CN1053229A - Synthetic process for " metholazine " - Google Patents
Synthetic process for " metholazine " Download PDFInfo
- Publication number
- CN1053229A CN1053229A CN 91100481 CN91100481A CN1053229A CN 1053229 A CN1053229 A CN 1053229A CN 91100481 CN91100481 CN 91100481 CN 91100481 A CN91100481 A CN 91100481A CN 1053229 A CN1053229 A CN 1053229A
- Authority
- CN
- China
- Prior art keywords
- acid
- reaction
- masalazine
- synthetic process
- metholazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000006396 nitration reaction Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 230000000694 effects Effects 0.000 claims 2
- 239000003929 acidic solution Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- 238000001914 filtration Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- XVMIKRZPDSXBTP-UHFFFAOYSA-N 1,3-dibromobutan-2-one Chemical compound CC(Br)C(=O)CBr XVMIKRZPDSXBTP-UHFFFAOYSA-N 0.000 description 1
- GZJIQNJINXQYTG-UHFFFAOYSA-N 2-nitrooxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1O[N+]([O-])=O GZJIQNJINXQYTG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Synthetic process for " metholazine ".
Masalazine is a new treatment ulcerative colitis medicine, and the present invention is starting raw material with the Whitfield's ointment, prepares Masalazine through reactions steps such as nitrated and reduction.
Description
The invention belongs to meticulous organic chemical industry (medicine is synthetic) field.
H.Well et al. is at " Berlchte de Deutschen Chemlschen Gesellschaft " 1922, the disclosed relevant Masalazines (5-aminosalicylic acid) of 55B 2664 synthetic is to be starting raw material with the 5-nitrosalicylic acid, is that solvent avoided thermal response to make with zinc powder and concentrated hydrochloric acid with alkali lye.Its reaction formula is:
The present invention is starting raw material with the Whitfield's ointment through nitrated generation compound (I), and (I) generates Masalazine under acidic conditions and metallic reducing agent and acid row reduction reaction between 60-100 ℃.Its reaction formula is:
The new synthesis process of Masalazine is compared with preceding technology, and difference is the starting raw material difference, reaction reagent, and the processing mode after condition and reaction are finished is also different.Novel process is a starting raw material with the Whitfield's ointment, has increased nitration reaction technology; Former technology is starting raw material with the nitrosalicylic acid, and the domestic market does not have this raw material and sells.Novel process reaction conditions in reduction process be acid and between 60-100 ℃ the prepared in reaction Masalazine; Avoid overheated and react and former technology is solvent with alkali lye.Novel process can use metallic iron as going back original reagent; And former technology is to use zinc powder to make reductive agent, and cost is higher.Novel process uses molten acid folding of alkali or sour molten alkali to analyse after reduction reaction is finished and the method for adding antioxidant obtains Masalazine; And former technology obtains Masalazine with salt by salting-out process.In a word, the invention provides and a kind ofly prepare the novel process of Masalazine by Whitfield's ointment, its cost value is cheap, the processing condition gentleness.
Embodiment:
Whitfield's ointment 69g is suspended among the water 70ml, drips 70% nitric acid 87.5ml, insulation reaction 1 hour about 70 ℃, in the impouring 700ml frozen water, place 1 hour after-filtration, filter residue adds 650ml water and is heated to and boils, heat filtering, washing filter residue secondary gets light yellow solid (I) 30.4g, mp227-230 ℃.
Water 250ml is warming up to more than 60 ℃, adds the iron powder 14g of hydrochloric acid 17ml and full dose 1/3, is heated to boiling, iron powder and (I) of surplus are alternately dropped into, insulation reaction 1 hour is cooled to 80 ℃, adds caustic lye of soda and regulates PH to alkalescence, discard after filtration, the filter residue washing, the powder 5.6g that takes a policy filters, and adds 40% sulfuric acid after the cooling to slightly acidic, filter dry light grey Masalazine crude product 24.7g.
Above-mentioned crude product 48g is dissolved in 800ml water and hydrochloric acid 36ml, adds gac, is heated to filtrations of boiling, and cooling is stirred and dripped solution of ammonium hydroxide down to PH2-3, filters, and washing, dryly gets Masalazine 43.2g, mp274 ℃ (decomposition).
Claims (4)
1, a kind of employing Whitfield's ointment is a starting raw material, through the certain reaction step, makes the new synthetic process of the ulcerative colitis medicine Masalazine that obtains medical treatment, and it is characterized in that making Whitfield's ointment and nitric acid effect to carry out nitration reaction and generates compound (1).(1) reaction in acidic solution generates Masalazine with metallic reducing agent and acid.Its reaction formula is:
2, according to the said synthetic process for " metholazine " of claim 1, when carrying out nitration reaction generation compound (I) by Whitfield's ointment and nitric acid effect, its feature is being a reaction medium with water or acetic acid, and concentration of nitric acid is more than 25%, and reaction is 1-2 hour between 20-95 ℃.
3, according to the said synthetic process for " metholazine " of claim 1, when reacting the generation Masalazine by (I) with metallic reducing agent and acid in acid liquid, its feature is being solvent with dilute hydrochloric acid, and metallic reducing agent is an iron, acid is hydrochloric acid, and reaction is 1-2 hour between 60-100 ℃.
4,, it is characterized in that reacting the method for using alkali-soluble acid analysis or sour molten alkali to analyse after finishing and obtain Masalazine, and in this process, use antioxidant according to claim 1 or 3 said synthetic process for " metholazine ".
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91100481 CN1053229A (en) | 1991-01-23 | 1991-01-23 | Synthetic process for " metholazine " |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91100481 CN1053229A (en) | 1991-01-23 | 1991-01-23 | Synthetic process for " metholazine " |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1053229A true CN1053229A (en) | 1991-07-24 |
Family
ID=4904652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 91100481 Pending CN1053229A (en) | 1991-01-23 | 1991-01-23 | Synthetic process for " metholazine " |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1053229A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999040060A1 (en) * | 1998-02-06 | 1999-08-12 | Rhodia Chimie | Method for hydrogenating 5-nitrosalicylic acids |
| CN1850334B (en) * | 2006-05-26 | 2012-03-28 | 中国科学院上海有机化学研究所 | Use of Zr compound in catalyzing clean nitration of salicylic-acids compounds |
| CN103201255A (en) * | 2010-12-25 | 2013-07-10 | 浙江华海药业股份有限公司 | Preparation of 5-aminosalicylic acid by gas-phase catalytic carboxylation |
| CN106831460A (en) * | 2017-02-24 | 2017-06-13 | 青铜峡市嘉华化工有限公司 | The preparation method of the aminobenzoic acid of 3 methyl 4 |
| US11249150B2 (en) | 2019-11-14 | 2022-02-15 | Institute Of Semiconductors, Chinese Academy Of Sciences | Spin valve and spintronic device comprising the same |
| CN114605277A (en) * | 2022-04-18 | 2022-06-10 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
-
1991
- 1991-01-23 CN CN 91100481 patent/CN1053229A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999040060A1 (en) * | 1998-02-06 | 1999-08-12 | Rhodia Chimie | Method for hydrogenating 5-nitrosalicylic acids |
| FR2774685A1 (en) * | 1998-02-06 | 1999-08-13 | Rhodia Chimie Sa | PROCESS FOR HYDROGENATION OF NITROSALICYLIC ACIDS |
| CN1850334B (en) * | 2006-05-26 | 2012-03-28 | 中国科学院上海有机化学研究所 | Use of Zr compound in catalyzing clean nitration of salicylic-acids compounds |
| CN103201255A (en) * | 2010-12-25 | 2013-07-10 | 浙江华海药业股份有限公司 | Preparation of 5-aminosalicylic acid by gas-phase catalytic carboxylation |
| CN103201255B (en) * | 2010-12-25 | 2014-11-19 | 浙江华海药业股份有限公司 | Preparation of 5-aminosalicylic acid by gas-phase catalytic carboxylation |
| US9067867B2 (en) | 2010-12-25 | 2015-06-30 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Preparation of 5-aminosalicylic acid by gas phase catalytic carboxylation |
| CN106831460A (en) * | 2017-02-24 | 2017-06-13 | 青铜峡市嘉华化工有限公司 | The preparation method of the aminobenzoic acid of 3 methyl 4 |
| US11249150B2 (en) | 2019-11-14 | 2022-02-15 | Institute Of Semiconductors, Chinese Academy Of Sciences | Spin valve and spintronic device comprising the same |
| CN114605277A (en) * | 2022-04-18 | 2022-06-10 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
| CN114605277B (en) * | 2022-04-18 | 2022-10-11 | 宁波怡和医药科技有限公司 | Synthesis method of mesalazine |
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| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |