CN104610408A - Preparation method for prednisone acetate and intermediate of same - Google Patents
Preparation method for prednisone acetate and intermediate of same Download PDFInfo
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- CN104610408A CN104610408A CN201510076695.6A CN201510076695A CN104610408A CN 104610408 A CN104610408 A CN 104610408A CN 201510076695 A CN201510076695 A CN 201510076695A CN 104610408 A CN104610408 A CN 104610408A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
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Abstract
The invention relates to the field of preparation of steroid drugs and an intermediate of the same, and in particular relates to a preparation method for prednisone acetate. The method comprises the steps of taking 11 alpha, 17 alpha-dyhydroxy Pregnene-1,4-diene-3,20-dione as an initial material, oxidizing to obtain 17 alpha-hydroxy Pregnene-1,4-diene-3,11,20-trione, and carrying out iodization reacting to obtain the prednisone acetate. The invention provides a novel oxidation technology more suitable for production of the intermediate of the prednisone acetate, the synthesis path has the characteristics of low cost and simple operation, environment pollution pressure can be greatly reduce, and the yield and quality of the prednisone acetate can reach a satisfactory level.
Description
Technical field
The present invention relates to the preparation method of steroid drugs and intermediate thereof, be specifically related to a kind of Prednisone acetate and the intermediate (pregnant steroid-Isosorbide-5-Nitrae-diene-3,11 of 17 Alpha-hydroxy thereof, 20-triketone) preparation method, invented a kind of Prednisone acetate intermediate oxidation technique being more suitable for producing completely newly.
Background technology
Steroid hormone has very strong anti-infective, antianaphylaxis, antiviral and antishock pharmacological action, is treatment rheumatism, cardiovascular, leukemic lymphoblastoid, cellularity encephalitis, tetter, antitumor and rescue the important medication of urgent patient.Prednisone acetate is a kind of important steroid drugs, be mainly used in various acute severe bacterial infections, severe allergic disease, collagen disease (lupus erythematosus, periarteritis nodosa etc.), rheumatosis, rheumatoid arthritis, nephrotic syndrome, serious bronchial asthma, acute lymphatic leukaemia, various Adrenal cortex function insufficiency diseases etc.The structural formula of Prednisone acetate is as follows:
, one of them important intermediate (starting raw material), chemistry 11 α by name, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, its structural formula:
, obtain 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones (Isosorbide-5-Nitrae-diene-17 α-ol-3,11,20-trione) after 11 hydroxyl oxidizes, its structural formula:
。
The method of Prednisone acetate is prepared in currently available technology, the mode mainly adopting biological fermentation and chemosynthesis to combine realizes, the starting raw material that domestic production Prednisone acetate is commonly used is the mold oxide deriving from diene, it first through C11 position oxidation after again through C1,2 dehydrogenations, carry out modification at side chain more afterwards and obtain Prednisone acetate.The difficult point of this technique is the introducing of C11 position carbonyl and C1,2 double bonds, due to around C11 position, does not have activity functional groups to play impact to it, is difficult to C11 position hydroxyl oxygen to change into C11 position carbonyl under normal condition; And Ovshinsky oxide compound is after the oxidation of C11 position, next step C1,2 dehydrogenations are difficult to carry out, and there is the problem that yield is low, cost is high.Also there is direct cortisone acetate to make starting raw material, carry out C1, the biological fermentation of 2, obtain Prednisone acetate.The shortcoming of this technique is that the yield of biological fermentation is low, causes cost high.In addition, along with the rise of diene price in recent years, very limited by the profit margin of existing explained hereafter Prednisone acetate, new technological breakthrough point must be found.
Document CN201210070704.7 reports the chemical synthesis route that is prepared prednisone, take mold oxide as starting raw material, through Pu Shi oxidation, debrominate, the synthesis of upper iodization.Described in this patented method, products therefrom should be cortisone acetate, instead of prednisone, because it has lacked the introducing of C1,2 double bonds.
Document CN201110101279.9 reports the novel process of an oxidative synthesis pregnant steroid C11 position ketone group, it uses piperidine nitroxide free-radical as oxide catalyst, use nominal price halogenide as oxygenant, C11 position hydroxyl oxygen is changed into C11 position carbonyl, the yield of this method for oxidation is on the low side, high expensive.
Document CN201310594449.0 reports the chemical synthesis route that is prepared prednisone; it obtains through oxidizing reaction, cyano group substitution reaction, the protective reaction of silicon alkoxyl group, intramolecular nucleophilic substitution reaction and esterification; this technique needs the cyanating reagent used to be highly toxic product; need the basic metal reagent used to be easy detonation product, be unfavorable for industrialized production.
For the produce difficult point of Prednisone acetate, namely existing technique is for C11 position carbonyl and 1, and the introducing of 2 double bonds is all undesirable, therefore, finds new starting raw material with alternative mold oxide, perhaps relatively easily can solve this two critical technological points.In recent years, along with the continuous progress of China's medicine production technology, utilize the technology of bio-manufacturing method degradation selectivity plant sterol side chain production steroidal intermediate Androstenedione (4AD) very ripe, and plant sterols is extensively present in the root of plant, stem, leaf, fruit and seed, it is the integral part of plant cell membrane, all contain sterol all deriving from the grease of plant seed, utilizing maximum is at present Sitosterol, Stigmasterol and campesterol etc.Because of plant sterols wide material sources, fermentation technique is ripe, and make the manufacturing cost of 4AD cheaper, particularly in recent years, rising steadily of another steroidal intermediate diene price is correspondingly that raw material has good cost advantage to prepare steroid drugs with 4AD.The present inventor puts forth effort on and adopts raw material based on 4AD to carry out acetic acid synthesized prednisone, by company technique personnel unremitting effort, has in succession got through operational path, has achieved industrialized production.First 4AD can synthesize the important intermediate 17 Alpha-hydroxy Progesterone obtaining steroid drugs through three-step reaction, and the industrialized production of this intermediate, has a large amount of supply on the market, next step introduces 11 hydroxyls, because 17 Alpha-hydroxy Progesterone have 17 hydroxyls, is easy to adopt biological fermentation to obtain 11 α, 17 alpha-dihydroxy-Progesterone, introduce 11 hydroxyls, biological fermentation next can be adopted equally to introduce 1,2 double bonds, obtain 11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone intermediate, what finally need to solve is the introducing of 11 carbonyls, method for oxidation can be adopted realize, the present inventor successively tests some common method for oxidation, as the Pu Shi method for oxidation in document CN201210070704.7 report, this method for oxidation is used for being oxidized this intermediate, and one is that yield is low, can only about 80% be reached, two is that purity is low, and HPLC purity ability 85% is not obviously very applicable, and for example document CN201110101279.9 reports and uses nominal price halogenide (hypohalous acid and salt thereof) as oxygenant, and 11 hydroxyl oxygens are changed into 11 carbonyls, and it is on the low side that this method for oxidation exists yield equally, the problem of high expensive, in addition, the present inventor also tests Ovshinsky method for oxidation, polite oxidation (Swern oxidation) method, Dai Si-Martin reagent oxidation style, PCC reagent oxidation method, Collins reagent oxidation method, pyridine-sulfotrioxide oxidation style etc., the reagent cost superelevation had in these method for oxidation, some reagent oxidation effects are undesirable, do not reach expected result, through the scientific experiment that the present inventor is a large amount of, finally have found a kind of new method for oxidation, this method not only yield is high, and technological operation is simple, stable, be applicable to industrialized production, be oxidized the pregnant steroid-1 of 17 Alpha-hydroxy obtained, 4-diene-3, 11, 20-triketone, namely last reaction through simple upper iodization again obtain Prednisone acetate, whole piece route is with low cost, simple to operate, greatly reduce the pressure of environmental pollution.
Summary of the invention
For the shortcoming and defect that above-mentioned prior art exists, the present invention aims to provide the preparation method of a kind of Prednisone acetate, and this synthetic route has with low cost, feature simple to operate, and the pressure that can greatly reduce environmental pollution.
Particularly, contriver provides following technical scheme:
The reaction scheme of Prednisone acetate of the present invention is as follows, with 11 α, the pregnant steroid-Isosorbide-5-Nitrae-diene-3 of 17 alpha-dihydroxy-, 20-diketone is starting raw material, through peroxidation, obtain the pregnant steroid-Isosorbide-5-Nitrae-diene-3 of 17 Alpha-hydroxy, 11,20-triketone, then through the obtained Prednisone acetate of upper iodization reaction, route is as follows:
。
A preparation method for Prednisone acetate, comprising:
(1) oxide compound-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone is prepared
(1.1) in preparing tank, add the water of 1 ~ 5 weight part, then add the acid of 0.5 ~ 2 weight part a bit slowly, stirred for several minute, then the oxidising agent adding 0.5 ~ 2 weight part, stir clearly molten, is then cooled to 0 ~ 30 DEG C, obtains oxygenant A, for subsequent use
(1.2) in retort, add raw material i.e. 11 α of the solvent of 5 ~ 50 weight parts, the acid of 0 ~ 10 weight part, the metal oxide of 0 ~ 2 weight part and 1 weight part, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, stir clearly molten, control temperature, at-20 ~ 80 DEG C, drips the oxygenant A prepared, dropwises, stir, till raw material reaction completely; Drip the quencher of 0.1 ~ 10 weight part, control temperature, below 55 DEG C, stirs, then adds the alkaline solution of 0 ~ 10 weight part, adjust pH to 6 ~ 7, then concentrating under reduced pressure, to solvent concentration is complete; Add the water of 5 ~ 50 parts by volume again, be cooled to temperature 20 ~ 25 DEG C; Leave standstill, blowing is centrifugal; Then rinse with water, then dry, dry material, obtain soild oxide i.e. 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones of off-white color.
(2) Prednisone acetate is prepared
(2.1) prepare iodine liquid: the methyl alcohol adding the Calcium Chloride Powder Anhydrous of 0.15 weight part, the iodine of 0.8 ~ 1.0 weight part and 1.2 weight parts in iodine liquid preparing tank, stir cooling and dissolve, for subsequent use;
Preparation Calcium Chloride Powder Anhydrous methanol solution: add the Calcium Chloride Powder Anhydrous of 0.15 weight part and the methyl alcohol of 1.2 weight parts in preparing tank, stirring and dissolving, for subsequent use;
Preparation aqueous ammonium chloride solution: add the ammonium chloride of 1 weight part and the water of 5 parts by volume in ammonium chloride batch tank, stirring and dissolving, for subsequent use;
(2.2) in upper Iod R tank, put into the oxide compound i.e. pregnant steroid-1 of 17 Alpha-hydroxy of the chloroform of 5 parts by volume, 1 weight part, 4-diene-3, the Calcium Chloride Powder Anhydrous methanol solution that 11,20-triketone, (2.1) prepare, the calcium oxide of 0.5 weight part, stir, be cooled to 2-5 DEG C, start the iodine liquid that dropping (2.1) prepares, drip 2-4 hour, then continue insulation reaction, middle control, until stopped reaction when reacting completely.
Add the aqueous ammonium chloride solution that (2.1) prepare and do cancellation reaction, layering after leaving standstill, chloroform layer enters concentration tank, water layer chloroform extraction several, combined chloroform layer is incorporated to concentration tank, is evaporated to dry, and the dimethyl formamide adding 2 parts by volume in the material obtained after concentrated fully dissolves, be cooled to 20-25 DEG C, proceeded to replacement(metathesis)reaction tank;
Turn and finish, in replacement(metathesis)reaction tank, drop into 1.0 parts by weight acetic acid potassium, stir, start to heat up, within first hour, be warming up to 30-35 DEG C, within second hour, be warming up to 53-62 DEG C from 30-35 DEG C, with 53 DEG C start timing, insulation reaction till reacting completely, after having reacted, start to be cooled to-2 DEG C to-6 DEG C dischargings, rinse material with water, dry, moisture eliminator is delivered in discharging, temperature controls, 90-110 DEG C of drying, to obtain Prednisone acetate.
As preferably, in step of the present invention (1.1): acid includes, but are not limited to the mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, the organic acid such as Glacial acetic acid, citric acid; Oxidising agent includes, but are not limited to: manganese oxide, potassium permanganate etc. are containing the metal oxide of manganese, potassium bichromate, chromic acid etc. are containing the metal oxide of chromium, the peralcohol such as ferric iron compound, sodium peroxide, and soluble compound in other common water.
As preferably, in step of the present invention (1.2), solvent comprises and being not limited to: the ester compound that chloroform, methylene dichloride, acetone, tetrahydrofuran (THF), dioxane, DMF, DMSO, ethyl acetate etc. are common; Acid comprises mineral acids such as being not limited to hydrochloric acid, nitric acid, sulfuric acid, the organic acid such as Glacial acetic acid, citric acid; Catalyzer comprises the compounds being not limited to manganous carbonate, Manganous chloride tetrahydrate etc. and containing manganese, and cobalt chloride, cobaltous carbonate etc. are containing a compounds of cobalt; Quencher comprises and being not limited to: the alcohols such as methyl alcohol, Virahol, the reductive agent of the sulfur-bearings such as sodium sulphite, sodium bisulfite, V-Brite B; Alkali comprises and is not limited to the highly basic such as potassium hydroxide or sodium hydroxide, the subsalt such as salt of wormwood or sodium bicarbonate, the mineral alkali such as triethylamine, aniline.
As preferably, in step of the present invention (1.2): the oxygenant A that dropping prepares, within 0.1 ~ 10 hour, be added dropwise to complete.
As preferably, in step of the present invention (1.2): drip the oxygenant A prepared, dropwise, stir, thin-layer chromatographic analysis, till raw material reaction completely.
Present invention also offers a kind of preparation method of Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method comprises:
(1) in preparing tank, add the water of 1 ~ 5 weight part, then add the acid of 0.5 ~ 2 weight part a bit slowly, stirred for several minute, then the oxidising agent adding 0.5 ~ 2 weight part, stir clearly molten, is then cooled to 0 ~ 30 DEG C, obtains oxygenant A, for subsequent use;
(2) in retort, add raw material i.e. 11 α of the solvent of 5 ~ 50 weight parts, the acid of 0 ~ 10 weight part, the metal oxide of 0 ~ 2 weight part and 1 weight part, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, stir clearly molten, control temperature, at-20 ~ 80 DEG C, drips the oxygenant A prepared, dropwises, stir, till raw material reaction completely; Drip the quencher of 0.1 ~ 10 weight part, control temperature, below 55 DEG C, stirs, then adds the alkaline solution of 0 ~ 10 weight part, adjust pH to 6 ~ 7, then concentrating under reduced pressure, to solvent concentration is complete; Add the water of 5 ~ 50 parts by volume again, be cooled to temperature 20 ~ 25 DEG C; Leave standstill, blowing is centrifugal; Then rinse with water, then dry, dry material, obtain soild oxide i.e. 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones of off-white color.
As preferably, in preparation method's step (1) of Prednisone acetate intermediate of the present invention: acid includes, but are not limited to the mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, the organic acid such as Glacial acetic acid, citric acid; Oxidising agent includes, but are not limited to: manganese oxide, potassium permanganate etc. are containing the metal oxide of manganese, potassium bichromate, chromic acid etc. are containing the metal oxide of chromium, the peralcohol such as ferric iron compound, sodium peroxide, and soluble compound in other common water.
As preferably, in preparation method's step (2) of Prednisone acetate intermediate of the present invention: solvent comprises and being not limited to: the ester compound that chloroform, methylene dichloride, acetone, tetrahydrofuran (THF), dioxane, DMF, DMSO, ethyl acetate etc. are common; Acid comprises mineral acids such as being not limited to hydrochloric acid, nitric acid, sulfuric acid, the organic acid such as Glacial acetic acid, citric acid; Catalyzer comprises the compounds being not limited to manganous carbonate, Manganous chloride tetrahydrate etc. and containing manganese, and cobalt chloride, cobaltous carbonate etc. are containing a compounds of cobalt; Quencher comprises and being not limited to: the alcohols such as methyl alcohol, Virahol, the reductive agent of the sulfur-bearings such as sodium sulphite, sodium bisulfite, V-Brite B; Alkali comprises and is not limited to the highly basic such as potassium hydroxide or sodium hydroxide, the subsalt such as salt of wormwood or sodium bicarbonate, the mineral alkali such as triethylamine, aniline.
As preferably, in preparation method's step (1) of Prednisone acetate intermediate of the present invention: the oxygenant A that dropping prepares, within 0.1 ~ 10 hour, be added dropwise to complete.
As preferably, in preparation method's step (2) of Prednisone acetate intermediate of the present invention: drip the oxygenant A prepared, dropwise, stir, thin-layer chromatographic analysis, till raw material reaction completely.
Compared with prior art, the effective effect of the present invention is:
The invention provides a kind of brand-new oxidation system, can by compound 11 α, the C11 position hydroxyl oxygen of 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone changes into C11 position carbonyl, and this method for oxidation cost is lower, easily operates, and pollutes little, is applicable to industrialized production.Adopt this route to prepare Prednisone acetate, its yield and quality can reach satisfied level.
Accompanying drawing explanation
Fig. 1 is the hydrogen spectrogram of product Prednisone acetate of the present invention.
Fig. 2 is the carbon spectrogram of product Prednisone acetate of the present invention.
Fig. 3 is the mass spectrum of product Prednisone acetate of the present invention.
Embodiment
Below in conjunction with embodiment, further illustrate content of the present invention.It should be pointed out that following examples are only the more representational examples of the present invention.Obviously, technical scheme of the present invention is not limited to following embodiment, can also have many distortion.Every all distortion of directly deriving from content disclosed by the invention or associating, all should think protection scope of the present invention.
In the present invention, if not refer in particular to, all parts, per-cent are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is conventional.Method in following embodiment, if no special instructions, is the ordinary method of this area.
embodiment 1
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method comprises:
In preparing tank, add 10Kg water, then add 5Kg concentrated nitric acid slowly, stir ten minutes.Add 5 Kg manganese oxide again, stir clearly molten, be cooled to 10 ~ 15 DEG C, obtain oxygenant A, for subsequent use.
In retort, add 50Kg acetone, 10Kg Glacial acetic acid, 1.2Kg Manganous chloride tetrahydrate and 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone), stir clearly molten.Control temperature is at 0 ~ 5 DEG C.Drip the oxygenant A prepared, control temperature, at 0 ~ 5 DEG C, is added dropwise to complete for about 1.5 hours.Stir, thin-layer chromatographic analysis, till raw material reaction completely.Drip the mixing solutions of 5Kg sodium bisulfite and 50Kg water, control temperature is below 30 DEG C, and stir half hour, add the aqueous solution of 6Kg sodium hydroxide, adjust pH is about 6 ~ 7, concentrating under reduced pressure, to acetone concentrates completely.Add 50 Kg water, be cooled to 20 ~ 25 DEG C.Leave standstill half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.Dry material at 90 ~ 120 DEG C, obtain off-white color soild oxide 9.61Kg, analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 98.6%.
embodiment 2
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method comprises:
In preparing tank, add 20Kg water, then add the 10Kg vitriol oil slowly, stir ten minutes.Add 10 Kg chromium trioxides, stir clearly molten.Be cooled to 0 ~ 10 DEG C, obtain oxygenant A, for subsequent use.
In retort, add 250 Kg dioxane, 5Kg Glacial acetic acid, 1.5Kg Manganous chloride tetrahydrate and 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone), stir clearly molten.Control temperature is at 20 ~ 30 DEG C.Drip the oxygenant A prepared, control temperature, at 20 ~ 30 DEG C, is added dropwise to complete for about 0.5 hour.Stir, thin-layer chromatographic analysis, till raw material reaction completely.Drip the mixing solutions of 12 Kg V-Brite Bs and 50Kg water, control temperature is below 30 DEG C, and stir half hour, add the aqueous solution of 12Kg sodium bicarbonate, adjust pH is about 6 ~ 7, concentrating under reduced pressure, to dioxane concentrates completely.Add 120 Kg water, be cooled to 20 ~ 25 DEG C.Leave standstill half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 9.42 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 97.9%.
embodiment 3
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method comprises:
In preparing tank, add 20Kg water, then add the 5.5Kg vitriol oil slowly, stir ten minutes.Add 6 .8Kg chromium trioxides, stir clearly molten.Be cooled to 20 ~ 30 DEG C, obtain oxygenant A, for subsequent use.
In retort, add 330 Kg methylene dichloride, 10Kg Glacial acetic acid, 1.5Kg Manganous chloride tetrahydrate and 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone), stir clearly molten.Control temperature is at-20 ~ 10 DEG C.Drip the oxygenant A prepared, control temperature, at-20 ~ 10 DEG C, is added dropwise to complete for about 0.5 hour.Stir, thin-layer chromatographic analysis, till raw material reaction completely.Drip the mixing solutions of 8 Kg V-Brite Bs and 50Kg water, control temperature is below 30 DEG C, and stir half hour, add the aqueous solution of 20 Kg sodium bicarbonates, adjust pH is about 6 ~ 7, concentrating under reduced pressure, to methylene dichloride concentrates completely.Add 200Kg water, be cooled to 20 ~ 25 DEG C.Leave standstill half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 9.03 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 97.4%.
embodiment 4
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method comprises:
In preparing tank, add 10Kg water, then add 8Kg concentrated nitric acid slowly, stir ten minutes.Add 7Kg chromium trioxide, stir clearly molten.Be cooled to 10 ~ 15 DEG C, obtain oxygenant A.For subsequent use.
In retort, add 330 Kg chloroforms, 10Kg Glacial acetic acid, 10Kg Manganous chloride tetrahydrate and 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone), stir clearly molten.Control temperature is at 10 ~ 15 DEG C.Drip the oxygenant A prepared, control temperature, below 15 DEG C, is added dropwise to complete for about 0.5 hour.Stir, thin-layer chromatographic analysis, till raw material reaction completely.Drip the mixing solutions of 15Kg V-Brite B and 100Kg water, control temperature is below 30 DEG C, and stir half hour, add the aqueous solution of 15 Kg sodium bicarbonates, adjust pH is about 6 ~ 7, concentrating under reduced pressure, to chloroform concentrates completely.Add 250 Kg water, be cooled to 20 ~ 25 DEG C.Static half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 9.63 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 97.2%.
embodiment 5
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method comprises:
In preparing tank, add 50Kg water, then add 20Kg concentrated hydrochloric acid slowly, stir ten minutes.Add 20Kg potassium bichromate, stir clearly molten.Be cooled to 10 ~ 15 DEG C, obtain oxygenant A.For subsequent use
In retort, add 500Kg tetrahydrofuran (THF), 100Kg Glacial acetic acid, 20Kg Manganous chloride tetrahydrate, 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone), stir clearly molten.Control temperature is at 0 ~ 5 DEG C, and drip the oxygenant A-i.e. potassium bichromate solution prepared, control temperature, below 25 DEG C, is added dropwise to complete for about 2 hours.Stir, thin-layer chromatographic analysis, till raw material reaction completely.Drip the aqueous solution of 20Kg sodium sulphite, control temperature is below 25 DEG C.Stir half hour, add the aqueous solution of 80 Kg sodium hydroxide.Concentrating under reduced pressure, to tetrahydrofuran (THF) is complete.Add 500 kg water, be cooled to 20 ~ 25 DEG C.Static half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 9.16 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 97.0%.
embodiment 6
A preparation method for Prednisone acetate, comprising:
(1) oxide compound-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone is prepared
With embodiment 1 or 2 or 3 or 4 or 5.
(2) Prednisone acetate is prepared
Preparation iodine liquid: add 1.5 Kg Calcium Chloride Powder Anhydrouss, 9 Kg iodine, 12 Kg methyl alcohol in iodine liquid preparing tank, stirs cooling and dissolves, for subsequent use;
Preparation Calcium Chloride Powder Anhydrous methanol solution: add 1.5K g Calcium Chloride Powder Anhydrous, 12 Kg methyl alcohol in preparing tank, stirring and dissolving, for subsequent use.
Preparation aqueous ammonium chloride solution: add 10 Kg ammonium chlorides in ammonium chloride batch tank, 50 Kg water, stirring and dissolving, for subsequent use.
In upper Iod R tank, put into 50 L chloroforms, 10 Kg oxide compounds (17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone), the Calcium Chloride Powder Anhydrous methanol solution prepared, 5 Kg calcium oxide, stir, be cooled to 2-5 DEG C, start to drip the iodine liquid prepared.About dropping 2-4 hour, then continue insulation reaction, control in TLC, until stopped reaction when reacting completely.
Add the aqueous ammonium chloride solution prepared and do cancellation reaction, layering after leaving standstill.Chloroform layer enters concentration tank, and water layer chloroform extraction 3 times, each 25 L chloroforms, combined chloroform layer is incorporated to concentration tank.
Be evaporated to dry, in the material obtained after concentrated, add 20 L dimethyl formamides fully dissolve, be cooled to 20-25 DEG C, proceeded to replacement(metathesis)reaction tank;
Turn and finish, in replacement(metathesis)reaction tank, drop into 10 Kg Potassium ethanoates, stir, start to heat up, within first hour, be warming up to 30-35 DEG C, within second hour, be warming up to 53-62 DEG C from 30-35 DEG C, with 53 DEG C start timing, insulation reaction till reacting completely, after having reacted, start to be cooled to-2 DEG C to-6 DEG C, centrifugal discharge, rinse material with water, dry, moisture eliminator is delivered in discharging, and temperature controls, 90-110 DEG C of drying, to obtain Prednisone acetate 10 Kg.With oxide basis, yield is 100%.HPLC content is 98.5%.
The detection data of Prednisone acetate product of the present invention are as follows:
1H NMR (400 MHz, CDCl
3) δ 7.72 (d,
J = 10.2 Hz, 1H), 6.20 (dd,
J = 10.2, 1.7 Hz, 1H),
6.07 (s, 1H), 5.07 (d,
J = 17.6 Hz, 1H), 4.72 (d,
J = 17.6 Hz, 1H), 3.50 (s, 1H), 2.90 (d,
J =
12.3 Hz, 1H), 2.83 – 2.72 (m, 1H), 2.52 (td,
J = 13.4, 4.0 Hz, 1H), 2.44 – 2.28 (m, 3H), 2.16
(s, 3H), 2.14 – 1.88 (m, 4H), 1.72 (ddd,
J = 15.2, 9.3, 6.1 Hz, 1H), 1.54 – 1.39 (m, 4H), 1.33
– 1.20 (m, 1H), 0.69 (s, 3H).
13C NMR (101 MHz, CDCl
3) δ 208.95, 204.88, 186.67, 170.67, 167.27, 155.85, 127.46, 124.48,
88.62, 67.84, 60.14, 51.44, 49.63, 49.59, 42.50, 36.07, 34.91, 33.71, 32.28, 20.54, 18.77, 15.47.
The hydrogen spectrogram of prednisone acetate of the present invention, carbon spectrogram and mass spectrum are shown in Figure of description Fig. 1, Fig. 2 and Fig. 3.
comparative example 1
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method is PCC reagent oxidation method:
In preparing tank, add 4Kg water and 4Kg refines hydrochloric acid, stir and be cooled to 0 DEG C, slowly add chromium trioxide 4Kg, control temperature, below 10 DEG C, finishes, continue to stir half an hour, when temperature is below 0 DEG C, slowly drip 3.2 Kg pyridines, control temperature is below 10 DEG C, drip and finish, continue to stir half an hour, suction filtration is to dry, obtained oxygenant A, for subsequent use.
In retort, add 200 Kg chloroforms, 10 kg silica gel, add 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone) under stirring, mixing control temperature is at 25 ~ 30 DEG C, and gradation adds the oxygenant A prepared, and within about 1 hour, adds.Insulation, thin-layer chromatographic analysis, till raw material reaction completely.By reaction solution suction filtration, filtrate adds 10 kg water washings, separatory, and chloroform layer is evaporated to dry, and add 150 kg water dispersed with stirring, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 9.06 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 94.2%.
comparative example 2
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method is Pu Shi oxidation style:
In preparing tank, add 5Kg water, under stirring, slowly add chromium trioxide 2.6Kg, be stirred to entirely molten, obtained oxygenant A, for subsequent use.
In retort, add 20 Kg Glacial acetic acid, add 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone) under stirring, mixing control temperature, at 5 ~ 10 DEG C, drips the oxygenant A prepared, within about 2 hours, is added dropwise to complete.Insulation, thin-layer chromatographic analysis, till raw material reaction completely.Finish, by reaction solution suction crystallization tank, add 100 kg elutriations crystalline substances, after half an hour, start centrifugal, rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 8.84 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 90.8%.
comparative example 3
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method is Collins reagent oxidation method:
In preparing tank, add 50Kg methylene dichloride, under stirring, slowly add chromic anhydride pyridine complex 10Kg, be stirred to entirely molten, obtained oxygenant A, for subsequent use.
In retort, add 100 Kg methylene dichloride, add 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone) under stirring, mixing control temperature, at 5 ~ 10 DEG C, drips the oxygenant A prepared, within about 2 hours, is added dropwise to complete.Insulation, thin-layer chromatographic analysis, till raw material reaction completely.Drip the mixing solutions of 10 Kg V-Brite Bs and 80Kg water, control temperature is below 30 DEG C, and stir half hour, add the aqueous solution of 2 Kg sodium bicarbonates, adjust pH is about 6 ~ 7, concentrating under reduced pressure, to methylene dichloride concentrates completely.Add 200Kg water, be cooled to 20 ~ 25 DEG C.Leave standstill half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 8.24 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 90.3%.
comparative example 4
A preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and described preparation method is Swern reagent oxidation method:
In preparing tank, add 50Kg methylene dichloride, slowly add 10 kg raw materials (11 α, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone) under stirring, be stirred to entirely molten, for subsequent use.
In retort, add 300 Kg methylene dichloride, be cooled to-78 DEG C, drip 10Kg DMSO, mixing control temperature, below-70 DEG C, is dripped and is finished, be slowly warming up to-65 DEG C, drips the methylene dichloride in preparing tank and raw material, within about 2 hours, is added dropwise to complete.Drip and finish, be slowly warming up to-45 DEG C, insulation, thin-layer chromatographic analysis, till raw material reaction completely.Finish, drip 23 kg diisopropylethylamine, drip and finish, be slowly warming up to 0 DEG C, drip and prepare dilute hydrochloric acid (5 kg concentrated hydrochloric acids and 45kg water are mixed with) in advance, regulate PH=7.Separatory, water washing organic phase is to neutral.Concentrating under reduced pressure, to methylene dichloride concentrates completely.Add 200Kg water, be cooled to 20 ~ 25 DEG C.Leave standstill half hour, blowing is centrifugal.Rinse with large water gaging, about half hour.Dry 1 hour.90 ~ 120 DEG C are dried material, obtain off-white color soild oxide 7.87 Kg, and analyze after testing as target product-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone, HPLC content is 88.4%.
Claims (10)
1. a preparation method for Prednisone acetate, is characterized in that comprising:
(1) oxide compound-17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketone is prepared
(1.1) in preparing tank, add the water of 1 ~ 5 weight part, then add the acid of 0.5 ~ 2 weight part a bit slowly, stirred for several minute, then the oxidising agent adding 0.5 ~ 2 weight part, stir clearly molten, is then cooled to 0 ~ 30 DEG C, obtains oxygenant A, for subsequent use;
(1.2) in retort, add raw material i.e. 11 α of the solvent of 5 ~ 50 weight parts, the acid of 0 ~ 10 weight part, the metal oxide of 0 ~ 2 weight part and 1 weight part, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, stir clearly molten, control temperature, at-20 ~ 80 DEG C, drips the oxygenant A prepared, dropwises, stir, till raw material reaction completely; Drip the quencher of 0.1 ~ 10 weight part, control temperature, below 55 DEG C, stirs, then adds the alkaline solution of 0 ~ 10 weight part, adjust pH to 6 ~ 7, then concentrating under reduced pressure, to solvent concentration is complete; Add the water of 5 ~ 50 parts by volume again, be cooled to temperature 20 ~ 25 DEG C; Leave standstill, blowing is centrifugal; Then rinse with water, then dry, dry material, obtain soild oxide i.e. 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones of off-white color,
(2) Prednisone acetate is prepared
(2.1) prepare iodine liquid: the methyl alcohol adding the Calcium Chloride Powder Anhydrous of 0.10 ~ 0.20 weight part, the iodine of 0.8 ~ 1.0 weight part and 1.0 ~ 2.0 weight parts in iodine liquid preparing tank, stir cooling and dissolve, for subsequent use;
Preparation Calcium Chloride Powder Anhydrous methanol solution: add the Calcium Chloride Powder Anhydrous of 0.10 ~ 0.20 weight part and the methyl alcohol of 1.0 ~ 2.0 weight parts in preparing tank, stirring and dissolving, for subsequent use;
Preparation aqueous ammonium chloride solution: add the ammonium chloride of 0.5 ~ 2.0 weight part and the water of 5.0 ~ 8.0 parts by volume in ammonium chloride batch tank, stirring and dissolving, for subsequent use;
(2.2) in upper Iod R tank, put into the oxide compound i.e. pregnant steroid-1 of 17 Alpha-hydroxy of the chloroform of 5 ~ 8 parts by volume, 1.0 weight parts, the Calcium Chloride Powder Anhydrous methanol solution that 4-diene-3,11,20-triketone, (2.1) prepare, the calcium oxide of 0.4 ~ 0.8 weight part, stir, be cooled to 2-5 DEG C, start the iodine liquid that dropping (2.1) prepares, drip 2-4 hour, continue insulation reaction again, middle control, until stopped reaction when reacting completely
Add the aqueous ammonium chloride solution that (2.1) prepare and do cancellation reaction, layering after leaving standstill, chloroform layer enters concentration tank, water layer chloroform extraction several, combined chloroform layer is incorporated to concentration tank, is evaporated to dry, and the dimethyl formamide adding 1.0 ~ 5.0 parts by volume in the material obtained after concentrated fully dissolves, be cooled to 20-25 DEG C, proceeded to replacement(metathesis)reaction tank;
Turn and finish, in replacement(metathesis)reaction tank, drop into 1.0 ~ 5.0 parts by weight acetic acid potassium, stir, start to heat up, within first hour, be warming up to 30-35 DEG C, within second hour, be warming up to 53-62 DEG C from 30-35 DEG C, with 53 DEG C start timing, insulation reaction till reacting completely, after having reacted, start to be cooled to-2 DEG C to-6 DEG C dischargings, rinse material with water, dry, moisture eliminator is delivered in discharging, temperature controls, 90-110 DEG C of drying, to obtain Prednisone acetate.
2. the preparation method of a kind of Prednisone acetate as claimed in claim 1, is characterized in that, in described step (1.1), acid is selected from hydrochloric acid, nitric acid, sulfuric acid, Glacial acetic acid, citric acid, or the arbitrary combination of two or more material; And/or oxidising agent is selected from manganese oxide, potassium permanganate, potassium bichromate, the metal oxide of chromic acid, ferric iron compound, sodium peroxide, or the arbitrary combination of two or more material.
3. the preparation method of a kind of Prednisone acetate as claimed in claim 1, is characterized in that, solvent selected from chloroform, methylene dichloride, acetone, tetrahydrofuran (THF), dioxane, DMF, DMSO, ethyl acetate in described step (1.2); Acid is from hydrochloric acid, nitric acid, sulfuric acid, Glacial acetic acid, citric acid, or the arbitrary combination of two or more material; And/or metal oxide is selected from manganous carbonate, Manganous chloride tetrahydrate, cobalt chloride, cobaltous carbonate, or the arbitrary combination of two or more material; And/or quencher is selected from methyl alcohol, Virahol, sodium sulphite, sodium bisulfite, V-Brite B, or the arbitrary combination of two or more material; Alkali is selected from potassium hydroxide, sodium hydroxide, salt of wormwood, sodium bicarbonate, triethylamine, aniline, or the arbitrary combination of two or more material.
4. the preparation method of a kind of Prednisone acetate as claimed in claim 1, is characterized in that, in described step (1.2): drip the oxygenant A prepared, within 0.1 ~ 10 hour, be added dropwise to complete.
5. the preparation method of a kind of Prednisone acetate as claimed in claim 1, is characterized in that, in described step (1.2): drip the oxygenant A prepared, dropwise, and stirs, thin-layer chromatographic analysis, till raw material reaction completely.
6. a preparation method for Prednisone acetate intermediate, described Prednisone acetate intermediate refers to 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones, and it is characterized in that, described preparation method comprises:
(1) in preparing tank, add the water of 1 ~ 5 weight part, then add the acid of 0.5 ~ 2 weight part a bit slowly, stirred for several minute, then the oxidising agent adding 0.5 ~ 2 weight part, stir clearly molten, is then cooled to 0 ~ 30 DEG C, obtains oxygenant A, for subsequent use;
(2) in retort, add raw material i.e. 11 α of the solvent of 5 ~ 50 weight parts, the acid of 0 ~ 10 weight part, the metal oxide of 0 ~ 2 weight part and 1 weight part, 17 alpha-dihydroxy-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, stir clearly molten, control temperature, at-20 ~ 80 DEG C, drips the oxygenant A prepared, dropwises, stir, till raw material reaction completely; Drip the quencher of 0.1 ~ 10 weight part, control temperature, below 55 DEG C, stirs, then adds the alkaline solution of 0 ~ 10 weight part, adjust pH to 6 ~ 7, then concentrating under reduced pressure, to solvent concentration is complete; Add the water of 5 ~ 50 parts by volume again, be cooled to temperature 20 ~ 25 DEG C; Leave standstill, blowing is centrifugal; Then rinse with water, then dry, dry material, obtain soild oxide i.e. 17 Alpha-hydroxy pregnant steroid-Isosorbide-5-Nitrae-diene-3,11,20-triketones of off-white color.
7. the preparation method of a kind of Prednisone acetate intermediate as claimed in claim 6, is characterized in that, in described step (1), acid is from hydrochloric acid, nitric acid, sulfuric acid, Glacial acetic acid, citric acid; Oxidising agent is from metal oxide, ferric iron compound, the sodium peroxide of manganese oxide, potassium permanganate, potassium bichromate, chromic acid.
8. the preparation method of a kind of Prednisone acetate intermediate as claimed in claim 6, is characterized in that, in described step (2), solvent is from chloroform, methylene dichloride, acetone, tetrahydrofuran (THF), dioxane, DMF, DMSO, ethyl acetate; Acid is from hydrochloric acid, nitric acid, sulfuric acid, Glacial acetic acid, citric acid; Metal oxide is from manganous carbonate, Manganous chloride tetrahydrate, cobalt chloride, cobaltous carbonate; Quencher is from methyl alcohol, Virahol, sodium sulphite, sodium bisulfite, V-Brite B; Alkali is from potassium hydroxide, sodium hydroxide, salt of wormwood, sodium bicarbonate, triethylamine, aniline.
9. the preparation method of a kind of Prednisone acetate intermediate as claimed in claim 6, is characterized in that, in described step (2): drip the oxygenant A prepared, within 0.1 ~ 10 hour, be added dropwise to complete.
10. the preparation method of a kind of Prednisone acetate intermediate as claimed in claim 6, is characterized in that, in described step (2): drip the oxygenant A prepared, dropwise, and stirs, thin-layer chromatographic analysis, till raw material reaction completely.
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| CN107058452A (en) * | 2017-04-28 | 2017-08-18 | 江苏远大仙乐药业有限公司 | A kind of prednisone acetate and its preparation method of intermediate |
| CN110964077A (en) * | 2018-09-30 | 2020-04-07 | 天津药业研究院有限公司 | Oxidation synthesis method of steroid 11-keto compound |
| CN111333690A (en) * | 2018-12-18 | 2020-06-26 | 奥锐特药业股份有限公司 | Preparation method of 9-site dehalogenation of 9-halogenated steroid hormone compound |
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