃, uniformly stirring, filtering and drying to obtain 10.2g of hydrocortisone acetate.
The yield was 102% and the HPLC purity was 99.6%.
Example 8
Adding 10g of hydrocortisone, 20g of sodium bicarbonate and 100ml of tetrahydrofuran into a dry and clean reaction bottle, stirring and heating to 30 ℃, adding 20g of propionic anhydride, continuously heating to 40 ℃, keeping the temperature for reaction for 5 hours, detecting by TLC (thin layer chromatography) to complete the reaction, adding 12g of water for quenching reaction, concentrating under reduced pressure, pouring into 120g of water with the temperature of 5 ℃, uniformly stirring, filtering and drying to obtain 10.8g of hydrocortisone acetate.
Yield 108% and HPLC purity 99.5%.
Table 1 yield, yield and purity of the products of examples 1-8
As can be seen from table 1, the yields of 21-bit acylates of steroid drug substances prepared in embodiments 1 to 8 of the present invention are all over 102%, and the HPLC purities are all over 99.0%, and the maximum yield is 99.6%. Compared with the acetylation process for removing pyridine in the prior art, the acylation process provided by the invention has the advantages that the product quality and yield are obviously improved.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A method for acylation of 21-position of steroid bulk drug is characterized by comprising the following steps:
performing acylation reaction on the steroid bulk drug and an acylation reagent in an organic solvent under the action of a catalyst to obtain 21-bit acylate of the steroid bulk drug;
the catalyst is alkali metal carbonate;
the acylation reagent is one or two of acetic anhydride and propionic anhydride;
the organic solvent is any one or two of acetone and tetrahydrofuran;
the structural formula of the steroid bulk drug is as follows:
wherein R is1Is H or alkene, R2Is H or F, R3Is H or F or alkene, R4Is OH or a ketone, R5Is alpha methyl or beta methyl, R6Is OH or an ester group.
2. The method for acylation of 21-position of a steroid drug substance according to claim 1, wherein the mass ratio of the steroid drug substance, the organic solvent, the acylating agent and the catalyst is 1: (5-10): (0.4-2.0): (0.3-2).
3. The method for acylation of 21-position of steroid drug substance according to claim 1, wherein the alkali metal carbonate is any one or more of sodium carbonate, potassium carbonate and sodium bicarbonate.
4. The method for acylation of 21-position of steroid drug substance according to claim 1, wherein the temperature is controlled at 35-40 ℃ for 3-5h during the acylation reaction.
5. The method for acylation of 21-position of steroid drug substance according to claim 1, characterized in that after the acylation reaction is completed, quenching, concentrating, water washing, filtering and drying are sequentially performed to obtain 21-position acylate of steroid drug substance.
6. The method for acylation of 21-position of steroid drug substance according to claim 5, wherein quenching is carried out using a quenching agent selected from the group consisting of aqueous solution of ammonium chloride and water;
preferably, the dosage of the quenching agent is 0.8-1.2 times of that of the steroid bulk drug.
7. The method for 21-acylation of a steroid drug substance according to claim 5, wherein the amount of water used is controlled to be 8-12 times that of the steroid drug substance in the water washing process, and the temperature is controlled to be 0-5 ℃.
8. The method for 21-bit acylation of steroid bulk drugs according to claim 1, characterized in that dexamethasone and sodium carbonate are added to acetone, the temperature is raised to 30-35 ℃, acetic anhydride is added, the reaction is carried out for 3-5h at 35-40 ℃, after the reaction is completed, quenching, concentration, water washing, filtering and drying are carried out in sequence to obtain dexamethasone acetate;
preferably, the mass ratio of the dexamethasone to the acetone to the acetic anhydride to the sodium carbonate is 1: (5-10): (0.4-2.0): (0.3-2);
preferably, the yield of the dexamethasone acetate is 100-110%, and the HPLC purity is 99.0-99.9%.
9. The method for 21-bit acylation of steroid bulk drugs according to claim 1, characterized in that, prednisolone and potassium carbonate are added into tetrahydrofuran, the temperature is raised to 30-35 ℃, acetic anhydride is added, the mixture is reacted at 35-40 ℃ for 3-5h, and after the reaction is completed, the mixture is sequentially quenched, concentrated, washed, filtered and dried to obtain prednisolone acetate;
preferably, the mass ratio of prednisolone to tetrahydrofuran to acetic anhydride to potassium carbonate is 1: (5-10): (0.4-2.0): (0.3-2);
preferably, the yield of the prednisolone acetate is 100-110%, and the HPLC purity is 99.0-99.9%.
10. The method for 21-bit acylation of steroid bulk drugs according to claim 1, characterized in that the steroid bulk drug betamethasone-17-propionate and sodium carbonate are added into acetone, heated to 30-35 ℃, added with propionic anhydride, reacted at 35-40 ℃ for 3-5h, and after the reaction is completed, sequentially quenched, concentrated, washed with water, filtered and dried to obtain betamethasone dipropionate;
preferably, the mass ratio of the betamethasone-17-propionate, the acetone, the propionic anhydride and the sodium carbonate is 1: (5-10): (0.4-2.0): (0.3-2);
preferably, the yield of betamethasone dipropionate is 100-110%, and the HPLC purity is 99.0-99.9%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52144664A (en) * | 1976-05-25 | 1977-12-02 | Takeda Chem Ind Ltd | Steroid derivatives |
| CN104710494A (en) * | 2015-01-19 | 2015-06-17 | 河南利华制药有限公司 | Production technology of hydrocortisone acetate |
| CN104761607A (en) * | 2015-03-17 | 2015-07-08 | 河南利华制药有限公司 | Preparation of prednisolone acetate |
| CN108752411A (en) * | 2018-07-02 | 2018-11-06 | 河南利华制药有限公司 | A kind of 21 acetylization reaction techniques of C21 steroids |
| CN109096355A (en) * | 2018-10-23 | 2018-12-28 | 山东泰华生物科技股份有限公司 | A kind of preparation method of dexamethasone acetate |
-
2021
- 2021-12-16 CN CN202111541723.9A patent/CN114395008A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52144664A (en) * | 1976-05-25 | 1977-12-02 | Takeda Chem Ind Ltd | Steroid derivatives |
| CN104710494A (en) * | 2015-01-19 | 2015-06-17 | 河南利华制药有限公司 | Production technology of hydrocortisone acetate |
| CN104761607A (en) * | 2015-03-17 | 2015-07-08 | 河南利华制药有限公司 | Preparation of prednisolone acetate |
| CN108752411A (en) * | 2018-07-02 | 2018-11-06 | 河南利华制药有限公司 | A kind of 21 acetylization reaction techniques of C21 steroids |
| CN109096355A (en) * | 2018-10-23 | 2018-12-28 | 山东泰华生物科技股份有限公司 | A kind of preparation method of dexamethasone acetate |
Non-Patent Citations (2)
| Title |
|---|
| HULCOOP DG: "Expedient synthesis of 17α,21-dihydroxy-9β,11β-epoxy- 16α-methylpregna-1,4-diene-3,20-dione 21-acetate from prednisolone utilising a novel Mattox rearrangement", 《STEROIDS》 * |
| 殷莉梅: "丙酸氟替卡松的合成工艺改进", 《中国药物化学杂志》 * |
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