CN1724522A - Preparation method of methazolamide - Google Patents
Preparation method of methazolamide Download PDFInfo
- Publication number
- CN1724522A CN1724522A CN 200510050599 CN200510050599A CN1724522A CN 1724522 A CN1724522 A CN 1724522A CN 200510050599 CN200510050599 CN 200510050599 CN 200510050599 A CN200510050599 A CN 200510050599A CN 1724522 A CN1724522 A CN 1724522A
- Authority
- CN
- China
- Prior art keywords
- methazolamide
- reaction
- crude product
- oxidation
- preparation
- 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.)
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- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 title claims abstract description 42
- 229960004083 methazolamide Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 238000005576 amination reaction Methods 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 18
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 230000003647 oxidation Effects 0.000 claims abstract description 13
- 239000000047 product Substances 0.000 claims abstract description 13
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000005494 condensation Effects 0.000 claims abstract description 6
- 238000007670 refining Methods 0.000 claims abstract description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 229910052742 iron Inorganic materials 0.000 claims description 7
- -1 5-amino-2-mercapto phenyl Chemical group 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- GDGIVSREGUOIJZ-UHFFFAOYSA-N 5-amino-3h-1,3,4-thiadiazole-2-thione Chemical compound NC1=NN=C(S)S1 GDGIVSREGUOIJZ-UHFFFAOYSA-N 0.000 abstract 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 abstract 1
- 239000005708 Sodium hypochlorite Substances 0.000 abstract 1
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000006482 condensation reaction Methods 0.000 abstract 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000001384 anti-glaucoma Effects 0.000 description 2
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- FLOSMHQXBMRNHR-UHFFFAOYSA-N N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2-ylidene)acetamide Chemical compound CC(=O)N=C1SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-UHFFFAOYSA-N 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
A preparation method of methazolamide takes 5-amino-2-mercapto-1, 3, 4-thiadiazole as a raw material, and comprises the steps of obtaining a methazolamide crude product through condensation, acetylation, methylation, oxidation and amination reaction, refining to obtain a methazolamide refined product, adding a sodium hypochlorite raw material in the oxidation and amination reaction process, reacting in the presence of a catalyst ferric chloride, and performing amination reaction on an intermediate obtained through the reaction to obtain the methazolamide crude product; the method has the characteristics of reducing the danger in the reaction process, reducing the reaction time, being easy to operate, reducing the cost, not needing to add special equipment, and the like.
Description
Technical field
The present invention relates to a kind of preparation method of carbonic anhydrase inhibitor class anti-glaucoma medicine methazolamide, belong to meticulous organic chemical industry's the synthetic field of medicine.
Background technology
Methazolamide, the different name methazolamide, external trade(brand)name: Naptazane, English name: Methazolamide, American Pharmacopeia records already.This product is a kind of anti-glaucoma medicine of carbonic anhydrase inhibitor class, is mainly used in the chronic open angle glaucoma of treatment clinically, acute narrow-angle glaucoma, and secondary glaucoma and ophthalmologic operation reduce intraocular pressure etc.
English Patent has been announced the synthesis technique of a methazolamide (Methazolamide); it is with 5-amino-2-mercapto phenyl formic-1; 3; the 4-thiadiazoles is a raw material; through condensation, acetylize makes 5-acetamido-2 benzyl-mercapto-1,3; behind the 4-thiadiazoles, make N-(4-methyl-2-sulfamyl-Δ by methylation reaction
2-1,3,4-Thiadiazoline-5-subunit) ethanamide, this methylate obtains the methazolamide crude product by oxychloride and amination reaction, again through the refining methazolamide highly finished product that obtain.Its reaction formula is:
1, condensation (5-amino-2-benzyl-mercapto-1,3, the preparation of 4-thiadiazoles)
2, acetylize (5-acetamido-2 benzyl-mercapto-1,3, the preparation of 4-thiadiazoles)
3, (N-(4-methyl-2-benzyl-mercapto-Δ methylates
2-1,3,4-Thiadiazoline-5-fork)-preparation of ethanamide)
4, oxidation (N-(4-methyl-2-SULPHURYL CHLORIDE-Δ
2-1,3,4-Thiadiazoline-5-fork) preparation of ethanamide)
5, amination (preparation of methazolamide)
Among the above-mentioned preparation technology, employing chlorine is reaction raw materials, because chlorine has very big danger in reaction process; And after reaction finishes, also need to carry out aftertreatment, obtain intermediate N (4-methyl-2-SULPHURYL CHLORIDE-Δ
2-1,3,4-Thiadiazoline-5-fork) ethanamide and then carry out amination reaction with ammoniacal liquor; In addition in the methazolamide purification step, above-mentioned process using be to be dissolution with solvents methazolamide crude product with ammoniacal liquor, and then, regulate PH and separate out methazolamide through decolouring, obtain highly finished product; In this reaction, the ammoniacal liquor of use has volatile characteristics, and the amount that needs is very big.
Summary of the invention
The object of the present invention is to provide a kind of danger that can effectively reduce in the reaction process, reduce the reaction times, and processing ease, the preparation method of the methazolamide that can reduce cost.This method is with 5-amino-2-mercapto phenyl formic-1; 3; the 4-thiadiazoles is a raw material; through condensation, acetylize, methylate, oxidation, amination reaction obtain the methazolamide crude product, again through the refining methazolamide highly finished product that obtain, in described oxidation and the amination reaction process; add the clorox raw material; react in the presence of catalyzer iron(ic) chloride, the intermediate that reaction obtains carries out amination reaction, makes the methazolamide crude product.
In the described oxidation reaction process, the temperature of reaction of control is at 35---50 ℃.
Described methazolamide crude product obtains precipitate after adding 5% hydrochloric acid and regulating PH=4-5, make finished product through washing drying.
The invention belongs to a kind of improvement to prior art, it is compared with former technology and has following several characteristics:
1, former process using chlorine is reaction raw materials, because chlorine has very big danger in reaction process; It is raw material that the present invention adopts clorox, reacts in the presence of catalyzer iron(ic) chloride;
2, in the methazolamide purification step, former process using be to be dissolution with solvents methazolamide crude product with ammoniacal liquor, and then, regulate PH and separate out methazolamide through decolouring, obtain highly finished product; In this reaction, the ammoniacal liquor of use has volatile characteristics, and the amount that needs is very big; The present invention adopts 5%NaOH solution to replace ammoniacal liquor as solvent, compares with ammoniacal liquor, and NaOH is non-volatile, and only needs amount seldom can arrive the effect of dissolving methazolamide.In a word, the present invention compares with former technology to have and has reduced the danger in the reaction process, has reduced the reaction times, and processing ease reduces cost, and does not need to add characteristics such as special equipment again.
The present invention and former technology also can obtain comparison by following reaction process:
One, in methazolamide oxidation, amination reaction, former technological reaction process is:
Chlorine
↓
Methide → oxidation → crystallisation by cooling → separation → washing → oxide compound
Ammoniacal liquor
↓
Oxide compound → amination → crystallization → separation → washing → drying → methazolamide crude product
Technological reaction process of the present invention is
Clorox ammoniacal liquor
↓ (iron(ic) chloride) ↓
Methide → oxidation → oxide compound reaction solution → amination → acidifying →
Ethanol water
↓ ↓
Crystallization → separation → washing → drying → methazolamide crude product
Reaction formula of the present invention is as follows:
Embodiment
The present invention will be described in detail below in conjunction with specific embodiment: the present invention is the improvement to prior art, therefore, with 5-amino-2-mercapto phenyl formic-1,3, the 4-thiadiazoles is a raw material, through condensation, acetylize, methylate, oxidation, amination reaction obtains the methazolamide crude product, again through the refining existing known content of whole preparation process that obtains the methazolamide highly finished product, main contents of the present invention are: in described oxidation and amination reaction process, add the clorox raw material, the amount that is added can be with reference to the amount of chlorine that former technology adds, or obtains accurate data through normal experiment; After adding the clorox raw material and react in the presence of catalyzer iron(ic) chloride, in oxidation reaction process, the temperature of reaction of control is at 35---50 ℃; The intermediate that reaction obtains carries out amination reaction, makes the methazolamide crude product; Described methazolamide crude product obtains precipitate after adding 5% hydrochloric acid and regulating PH=4-5, make finished product through washing drying.Described 5-amino-2-mercapto phenyl formic-1,3,4-thiadiazoles raw material can be referred to as methide again, and specific embodiment is as follows:
Embodiment one:
In the there-necked flask of 1000ml, add Glacial acetic acid 100ml, water 16ml, methide 45g, stir, treat to add 1g iron(ic) chloride after the methide dissolving, drip the 250ml clorox, the temperature of control reaction solution is 40 ℃-50 ℃, and control PH is 2 in the reaction process, react stopped reaction after 6 hours, be cooled to 20 ℃, on the rocks, separate out crystallization, filter and clean, add 200ml ammoniacal liquor again, 130g ice, stir, treat that temperature is reduced to below 10 ℃, the reaction 1.5 hours that picks up counting, back water-bath slowly is heated to 35 ℃-40 ℃, remove amine, reaction solution is transferred in the beaker, adds the dilution of 100ml water, the frozen water cooling drips the concentrated hydrochloric acid acidifying, when PH=7, finished product begins to separate out, and after continuation drips and makes PH=4, stops to drip.Continue to stir suction filtration after 1 hour, wash with water to neutrality with after the washing with alcohol 3 times earlier again, drying must white solid 25g, yield 32.85%.Fusing point: 198.5-199.8 ℃.
Embodiment two:
In the there-necked flask of 1000ml, add Glacial acetic acid 100ml, water 12ml or 20ml, methide 40g or 56g, stir, treat to add 0.7g or 15g iron(ic) chloride after the methide dissolving, drip 200ml or 300ml clorox, the temperature of control reaction solution is 35 ℃-40 ℃, and control PH is 3 or 4 in the reaction process, react stopped reaction after 4 hours or 6 hours, be cooled to 10 ℃ or 30 ℃, on the rocks, separate out crystallization, filter to clean, add 150 or 250ml ammoniacal liquor again, 100g or 150g ice, stir, treat that temperature is reduced to below 10 ℃, the reaction 1.0 or 2.0 hours that picks up counting, back water-bath slowly is heated to 35 ℃-40 ℃, remove amine, reaction solution is transferred in the beaker, adds the dilution of 80ml or 120ml water, the frozen water cooling drips the concentrated hydrochloric acid acidifying, when PH=7, finished product begins to separate out, and after continuation drips and makes PH=4, stops to drip.Continue to stir suction filtration after at least 40 minutes, wash with water again to neutrality with after the washing with alcohol at least 2 times earlier, drying, white solid 25g, yield 32.85%.Fusing point: 198.5-199.8 ℃.
Embodiment three: get adding 5%NaOH solution 500ml in the 1000ml there-necked flask, stir, add crude product 30g, stirred 30 minutes under the room temperature, add gac 1g, decolouring in 30 minutes is stirred in continuation under the room temperature.Suction filtration, filtrate stop to add acid after regulating PH=4-5 with hydrochloric acid, and continuation was stirred 30 minutes, suction filtration, and washing is extremely neutral, the dry white solid 27.4g that gets.Fusing point: 203.5-204.8 ℃.
Claims (3)
1, a kind of preparation method of methazolamide; this method is with 5-amino-2-mercapto phenyl formic-1; 3, the 4-thiadiazoles is a raw material, through condensation, acetylize, methylate, oxidation, amination reaction obtain the methazolamide crude product; again through the refining methazolamide highly finished product that obtain; in described oxidation and the amination reaction process, add the clorox raw material, in the presence of catalyzer iron(ic) chloride, react; the intermediate that reaction obtains carries out amination reaction again, makes the methazolamide crude product.
2, the preparation method of methazolamide according to claim 1 is characterized in that in the oxidation reaction process, and the temperature of reaction of control is at 35---50C, and makes the methazolamide crude product by oxidation and amination reaction.
3, the preparation method of methazolamide according to claim 1 and 2 is characterized in that described methazolamide crude product obtains precipitate after adding 5% hydrochloric acid and regulating PH=1-5, make finished product through washing drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100505990A CN100387584C (en) | 2005-07-05 | 2005-07-05 | Preparation method of methazolamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100505990A CN100387584C (en) | 2005-07-05 | 2005-07-05 | Preparation method of methazolamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1724522A true CN1724522A (en) | 2006-01-25 |
| CN100387584C CN100387584C (en) | 2008-05-14 |
Family
ID=35924167
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100505990A Active CN100387584C (en) | 2005-07-05 | 2005-07-05 | Preparation method of methazolamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100387584C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716391A (en) * | 2022-04-24 | 2022-07-08 | 杭州仟源保灵药业有限公司 | Methazolamide impurity and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB795174A (en) * | 1954-10-13 | 1958-05-21 | Upjohn Co | Heterocyclic sulphonamides |
| US5157044A (en) * | 1983-02-04 | 1992-10-20 | University Of Iowa Research Foundation | Analogs of carbonic anhydrase inhibitors and their use as topical IOP inhibitors |
-
2005
- 2005-07-05 CN CNB2005100505990A patent/CN100387584C/en active Active
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716391A (en) * | 2022-04-24 | 2022-07-08 | 杭州仟源保灵药业有限公司 | Methazolamide impurity and preparation method and application thereof |
| CN114716391B (en) * | 2022-04-24 | 2023-12-12 | 杭州仟源保灵药业有限公司 | Methanazole impurity and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100387584C (en) | 2008-05-14 |
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Assignee: Hangzhou Aoyi Baoling Pharmaceutical Co., Ltd. Assignor: Hangzhou Baoling Co., Ltd. Contract fulfillment period: 2008.8.6 to 2025.7.5 Contract record no.: 2008330002016 Denomination of invention: Preparation method of methazolamide Granted publication date: 20080514 License type: Exclusive license Record date: 20081114 |
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Effective date of registration: 20160621 Address after: 310000 No. 23, No. 668, Hangzhou economic and Technological Development Zone, Hangzhou, Zhejiang Patentee after: Hangzhou Aoyi Baoling Pharmaceutical Co., Ltd. Address before: Hangzhou City, Zhejiang Province, Gongshu District Baolinglu No. 5 310022 Patentee before: Hangzhou Pollen Group Co.,Ltd. |
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