CN103709121A - Preparation method for pharmaceutical grade 2-mercaptobenzothiazole and derivative DM thereof - Google Patents
Preparation method for pharmaceutical grade 2-mercaptobenzothiazole and derivative DM thereof Download PDFInfo
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- CN103709121A CN103709121A CN201310604025.8A CN201310604025A CN103709121A CN 103709121 A CN103709121 A CN 103709121A CN 201310604025 A CN201310604025 A CN 201310604025A CN 103709121 A CN103709121 A CN 103709121A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/70—Sulfur atoms
- C07D277/72—2-Mercaptobenzothiazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/70—Sulfur atoms
- C07D277/76—Sulfur atoms attached to a second hetero atom
- C07D277/78—Sulfur atoms attached to a second hetero atom to a second sulphur atom
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Abstract
The invention provides a preparation method for pharmaceutical grade 2-mercaptobenzothiazole (M) and derivative DM (2,2'-dithiobis(benzothiazole)) thereof. The preparation method comprises: mixing industrial grade M and ammonia water or a sodium hydroxide solution according to a molar ratio of 1:1.0-2.5 and dissolving to prepare an ammonium salt or sodium salt solution of M, wherein the ammonia water or the sodium hydroxide solution has the mass concentration of 5-15%; removing impurities by using a filter aid, adding sulfuric acid or hydrochloric acid with a concentration of 5-25%, controlling the pH value at 6.5-8.5, so as to precipitate M, then filtering, washing with water and drying to prepare the pharmaceutical grade M with the melt point of 180 DEG C or more and the yield of 96% or more; mixing M and a solvent according to a W/V ratio of 1:3-15, then adding a catalyst, adding oxygen or hydrogen peroxide with a concentration of 10-50% at 20-80 DEG C for oxidation, wherein the molar ratio of M to hydrogen peroxide is 1:1.0-1.6; and performing separation, water washing and drying on the reactants to prepare the pharmaceutical grade DM with the melt point of 180 DEG C or more and the yield of 98% or more. According to the preparation method, no "three wastes (waste gas, waste water and industrial residue)" are discharged during the production process of M and DM; the technology is concise and the conversion rate is high; M in a slurry state in the solvent system is subjected to catalytic oxidation for producing DM, the molecular level oxidation is realized; and the melt points of pharmaceutical grade M and DM are both 180 DEG C or more, the melting ranges are short, and the product quality is high.
Description
Technical field
The present invention relates to the production technical field of pharmaceutical grade intermediate, particularly the preparation method of a kind of pharmaceutical grade 2-benzothiazolyl mercaptan (M) and derivative 2,2 thereof '-dibenzothiazyl disulfide (DM).
Background technology
Along with industrial expansion, the widespread use of pharmaceutical grade M and the high-quality DM of pharmaceutical grade, also more and more comes into one's own for their research and produce, and high-quality M can be used as metal special reagent, make intermediate, also can develop the derivative with superperformance of series of new.In the synthetic field of modern medicine, DM is as a kind of Medicine intermediate, the production process that is widely used in the products such as MEAM, cephalosporin analog antibiotic, in beta-lactam synthetic, substitute PyS (2-thiol group pyrimidine), thereby successfully synthesize target product beta-lactam, the advantages such as β-lactam antibitics has efficiently, low toxicity, wide spectrum are domestic and international antibiotic main flow kinds; In addition DM also can be used for synthetic cephalosporin antibiotic medicine precursor A E active ester (benzothiazole-2-base (Z)-2-methoxyimino-2-(thiazolamine-4-yl) thioacetate), it is worth noting that semisynthetic penicillin and Cephalosporins have become the widest microbiotic of current clinical use.Therefore, pursue high-quality DM and there is very important pharmaceutical use.
The production technique of pharmaceutical grade M there is no documents and materials report at present.Relevant open source information has: patent application 201110178075.5 " a kind of process for purification of pharmaceutical dibenzothiazyl disulfide ", to using industrial rubber auxiliary agent DM as raw material, adopting ethanol, ethyl acetate is that solvent carries out recrystallization production pharmaceutical grade DM, fusing point is 176 ℃, and its quality product is not high; Patent 200810139264.X " a kind of method of preparing pharmaceutical grade DM with technical grade DM ", to using technical grade DM as raw material, adopting toluene or zellon is raw material recrystallization production pharmaceutical grade DM, because solvent for use toxicity is large, contaminate environment, solvent method is produced medical DM inevitably will discharge noxious solvent in air, easy firing blast, poor stability, and also quality product is not high; Patent application 201110280098.7 " take the method for Sodium Nitrite as oxidant production pharmaceutical grade DM " and patent application 201110280137.3 " take the method for oxygen as oxidant production pharmaceutical grade DM " products obtained therefrom fusing point is about 178 ℃, its quality product is not high, and be to react under the pressure of 0.1-1.1Mpa, preparation condition is harsh.
Summary of the invention
The present invention seeks to overcome many defects that prior art exists, the specification of quality high-quality M and DM being improved constantly for meeting pharmaceutical industries, the preparation method of a kind of pharmaceutical grade 2-benzothiazolyl mercaptan and derivative DM thereof is provided, the method is simple to operate, mild condition, the M obtaining and DM yield is high, fusing point is high, without " three wastes " discharge.
For achieving the above object, the present invention proposes following technical scheme: a kind of pharmaceutical grade 2-benzothiazolyl mercaptan (M) and derivative 2 thereof, the preparation method of 2 '-dibenzothiazyl disulfide (DM), it is characterized in that: take technical grade M as raw material, the ammoniacal liquor that is 5-15% by technical grade M and mass concentration or sodium hydroxide join in reactor and dissolve, the mol ratio of M and ammoniacal liquor or sodium hydroxide is 1:1.0-2.5, makes ammonium salt or the sodium salt solution of M; Add the separation of absorption flocculating aids and remove impurity, adding mass concentration is that 5-25% sulfuric acid or salt acids mineral acid carry out acidifying, controlling pH value is 6.5-8.5, the M of acidifying is separated out, then after filtration, be washed to neutrality, make product fusing point >=180 ℃ after dry, once through yield reaches more than 96% pharmaceutical grade M;
Pharmaceutical grade M and solvent are made in slurry state input reactor according to the weightmeasurement ratio of 1:3-15, then to the catalyzer that adds pharmaceutical grade M weight 0～1.0% in reactor, under 20-80 ℃ of temperature of reaction, add the hydrogen peroxide that oxygen or mass concentration are 10-50% to be oxidized, the mol ratio of pharmaceutical grade M and hydrogen peroxide is: 1:1.0-1.6, and the purity that passes into oxygen is more than 99.9%; The reactant obtaining through centrifugation, be washed to neutrality, make product fusing point >=180 ℃ after dry, yield reaches more than 98% pharmaceutical grade DM.
Described absorption flocculating aids is any one in gac, wilkinite, atlapulgite, and absorption flocculating aids addition is the 0.1-10% of technical grade M weight.
Described solvent is that atmospheric pressure state boiling point is lower than below 200 ℃, this solvent comprises: the alcoholic solvent of methyl alcohol, ethanol, Virahol, butanols, the esters solvent of ethyl acetate, methyl-formiate, ethyl formate, the furans solvent of tetrahydrofuran (THF), methyltetrahydrofuran, the double solvents of the benzene kind solvent of benzene,toluene,xylene and dioxane, dioxolane, methylal any one or more than one assembly in them.
Described catalyzer is the metal-salt of ferrous sulfate class divalent iron salt or copper sulfate class cupric salt or rose vitriol class divalent cobalt.
Water in described washing is softening water.
Distinguishing feature of the present invention is: in pharmaceutical grade M and DM production process, Matter Transfer discharges without " three wastes "; Processing condition are gentle, technique is succinct, transformation efficiency is high, production cost is low; M starches state catalyzed oxidation and produces DM in solvent system, realizes molecular level oxidation, and the fusing point of pharmaceutical grade M and DM is all more than 180 ℃, and melting range is short, and quality product is high.
Embodiment
Below by embodiment, the present invention is specifically described.Following examples can make those skilled in the art understand better the present invention, but do not limit the present invention in any way.
Embodiment 1
500 grams of technical grade M are joined in reactor and dissolved according to the proportioning of M and sodium hydroxide mol ratio 1:1.5 with 15% sodium hydroxide, make the sodium salt solution of M, add 25 grams of absorption flocculating aids activity charcoal powders, stir after 2 hours, filter; To adding mass concentration in filtrate, be that 20% sulfuric acid carries out acidifying, controlling pH value is 6.5, and the M of acidifying is separated out, and then filters, and with softening water, is washed till neutrality, is dried; Make pharmaceutical grade M485 gram, 180.5 ℃ of product fusing points, yield 97%.
Selecting Virahol and ethyl acetate volume ratio 1:1 is double solvents system, by 485 grams of pharmaceutical grade M, 5 liters of double solventss are made into slurry state and drop in reactor, then in reactor, add 0.5 gram of iron vitriol catalyzer, and to drip mass concentration be that 50% hydrogen peroxide carries out oxidizing reaction at 80 ℃, until react completely with pharmaceutical grade M, the mol ratio of pharmaceutical grade M and hydrogen peroxide is: 1:1.5; That react assaying reaction thing fusing point >=180 ℃ is complete (if reaction not exclusively, reactant fusing point can lower than 180 ℃); Reactant is through centrifugation, and softening water is washed till neutrality, dry; Mother liquor recycles after rectifying is reclaimed.After dry, make pharmaceutical grade DM476 gram, measure 180.8 ℃ of pharmaceutical grade DM fusing points, 0.3 ℃ of melting range, yield 98.14%.
Embodiment 2
500 grams of technical grade M are joined in reactor and dissolved according to M and sodium hydroxide mol ratio 1:1.2 proportioning with 10% sodium hydroxide, make the sodium salt solution of M, add 15 grams of absorption flocculating aids activity charcoal powders, stir after 1 hour, filter; To adding mass concentration in filtrate, be that 15% sulfuric acid carries out acidifying, controlling pH value is 7.5, and the M of acidifying is separated out, and then filters, and with softening water, is washed till neutrality, is dried; Make pharmaceutical grade M488 gram, 180.2 ℃ of product fusing points, yield 97.6%.
Selecting ethanol and tetrahydrofuran (THF) volume ratio 1:0.2 is double solvents system, by 400 grams of pharmaceutical grade M, 3 liters of double solventss are made into slurry state and drop in reactor, then to adding 0.8 gram of cupric sulfate pentahydrate in reactor, be catalyzer, and to drip mass concentration be that 15% hydrogen peroxide carries out oxidizing reaction at 35 ℃, until react completely with pharmaceutical grade M, the mol ratio of pharmaceutical grade M and hydrogen peroxide is: 1:1.0; Assaying reaction thing fusing point >=180 ℃ react complete; Reactant is through centrifugation, and softening water is washed till neutrality, dry; Mother liquor recycles after rectifying is reclaimed.After dry, make pharmaceutical grade DM394.6 gram.Measure 181 ℃ of pharmaceutical grade DM fusing points, 0.4 ℃ of melting range, yield 98.5%.
Embodiment 3
500 grams of technical grade M are joined in reactor and dissolved according to M and ammoniacal liquor mol ratio 1:1.6 proportioning with 8% ammoniacal liquor, make the ammonium salt solution of M, add 15 grams of absorption flocculating aids atlapulgites, stir after 1.5 hours, filter; To adding mass concentration in filtrate, be that 15% hydrochloric acid carries out acidifying, controlling pH value is 7.0, and the M of acidifying is separated out, and then filters, with softening water, is washed till neutrality, after being dried, makes pharmaceutical grade M482.5 gram, 180.0 ℃ of product fusing points, yield 96.5%.
Selecting ethanol and volume of toluene is double solvents system than 1:0.3, by 400 grams of pharmaceutical grade M, 6 liters of double solventss are made into slurry state and drop in reactor, dripping mass concentration is that 20% hydrogen peroxide and pharmaceutical grade M carry out oxidizing reaction at 30 ℃, until react completely with pharmaceutical grade M, the mol ratio of pharmaceutical grade M and hydrogen peroxide is: 1:1.2; Assaying reaction thing fusing point >=180 ℃ are that oxidizing reaction is complete; Reactant is through centrifugation, and softening water is washed till neutrality, dry; Mother liquor recycles after rectifying is reclaimed.After dry, make pharmaceutical grade DM395 gram.Measure 180.4 ℃ of pharmaceutical grade DM fusing points, 0.5 ℃ of melting range, yield 98.7%.
Embodiment 4
500 grams of technical grade M are joined in reactor and dissolved according to M and ammoniacal liquor mol ratio 1:1.6 proportioning with 8% ammoniacal liquor, make the ammonium salt solution of M, add 30 grams of absorption flocculating aids wilkinites, stir after 1.5 hours, filter; To adding mass concentration in filtrate, be that 15% hydrochloric acid carries out acidifying, controlling pH value is 7.0, and the M of acidifying is separated out, and then filters, with softening water, is washed till neutrality, after being dried, makes pharmaceutical grade M487.3 gram, 180.4 ℃ of product fusing points, yield 97.5%.
Selecting ethanol, ethyl formate and butanols volume ratio 1:0.5:0.3 is double solvents system, by 400 grams of pharmaceutical grade M, 5 liters of double solventss are made into slurry state and drop in reactor, then to adding 1.0 grams of rose vitriols in reactor, be catalyzer, and at 45 ℃, carry out oxidizing reaction to the oxygen that passes into purity 99.9% in reactor; That react assaying reaction thing fusing point >=180 ℃ is complete (if reaction not exclusively, detecting reactant fusing point can lower than 180 ℃); Reactant is through centrifugation, and softening water is washed till neutrality, dry; Mother liquor recycles after rectifying is reclaimed.After dry, make pharmaceutical grade DM394.6 gram, measure 180.2 ℃ of pharmaceutical grade DM fusing points, 0.5 ℃ of melting range, yield 98.65%.
Claims (5)
1. a pharmaceutical grade 2-benzothiazolyl mercaptan (M) and derivative 2 thereof, the preparation method of 2 '-dibenzothiazyl disulfide (DM), it is characterized in that: take technical grade M as raw material, the ammoniacal liquor that is 5-15% by technical grade M and mass concentration or sodium hydroxide join in reactor and dissolve, the mol ratio of M and ammoniacal liquor or sodium hydroxide is 1:1.0-2.5, makes ammonium salt or the sodium salt solution of M; Add the separation of absorption flocculating aids and remove impurity, adding mass concentration is that 5-25% sulfuric acid or salt acids mineral acid carry out acidifying, controlling pH value is 6.5-8.5, the M of acidifying is separated out, then after filtration, be washed to neutrality, make product fusing point >=180 ℃ after dry, once through yield reaches more than 96% pharmaceutical grade M;
Pharmaceutical grade M and solvent are made in slurry state input reactor according to the weightmeasurement ratio of 1:3-15, then to the catalyzer that adds pharmaceutical grade M weight 0～1.0% in reactor, under 20-80 ℃ of temperature of reaction, add the hydrogen peroxide that oxygen or mass concentration are 10-50% to be oxidized, the mol ratio of pharmaceutical grade M and hydrogen peroxide is: 1:1.0-1.6, and the purity that passes into oxygen is more than 99.9%; The reactant obtaining through centrifugation, be washed to neutrality, make product fusing point >=180 ℃ after dry, yield reaches more than 98% pharmaceutical grade DM.
2. the preparation method of pharmaceutical grade 2-benzothiazolyl mercaptan according to claim 1 and derivative DM thereof, it is characterized in that: described absorption flocculating aids is any one in gac, wilkinite, atlapulgite, absorption flocculating aids addition is the 0.1-10% of technical grade M weight.
3. the preparation method of pharmaceutical grade 2-benzothiazolyl mercaptan according to claim 1 and derivative DM thereof, it is characterized in that: described solvent is that atmospheric pressure state boiling point is lower than below 200 ℃, this solvent comprises: the alcoholic solvent of methyl alcohol, ethanol, Virahol, butanols, the esters solvent of ethyl acetate, methyl-formiate, ethyl formate, the furans solvent that tetrahydrochysene furan is fed, methyl tetrahydrochysene furan is fed, the double solvents of the benzene kind solvent of benzene,toluene,xylene and dioxane, dioxolane, methylal any one or more than one assembly in them.
4. the preparation method of pharmaceutical grade 2-benzothiazolyl mercaptan according to claim 1 and derivative DM thereof, is characterized in that: described catalyzer is the metal-salt of ferrous sulfate class divalent iron salt or copper sulfate class cupric salt or rose vitriol class divalent cobalt.
5. the preparation method of pharmaceutical grade 2-benzothiazolyl mercaptan according to claim 1 and derivative DM thereof, is characterized in that: the water in described washing is softening water.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262288A (en) * | 2014-09-15 | 2015-01-07 | 河南省开仑化工有限责任公司 | Production method of rubber vulcanization accelerator DM |
| CN107879995A (en) * | 2017-10-26 | 2018-04-06 | 淄博鑫泉医药技术服务有限公司 | The method that the M synthesis DM reclaimed in raffinate is synthesized using cefotaxime acid |
| CN110776477A (en) * | 2019-11-27 | 2020-02-11 | 山东省化工研究院 | Method for preparing DM by oxidizing M with hydrogen peroxide |
| CN111039895A (en) * | 2019-11-29 | 2020-04-21 | 山东尚舜化工有限公司 | Treatment method for hydrogen peroxide oxidation M-Na over-end point |
| CN111253337A (en) * | 2020-03-31 | 2020-06-09 | 河南省开仑化工有限责任公司 | Novel process for anhydrous clean production of vulcanization accelerator DM |
| CN111875562A (en) * | 2020-08-24 | 2020-11-03 | 山东法恩新材料科技有限公司 | CO2New process for purifying crude product and commercial 2-mercaptobenzothiazole by method |
| CN115403827A (en) * | 2022-08-02 | 2022-11-29 | 山东戴瑞克新材料有限公司 | M resin treatment method |
| CN115716811A (en) * | 2022-09-26 | 2023-02-28 | 河北翰成生物科技有限公司 | Method for preparing pharmaceutical DM from industrial promoter M in one step |
| CN115716811B (en) * | 2022-09-26 | 2024-05-28 | 河北翰成生物科技有限公司 | Method for preparing pharmaceutical grade DM by one step by using industrial grade accelerator M |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262288A (en) * | 2014-09-15 | 2015-01-07 | 河南省开仑化工有限责任公司 | Production method of rubber vulcanization accelerator DM |
| CN104262288B (en) * | 2014-09-15 | 2019-03-08 | 河南省开仑化工有限责任公司 | A kind of production method of rubber vulcanization accelerator DM |
| CN107879995A (en) * | 2017-10-26 | 2018-04-06 | 淄博鑫泉医药技术服务有限公司 | The method that the M synthesis DM reclaimed in raffinate is synthesized using cefotaxime acid |
| CN110776477A (en) * | 2019-11-27 | 2020-02-11 | 山东省化工研究院 | Method for preparing DM by oxidizing M with hydrogen peroxide |
| CN110776477B (en) * | 2019-11-27 | 2023-03-10 | 山东省化工研究院 | Method for preparing DM by oxidizing M with hydrogen peroxide |
| CN111039895A (en) * | 2019-11-29 | 2020-04-21 | 山东尚舜化工有限公司 | Treatment method for hydrogen peroxide oxidation M-Na over-end point |
| CN111253337A (en) * | 2020-03-31 | 2020-06-09 | 河南省开仑化工有限责任公司 | Novel process for anhydrous clean production of vulcanization accelerator DM |
| CN111875562A (en) * | 2020-08-24 | 2020-11-03 | 山东法恩新材料科技有限公司 | CO2New process for purifying crude product and commercial 2-mercaptobenzothiazole by method |
| CN115403827A (en) * | 2022-08-02 | 2022-11-29 | 山东戴瑞克新材料有限公司 | M resin treatment method |
| CN115716811A (en) * | 2022-09-26 | 2023-02-28 | 河北翰成生物科技有限公司 | Method for preparing pharmaceutical DM from industrial promoter M in one step |
| CN115716811B (en) * | 2022-09-26 | 2024-05-28 | 河北翰成生物科技有限公司 | Method for preparing pharmaceutical grade DM by one step by using industrial grade accelerator M |
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