CN104945349A - Method for preparing 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide - Google Patents
Method for preparing 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide Download PDFInfo
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- CN104945349A CN104945349A CN201510416193.3A CN201510416193A CN104945349A CN 104945349 A CN104945349 A CN 104945349A CN 201510416193 A CN201510416193 A CN 201510416193A CN 104945349 A CN104945349 A CN 104945349A
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- butyl
- ketone
- benzisothiazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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- Thiazole And Isothizaole Compounds (AREA)
Abstract
A method for preparing 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide is characterized in that the method uses soluble saccharin dehydrate and n-butyl bromide as raw materials, reaction is performed under the effect of a composite catalyst at the temperature of 70-90 DEG C for 4-8 hours, a product precipitates after cooling, and centrifugal separation and drying are performed to obtain a high-purity white crystal finished product, wherein the composite catalyst is prepared by mixing water and fatty amine by the mole ratio of 1:0.02-1:5. The method has the advantages that the composite catalyst with the fatty amine as a main ingredient is adopted to prepare the 1,2-benzisothiazole-3(2H) ketone-2-butyl-1,1-dioxide for the first time, and a solvent is not needed for reaction, the product precipitates after reaction and cooling, and centrifugal separation and drying are performed to obtain the high-purity white crystal finished product, the step of removing a reaction solvent and non-reacted raw materials through distillation is omitted, ethyl alcohol for twice re-crystallization is not needed, accordingly a synthesis process is simplified, production cost is greatly reduced, environmental pollution caused by usage of a large amount of organic solvent is also avoided, and a green preparation process is achieved.
Description
Technical field
The present invention relates to one and prepare 1, the novel method of 2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide, especially relates to and adopts aliphatic amide as catalyst preparing 1, the novel method of 2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide.
Background technology
1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide (thiophene ketone) is a kind of novel infiltration accelerating agent, water insoluble, is soluble in ethanol, propylene glycol, chloroform, acetone and other organic solvent.The infiltration accelerating agent mainly dimethyl sulfoxide (DMSO) that the 70's of 20th century use, but its effective working concentration is large, and the pungency of medicine own is strong, and has the inevitable shortcomings such as stronger peculiar smell.American Studies person has synthesized infiltration accelerating agent azone (Azone) subsequently, due to its have that effective working concentration is low, free from extraneous odour, bland advantage and cause the concern of countries in the world, and day by day instead of dimethyl sulfoxide (DMSO).In the 90's of 20th century, Inst. of Applied chemistry, Beijing Normal Univ. scientific and technical personnel successfully have developed novel infiltration accelerating agent-thiophene ketone
[1]; The mechanism that thiophene ketone and azone are urged to ooze is similar, but it is to no skin irritation and anaphylaxis, and toxicity is minimum, mechanism is obviously better than azone, therefore thiophene ketone is the desirable regeneration product of azone, is a kind of newly, efficient, nontoxic infiltration accelerating agent, has broad application prospects.Thiophene ketone is applied to application compress and medicine for oral administration as infiltration accelerating agent, transdermal delivery system, compared with traditional methods of administration, the relative constancy of Plasma Concentration can be maintained within the longer time, avoid the first-pass effect of stomach and intestine and liver, reduce the individual difference because metabolism difference causes, while improving drug effect, reduce toxic side effect, interruptible price treatment if desired, is convenient to patient and uses
[2].Existing medicine 2/3 likely as the research object of percutaneous absorption type
[3], but many medicines are difficult to through complete skin under therapeutic dose, therefore, must promote the absorption of medicine to reduce drug dose by the effective infiltration accelerating agent of use safety simultaneously
[4].The advantage of thiophene ketone high effect nontoxic makes its having a extensive future at field of medicaments, and moreover, thiophene ketone is also widely used in makeup, healthcare products, weaving, dyeing industry, tanning industry and agroforestry.Obvious effect is had in raising curative effect, reduction dosage and industrial cost; in equal drug effect situation, the effective constituent of pesticide with high permeability to decline about 50 % than former agricultural chemicals; production cost can decline 30 ~ 60 %; pesticide residue can also be reduced simultaneously; not only be conducive to environment protection, but also the drug-fast formation and development of harmful organism can be delayed, therefore develop that a kind of cost is low, yield is high; product purity is high, technique is simple, and environment-friendly and green novel process is the task of top priority.
Reference:
[1] Xiong Lizeng. novel infiltration accelerating agent thiophene ketone [J]. meticulous and specialty chemicals, 2004,12 (21): 9-11.
[2] Wang Zhengang, Li Mingxia, Zhang Zhirong. novel pharmaceutical formulation and development prospect [J]. CHINESE JOURNAL OF INTERNAL MEDICINE, 1986,25 (3): 186-189.
[3] Jin Yan. percutaneous absorption fortifier [J]. pharmacy is in progress, and 1990,14 (1): 22-25.
[4] Agis P K. Transdermal delivery of drugs [J]. Boca Roton Florida: CRC press, 1987, 3: 17- 20。
Summary of the invention
The object of the invention is to provide the preparation 1 that a kind of technique is simple, cost is low, yield is high, product purity is high, green by improving on the basis of existing synthetic method, the method of 2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide.
Object of the present invention realizes by following technique measures:
Preparation 1 of the present invention, 2-benzisothiazole-3 (2H) ketone-2-butyl-1, the method of 1-dioxide is for raw material with two hydration soluble saccharins and bromination of n-butane, under the effect of composite catalyst, 70-90 DEG C of reaction 4-8 hour, can obtain highly purified white crystal finished product after separating out product centrifugation, drying after cooling; Described composite catalyst is mixed by the ratio of water and aliphatic amide 1:0.02 ~ 1:5 in molar ratio.
The optimum ratio of water described in the present invention and aliphatic amide is that the ratio of 1:0.03 ~ 1:1 in molar ratio mixes.
Aliphatic amide described in the present invention be selected from triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-amyl amine, three normal hexyl Amines, three positive heptyl amices or tri-n-octyl amine any one; Any one in preferred triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-amyl amine or three normal hexyl Amines.
Beneficial effect of the present invention is as follows:
After reaction terminates, product centrifugation is separated out in cooling, drying can obtain highly purified white crystals finished product, and without the need to dehydrated alcohol twice recrystallization, reaction, crystallization and purification are carried out simultaneously, embody the advantage of one kettle way; Water and aliphatic amide is adopted to be catalyst preparing thiophene ketone first; Greatly reduce production cost, reduce production cost 20 more than % than existing synthesis technique; Not with an organic solvent, need not steam except organic solvent and unreacted bromination of n-butane after reaction terminates, be green synthesis process to synthesis technique.
Embodiment
The present invention is further described below with reference to embodiment:
Preparation 1 of the present invention, 2-benzisothiazole-3 (2H) ketone-2-butyl-1, the method of 1-dioxide is for raw material with two hydration soluble saccharins and bromination of n-butane, under the effect of composite catalyst, 70-90 DEG C of reaction 4-8 hour, can obtain highly purified white crystal finished product after separating out product centrifugation, drying after cooling; Described composite catalyst is mixed by the ratio of water and aliphatic amide 1:0.02 ~ 1:5 in molar ratio.
The optimum ratio of water described in the present invention and aliphatic amide is that the ratio of 1:0.03 ~ 1:1 in molar ratio mixes.
Aliphatic amide described in the present invention be selected from triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-amyl amine, three normal hexyl Amines, three positive heptyl amices or tri-n-octyl amine any one; Any one in preferred triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-amyl amine or three normal hexyl Amines.
Specific embodiments of the invention are as follows, but do not limit the present invention.
Embodiment 1:
The aliphatic amide of the two hydration soluble saccharins of 120.5 grams (0.5 mol), the bromination of n-butane of 80.84 grams (0.59 mol), the water of 1.3 mol and 0.04 mol is joined in the reaction flask of 250 milliliters, 86 DEG C are reacted 6 hours, after naturally cooling to room temperature, refrigerator freezing 30 minutes, separate out product centrifugation, 32 DEG C of vacuum-drying 8 hours, obtain white needle-like crystal 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide 117.61 grams, yield is 98.3 %; Fusing point: 38-39.5 DEG C; IR (KBr compressing tablet, cm
1): 3093.8,2962.7,2931.8,2864.3,1728.2,1593.2,1458.2,1438.9,1375.3,1334.7,1300,1265.3,1184.3,1060.9,750.3;
1h NMR (400 MHz, CDCl
3) δ (ppm): 8.05 (m, 1H), 7.93 (m, 1H), 7.86 (m, 2H), 3.78 (t, 2H), 1.84 (m, 2H), 1.45 (m, 2H), 0.98 (t, 3H).
Embodiment 2:
The aliphatic amide of the two hydration soluble saccharins of 120.5 grams (0.5 mol), the bromination of n-butane of 83.58 grams (0.61 mol), the water of 1.3 mol and 0.06 mol is joined in the reaction flask of 250 milliliters, 86 DEG C are reacted 6 hours, after naturally cooling to room temperature, refrigerator freezing 30 minutes, separate out product centrifugation, 32 DEG C of vacuum-drying 8 hours, obtain white needle-like crystal 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide 118.52 grams, yield is 99.06 %; Fusing point: 38-39.5 DEG C; IR (KBr compressing tablet, cm
1): 3093.8,2962.7,2931.8,2864.3,1728.2,1593.2,1458.2,1438.9,1375.3,1334.7,1300,1265.3,1184.3,1060.9,750.3;
1h NMR (400 MHz, CDCl
3) δ (ppm): 8.05 (m, 1H), 7.93 (m, 1H), 7.86 (m, 2H), 3.78 (t, 2H), 1.84 (m, 2H), 1.45 (m, 2H), 0.98 (t, 3H).
Claims (4)
1. prepare 1 for one kind, 2-benzisothiazole-3 (2H) ketone-2-butyl-1, the method of 1-dioxide, it is characterized in that: described method is for raw material with two hydration soluble saccharins and bromination of n-butane, under the effect of composite catalyst, 70-90 DEG C of reaction 4-8 hour, can obtain highly purified white crystal finished product after separating out product centrifugation, drying after cooling; Described composite catalyst is mixed by the ratio of water and aliphatic amide 1:0.02 ~ 1:5 in molar ratio.
2. the method for preparation 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide according to claim 1, is characterized in that: the ratio of described water and aliphatic amide 1:0.03 ~ 1:1 in molar ratio mixes.
3. preparation 1 according to claim 2,2-benzisothiazole-3 (2H) ketone-2-butyl-1, the method of 1-dioxide, is characterized in that: described aliphatic amide be selected from triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-amyl amine, three normal hexyl Amines, three positive heptyl amices or tri-n-octyl amine any one.
4. preparation 1 according to claim 2,2-benzisothiazole-3 (2H) ketone-2-butyl-1, the method of 1-dioxide, is characterized in that: described aliphatic amide be selected from triethylamine, Tri-n-Propylamine, tri-n-butylamine, tri-n-amyl amine or three normal hexyl Amines any one.
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| CN201510416193.3A CN104945349A (en) | 2015-07-16 | 2015-07-16 | Method for preparing 1,2-benzisothiazole-3 (2H) ketone-2-butyl-1,1-dioxide |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4900739A (en) * | 1988-10-20 | 1990-02-13 | American Home Products Corp. | Novel spirosuccinimides as aldose reductase inhibitors and antihyperglycemic agents |
| CN1323791A (en) * | 2001-04-19 | 2001-11-28 | 容军 | Prepn. of N-butyl benzoyl-2-sulfonyl inner imine |
-
2015
- 2015-07-16 CN CN201510416193.3A patent/CN104945349A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4900739A (en) * | 1988-10-20 | 1990-02-13 | American Home Products Corp. | Novel spirosuccinimides as aldose reductase inhibitors and antihyperglycemic agents |
| CN1323791A (en) * | 2001-04-19 | 2001-11-28 | 容军 | Prepn. of N-butyl benzoyl-2-sulfonyl inner imine |
Non-Patent Citations (4)
| Title |
|---|
| HAROLD L.RICE，等: "An Improved Procedure for the Preparation of Alkyl Halide Derivatives of Saccharin", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| JAMES M. CHAPMAN，等: "Hypolipidemic Activity of Phthalimide Derivatives. 3. A Comparison of Phthalimide and 1,2-Benzisothiazolin-3-on1e, l-Dioxide Derivatives to Phthalimidine and 1,2-Benzisothiazoline 1,l-Dioxide Congeners", 《J.MED.CHEM.》 * |
| 袁天平，等: "1，2一苯并异噻唑一3(2H)一酮一2-正丁基一1，1一二氧化物的研究进展", 《化工时刊》 * |
| 钟琦，等: "糖精N-烃化反应的相转移催化", 《化学试剂》 * |
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Application publication date: 20150930 |