CN116082225A - Preparation method of hydroxynisone - Google Patents
Preparation method of hydroxynisone Download PDFInfo
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- CN116082225A CN116082225A CN202310048439.0A CN202310048439A CN116082225A CN 116082225 A CN116082225 A CN 116082225A CN 202310048439 A CN202310048439 A CN 202310048439A CN 116082225 A CN116082225 A CN 116082225A
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- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 238000001914 filtration Methods 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 13
- SOHMZGMHXUQHGE-UHFFFAOYSA-N 5-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(O)N=C1 SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 11
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 229910001431 copper ion Inorganic materials 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 3
- 239000012065 filter cake Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 208000019425 cirrhosis of liver Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000007670 refining Methods 0.000 description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- XMDITNSOBKTMIO-UHFFFAOYSA-N 1-(4-methoxyphenyl)-5-methylpyridin-2-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)C=CC(C)=C1 XMDITNSOBKTMIO-UHFFFAOYSA-N 0.000 description 3
- 206010019668 Hepatic fibrosis Diseases 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007731 hot pressing Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 230000009693 chronic damage Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a preparation method of hydroxy-nisdone, which has the advantages of simple operation, mild reaction condition, short reaction time, high yield, safety and suitability for mass production. The invention adopts ammonia water to treat the crude intermediate compound, which is beneficial to removing residual copper ions in the catalyst and separating out the product.
Description
Technical Field
The invention belongs to the field of medicines, in particular to a copper-catalyzed carbon-hybrid coupling reaction and application thereof, and particularly relates to a preparation method of hydroxynimidone.
Background
Liver fibrosis is a common pathological basis in the progress of chronic liver diseases, various chronic injuries cause degeneration and necrosis of liver cells, fibrous connective tissue is abnormally proliferated and excessively deposited to wrap regenerated liver cells, so that 'artificial lobules' are formed to destroy the original tissue structure of the liver, and finally the liver is nodular and hard, and liver functions are damaged and even completely disappear, so that cirrhosis is formed.
Various chronic diseases can cause liver fibrosis, such as chronic viral hepatitis, chronic alcoholism, cholestasis, congenital enzyme-deficient metabolic disorder, long-term exposure to toxins and drugs, etc. Liver fibrosis and cirrhosis are one of the main causes affecting the quality of life of patients with liver diseases and medical expenses. The market demand for liver-protecting medicaments has increased year by year. At present, few medicines for treating hepatic fibrosis are available, and the requirements of patients and doctors on safe and effective medicines are high. The share of the liver fibrosis drug market is estimated to be about 24 billion dollars in China and about 19 billion dollars in Japan. So far, no chemical medicine for treating hepatic fibrosis is available internationally, and early research on hydroxynisone (hereinafter simply referred to as a compound of formula I) shows that the compound has good pharmacological and toxicological characteristics and is an ideal oral medicine for treating and preventing hepatic fibrosis and liver cirrhosis.
The prior art discloses a synthesis method of a compound of a formula I, which takes 2-amino-5-methylpyridine as a starting material, me is used as a phenolic hydroxyl protecting group, the reagent used for deprotection is high in price, highly toxic gas is easy to form in the reaction process, sewage and waste are complex to treat, the operation is complex, and the yield is low (40%). In addition, most of the methods for preparing the hydroxynisone in the prior art relate to hydroxyl protection of p-bromophenol, and complicated reaction procedures are required to be added in the industrial process.
Therefore, there is an urgent need in the art to develop a preparation method of hydroxynisone, which is simple to operate, mild in reaction conditions, short in reaction time, high in yield, safer and suitable for mass production.
Disclosure of Invention
The invention aims to provide a preparation method and application of hydroxy-nisdone.
In a first aspect of the present invention there is provided a process for the preparation of a compound of formula I comprising the steps of:
(1) Reacting 2-hydroxy-5-methylpyridine with p-bromoanisole in a solvent in the presence of a catalyst to obtain a crude compound of formula II;
(2) Washing the crude product of the compound of the formula II with ammonia water to obtain a refined compound of the formula II; and
(3) Reacting the purified compound of formula II with HBr to produce the compound of formula I.
In another preferred embodiment, the molar ratio of 2-hydroxy-5-methylpyridine to para-bromoanisole is from 1:1 to 1:2 (preferably from 1:1 to 1:1.8, more preferably from 1:1 to 1:1.5, most preferably from 1:1 to 1:1.3).
In another preferred embodiment, the method further comprises step (4):
and (3) mixing the compound of the formula I obtained in the step (3) with a mixed solvent of ethanol and ethyl acetate, cooling, and filtering to obtain a white crystalline solid of the compound of the formula I.
In another preferred embodiment, in the step (4), the mass ratio of the compound of formula I to the mixed solvent of ethanol and ethyl acetate is 1.5-7.5, preferably 2.5-6.5, more preferably 3-4.5.
In another preferred example, in the step (4), the mass ratio of the ethanol to the ethyl acetate is (0.8-1.2) to (5.8-6.2).
In another preferred embodiment, in the step (1), the solvent is selected from the group consisting of: DMAC, DMF, or a combination thereof.
In another preferred embodiment, in the step (1), the catalyst is selected from the group consisting of: cuI, cuSO 4 ·5H 2 O、K 2 CO 3 Or combinations thereof, preferably CuI and K 2 CO 3 Or CuSO 4 ·5H 2 O and K 2 CO 3 Is a mixture of (a) and (b).
In another preferred embodiment, in the step (1), the solvent is DMF and the catalyst is CuSO 4 ·5H 2 O and K 2 CO 3 Is a mixture of (a) and (b).
In another preferred embodiment, in the step (1), the CuI and K 2 CO 3 The molar ratio of (2) is 1:50-1:80, preferably 1:55-1:70.
In another preferred embodiment, in the step (1), the solvent is DMAC and the catalyst is CuI and K 2 CO 3 Is a mixture of (a) and (b).
In another preferred embodiment, in the step (1), the heating reflux temperature is 130 to 150 ℃, preferably 135 to 145 ℃.
In another preferred embodiment, in the step (2), the ammonia concentration is 15 to 28wt%, preferably 16 to 25wt%, more preferably 17 to 20wt%.
In another preferred embodiment, before the step (3), the method further comprises a step (3-1): mixing the refined compound of the formula II obtained in the step (2) with ethyl acetate and active carbon, heating for refluxing, filtering, cooling and crystallizing.
In another preferred embodiment, in step (3-1), the mass ratio of ethyl acetate to crude compound of formula II is 1.0-10.0, preferably 2.0-8.0, more preferably 3.0-6.0.
In another preferred embodiment, in the step (3-1), the mass ratio of the activated carbon to the crude compound of formula II is from 0.01 to 0.1, preferably from 0.025 to 0.075, more preferably from 0.03 to 0.06.
In another preferred embodiment, in step (3), the molar ratio of the compound of formula II to HBr is from 1:5 to 1:10, preferably from 1:6 to 1:8.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have found, for the first time, a safe and efficient method for preparing hydroxynisone with high yield and mild reaction conditions through extensive and intensive studies. The invention adopts ammonia water to treat the crude product of the compound of the formula II, which is beneficial to removing residual copper ions in the catalyst and separating out products. The present invention has been completed on the basis of this finding.
Description of the terms
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 invention belongs.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
The invention has the main advantages that:
(1) The invention adopts ammonia water to treat the crude product of the compound of the formula II, which is beneficial to removing residual copper ions from the catalyst and separating out products.
(2) In the process of demethylation of the invention, HBr is adopted to replace BBr which is commonly used in the prior art and has high price and great toxicity 3 。
(3) The invention omits the step of protecting with the p-bromophenol in the prior art, and has simpler operation.
(4) The preparation method provided by the invention is simple and easy to operate, mild in reaction condition, short in reaction time, high in yield, safer and suitable for mass production.
Raw materials
The raw materials used in the present invention are listed in table 1 below:
| material name | Physical parameters |
| 2-hydroxy-5-methylpyridine | Yellow or yellowish crystalline solid |
| Para bromoanisole | Colorless transparent liquid |
| DMAC | Colorless transparent liquid |
| DMF | Colorless transparent liquid |
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Example 1-production route 1:
1. a compound of formula II: synthesis of N- (4-methoxyphenyl) -5-methyl-2-pyridone
The amounts and ratios of the above raw materials are shown in Table 2:
TABLE 2
| Material name | Feeding quantity (kg) |
| 2-hydroxy-5-methylpyridine | 35.0 |
| Para bromoanisole | 74.0 |
| Cuprous iodide | 1.22 |
| Anhydrous potassium carbonate | 65.0 |
| DMAC | 190.0 |
(1) DMAC (190 kg, 99 wt%) was heated to 50deg.C, 35kg of 2-hydroxy-5-methylpyridine, 65kg of anhydrous potassium carbonate, 74.0kg of p-bromoanisole and 1.22kg of cuprous iodide were added in this order, the temperature was raised to reflux, the reaction was continued for 12-14 hours, and after the starting point was reached by using a point plate (TCL), the heating was stopped. And then the liquid temperature is reduced to 80 ℃ for carrying out the filtering.
(2) And (3) returning the filtrate to the condensation kettle, carrying out reduced pressure distillation until no fraction flows out, putting the filtrate into a water washing water separation kettle, adding 55kg of ammonia water (18 wt%) and 156kg of water, stirring, washing, cooling, carrying out throwing filtration, and leaching with clear water until the mother liquor has no color. Taking out the filter cake, putting the filter cake into a tray, and airing to obtain 55.4kg (yield is 72% based on 2-hydroxy-5-methylpyridine) of the crude product of the compound of the formula II.
Results: the ultraviolet-visible spectrophotometry is used for detection, cu is not found + 。
2. Crude compound of formula II
130 kg of ethyl acetate (the concentration is more than or equal to 99.0%) and 1.95 kg of medicinal active carbon (the absorbance of a sample liquid is not more than that of a potassium dichromate chromaticity standard liquid) as well as 39 kg of a crude product of a compound of the formula II are put into a desolventizing refining kettle, stirred, heated, refluxed and decolored for 1 hour, filtered while the mixture is hot, filtered, pumped into a crystallization reaction kettle, filter residues are washed by 8kg of ethyl acetate, the filter residues are discarded, the filter residues are combined, and the desolventized, cooled and crystallized. After 70% of the filtrate is desolventized, slowly crystallizing under stirring, cooling to 0-5 ℃, stirring for 3-5 hours, and putting into a centrifugal separator. Centrifugal filtering to obtain refined compound of formula II, weighing, loading into tray, and air drying to obtain refined compound of formula II (purity 99.66%, yield 80%).
3. Preparation of a compound of formula I:
(3-1) preparation of crude compound of formula I:
n- (4-methoxyphenyl) -5-methyl-2-pyridone (30 kg) is put into a reaction kettle, 158kg of hydrobromic acid with the weight percent of 40% is slowly added dropwise under stirring, the temperature is raised to reflux after the dropwise addition is finished, and a point plate (TCL) is adopted for controlling until no raw material point exists. Cooling and neutralizing to PH=5-6, carrying out centrifugal filtration, putting the filter cake into a tray, and airing to obtain a crude product of the compound of the formula I (yield: 98%).
(3-2) pulping and refining:
taking 30kg of the crude product of the compound of the formula I obtained in the step (3-1), adding ethanol (with the concentration of 95%,15 kg) and ethyl acetate (with the concentration of 99%,90 kg), pulping and refluxing for 1h, cooling to 10 ℃, carrying out centrifugal filtration, recovering mother liquor, and airing a filter cake.
Pumping 900kg of purified water into a refining and decolorizing kettle, stirring, heating to boil, adding 30kg of the dried filter cake, adding 1.25kg of active carbon after the filter cake is completely dissolved, refluxing for 15 minutes, carrying out hot-pressing filtration until the filter cake is cooled to be crystallized, cooling to about 25 ℃, stirring, preserving heat for 2 hours, centrifuging, carrying out centrifugal filtration, leaching the filter cake with purified water for 2 times, and carrying out spin-drying to obtain a white crystallized solid of the compound of the formula I, drying at 60 ℃ in an oven under the control of temperature, and drying to obtain a finished product of the compound of the formula I (purity: 99.92%, yield: 90%).
Example 2 production route 2
1. A compound of formula II: synthesis of N- (4-methoxyphenyl) -5-methyl-2-pyridone
The amounts and ratios of the above raw materials are shown in table 3:
TABLE 3 Table 3
| Material name | Feeding quantity (kg) |
| 2-hydroxy-5-methylpyridine | 40.0 |
| Para bromoanisole | 75.0 |
| Pentahydrate copper sulfate | 10.8 |
| Anhydrous potassium carbonate | 108.0 |
| DMF | 230.0 |
(1) As shown in Table 3, p-bromoanisole, DMF, 2-hydroxy-5-methylpyridine, anhydrous potassium carbonate and copper sulfate pentahydrate were added in this order, the temperature was raised to reflux, the reaction was carried out for 12 to 14 hours, and after the reaction was carried out until no starting material point was reached, heating was stopped by using a point plate (TCL).
(2) Cooling the mixed solution to room temperature, carrying out the filtering, distilling the filtrate under reduced pressure until no distillate is distilled, cooling to 120 ℃, putting the filtrate into a water washing salting-out kettle containing 156kg of water, dropwise adding 56kg of ammonia water (18 wt%) into the water washing salting-out kettle, stirring, washing, cooling, carrying out the filtering, and eluting the filtrate with clear water until the filtrate has no color. Taking out the filter cake, putting the filter cake into a tray, and airing to obtain a crude product of the compound of the formula II.
The yield based on 2-hydroxy-5-methylpyridine was 80%.
2. Crude compound of formula II
170 kg of ethyl acetate (the concentration is more than or equal to 99.0%) and 2.75 kg of medicinal active carbon (the absorbance of a sample liquid is not more than that of a potassium dichromate chromaticity standard liquid) are put into a desolventizing refining kettle, 55kg of a crude product of a compound of the formula II is stirred, heated, refluxed and decolored for 1 hour, filtered while the mixture is hot, filtered liquid is pumped into a crystallization reaction kettle, filter residues are washed with 20 kg of ethyl acetate, the filter residues are discarded, the filtered liquid is combined, and the mixture is desolventized, cooled and crystallized. After 70% of the filtrate is desolventized, slowly crystallizing under stirring, cooling to 0-5 ℃, stirring for 3-5 hours, and putting into a centrifugal separator. Centrifugal filtering to obtain refined compound of formula II, weighing, loading into tray, and air drying to obtain refined compound of formula II with content of 99.64%.
3. Preparation of a compound of formula I:
(3-1) preparation of crude compound of formula I:
n- (4-methoxyphenyl) -5-methyl-2-pyridone (44 kg) was charged into a reaction vessel, 267kg of 40wt% hydrobromic acid was slowly added dropwise with stirring, and after the addition was completed, the temperature was raised to reflux, and the mixture was controlled to have no raw material point by using a point plate (TCL). Cooling and neutralizing to PH=6, carrying out centrifugal filtration, and putting a filter cake into a tray for airing to obtain a crude product of the compound of the formula I.
(3-2) pulping and refining:
taking 44kg of the crude product of the compound of the formula I obtained in the step (3-1), adding 0.5 times of ethanol (with the concentration of 95%,22 kg) and three times of ethyl acetate (with the concentration of 99%,132 kg), pulping and refluxing for 1h, cooling to 10 ℃, carrying out the filtration, recovering mother liquor, and airing a filter cake.
Pumping 900kg of purified water into a refining decoloration kettle, stirring, heating to boiling, adding 30kg of the dried filter cake, adding 1.5kg of active carbon after the filter cake is completely dissolved, refluxing for 15 minutes, hot-pressing and filtering to a cooling crystallization kettle, cooling to about 25 ℃, stirring and preserving heat for 2 hours, centrifuging and filtering, leaching the filter cake with purified water for 2 times, and then spin-drying to obtain white crystalline solid of the compound of the formula I, drying at 60 ℃ in an oven at a controlled temperature, and drying to obtain 24kg of the compound of the formula I (purity: 99.98%, yield: 80%).
Comparative example 1
The difference from example 1 is that in the case of the compounds of the formula II: in the synthesis step of N- (4-methoxyphenyl) -5-methyl-2-pyridone, water is used for replacing ammonia water for washing, and the yield of the crude product of the compound of the formula II is only 42%.
Results: cu detection by ultraviolet visible spectrophotometry + The concentration was 0.05. Mu.g/50 ml.
It can be seen that copper ions can be effectively removed after the ammonia water is used for washing, and meanwhile, the yield of the obtained intermediate compound of the formula II is higher, which is more beneficial to the precipitation of the product.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.
Claims (10)
1. A process for preparing a compound of formula I comprising the steps of:
(1) Reacting 2-hydroxy-5-methylpyridine with p-bromoanisole in a solvent in the presence of a catalyst to obtain a crude compound of formula II;
(2) Washing the crude product of the compound of the formula II with ammonia water to obtain a refined compound of the formula II; and
(3) Reacting the purified compound of formula II with HBr to produce the compound of formula I.
2. The process of claim 1, wherein the molar ratio of 2-hydroxy-5-methylpyridine to para-bromoanisole is from 1:1 to 1:2.
3. The method of claim 1, further comprising step (4):
and (3) mixing the compound of the formula I obtained in the step (3) with a mixed solvent of ethanol and ethyl acetate, cooling, and filtering to obtain a white crystalline solid of the compound of the formula I.
4. The method of claim 1, wherein in step (4), the mass ratio of the compound of formula I to the mixed solvent of ethanol and ethyl acetate is 1.5 to 7.5.
5. The method of claim 1, wherein in step (4), the mass ratio of the ethanol to the ethyl acetate is (0.8-1.2): 5.8-6.2.
6. The method of claim 1, wherein in step (1), the solvent is selected from the group consisting of: DMAC, DMF, or a combination thereof.
7. The method of claim 1, wherein in step (1), the catalyst is selected from the group consisting of: cuI, cuSO 4 ·5H 2 O、K 2 CO 3 Or a combination thereof.
8. The method of claim 1, wherein in step (2), the ammonia concentration is 15 to 28wt%.
9. The method of claim 1, further comprising, prior to step (3), step (3-1): mixing the refined compound of the formula II obtained in the step (2) with ethyl acetate and active carbon, heating for refluxing, filtering, cooling and crystallizing.
10. The process of claim 1, wherein in step (3), the molar ratio of the compound of formula II to HBr is from 1:5 to 1:10.
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| CN101558075A (en) * | 2006-12-14 | 2009-10-14 | 伊莱利利公司 | 5- [4- (azetidin-3-yl0xy) -phenyl] -2-phenyl-5h-thiaz0l0 [5,4-c] pyridin-4-0ne derivatives and their use as mch receptor antagonists |
| CN100569750C (en) * | 2007-08-07 | 2009-12-16 | 中国科学院长春应用化学研究所 | The organic electroluminescence device of dendroid material of main part and this compound |
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