CN103145641B - Preparation method of 2-acyl benzothiazole derivative - Google Patents
Preparation method of 2-acyl benzothiazole derivative Download PDFInfo
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- CN103145641B CN103145641B CN201310085448.3A CN201310085448A CN103145641B CN 103145641 B CN103145641 B CN 103145641B CN 201310085448 A CN201310085448 A CN 201310085448A CN 103145641 B CN103145641 B CN 103145641B
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Abstract
The invention discloses a preparation method of a 2-acyl benzothiazole derivative (I), belonging to the field of organic chemistry. According to the preparation method, the 2-acyl benzothiazole derivative is synthesized of a substituted benzothiazole derivative and dialkyl phosphite under the action of peroxide. The preparation method has the advantages that the raw materials are cheap and easily available, reaction conditions are moderate, operation is simple and convenient and synthesis yield is high; therefore the preparation method is beneficial to industrial production. The 2-acyl benzothiazole derivative has a potential application value in fields such as materials, chemical engineering and medicines. The invention provides a new approach to synthesis of the 2-acyl benzothiazole derivative.
Description
Technical field
The present invention relates to a kind of preparation method of 2-acyl group benzothiazole derivant, belong to organic chemistry filed.
Background technology
Benzothiazole is the extremely important heterogeneous ring compound of a class, and at medicine, agricultural chemicals, the fields such as material engineering have been widely used.Pharmaceutically, it can be used as sterilant, fungicides, can also be used for parasiticide, antituberculosis, wind resistance diseases caused by dampness and the medicine such as anticancer; Agriculturally, it has anti-agricultural fungi, desinsection, weeding, plant growth regulating isoreactivity; In material engineering field, it can be used as uv-absorbing agent, liquid crystal display material, electroluminescent material and fluorescence probe material etc. in thiofide, dyeing of plastics agent, makeup and sun glasses.In addition, the derivative of the benzothiazole benzothiazole that particularly 2-position replaces has very strong physiologically active, is widely used in sterilization, antiviral etc., is obtained for application and research widely in pharmaceutical chemistry or chemistry of pesticide.
At present, in all 2-acyl group benzothiazole derivant synthetic methods, obtained the reaction of final product by single step reaction, have not been reported.Document " Shunsaku, O.; Satoshi, H.; Hiroki, M.; Shinichi, T.; Masao; O. Synthesis of 2-acyl-1-methyl-1H-imidazoles and reactivity of the acyl group [J]. Heterocycles; 1985,23 (7): 1759-1764. " and " Chikashita, H.; Ishibaba, M.; Ori, K.; Ito, K. General reactivity of 2-lithiobenzothiazole to various electrophiles and the use as a formyl anion equivalent in the synthesis of a-hydroxy carbonyl compounds [J]. Bulletin of the Chemical Society of Japan, 1988,61 (10): 3637-3648. " with benzothiazole and n-Butyl Lithium and N; N-dimethylformamide is raw material, is obtained by reacting 2-ethanoyl benzothiazole under the cold condition of-78 DEG C; Document " Brenchley, G.; Farmer, L. J.; Harrington, E. M.; Et al. Preparation of thiazoles as inhibitors of protein kinases [P]. WO 2004087699. " be raw material with benzothiazole and N-methyl-N-methoxy ethanamide; under n-Butyl Lithium effect, under-78 DEG C of cold condition, obtain 2-acyl group benzothiazole.It is numerous and diverse to there is step in these synthetic methods, severe reaction conditions, and agents useful for same is difficult to preserve and the shortcoming such as expensive.Therefore, be badly in need of inquiring into a kind of step simple, mild condition, the synthetic method of the 2-acyl group benzothiazole derivant that yield is higher, this will promote the exploitation of 2-acyl group benzothiazole derivant, has great importance to the research and development of protection China independent intellectual property right.
Summary of the invention
Based on above-mentioned research background, the object of the present invention is to provide a kind of mild condition, yield is high, is obtained the new synthetic method of 2-acyl group benzothiazole derivant by single step reaction.
For realizing the object of the invention, the present invention, to replace benzothiazole and H-Phosphonate for raw material, synthesizes 2-acyl group benzothiazole derivant under peroxidation.2-acyl group benzothiazole derivant of the present invention has following general formula I.
Wherein R
1represent the monosubstituted of one of following group: hydrogen base, nitro, amino, kharophen, cyano group, halogen (-F ,-Cl ,-Br and-I), C1-3 alkyl, preferred H ,-NO
2, Br-,-CH
3,-C
2h
5deng; R
2represent the monosubstituted of one of following group: C1-5 alkyl, preferably-CH
3,-C
2h
5,-CH
2cH
2cH
3,-CH (CH
3)
2deng group.
The salt of Compound I is pharmaceutically acceptable salt.As more satisfactory salt, it can be the salt with mineral acid, example hydrochloric acid salt, hydrosulfate or similar salt, also can be the salt with organic acidic group, as methylsulphonic acid amine salt and similar salt.
Concrete technical scheme realizes as follows: first substituted benzothiazole derivatives and hydrogen dialkyl phosphite are dissolved and use solvent in a suitable solvent or not, then add superoxide, reacts at 60-90 DEG C.After reaction terminates, be cooled to room temperature, through extraction, dry, pressure reducing and steaming solvent, obtains general formula (I) 2-acyl group benzothiazole derivant crude product.
Replace the mol ratio preferably 1: 5: 10 of benzothiazole, hydrogen dialkyl phosphite and superoxide.
In solvent selection THF, toluene, dioxane, methyl alcohol, ethanol, methylene dichloride, chloroform, DMSO and acetonitrile etc., one or more are as solvent, preferably do not use any solvent.Superoxide selects hydrogen peroxide, peroxy tert-butyl alcohol, metachloroperbenzoic acid, ditertiary butyl peroxide, and preferred peroxy tert-butyl alcohol is as oxygenant.Preferred employing 90 DEG C is best temperature of reaction.
Reaction formula is as follows:
R in formula
1, R
2state the same.
Abstraction and purification 2-acyl group benzothiazole derivant crude product, such as, is undertaken being separated to obtain 2-acyl group benzothiazole derivant by silica gel column chromatography by crude product
(I),it is made to obtain better application.In addition, can pass through
(I)ethyl acetate solution in add dilute hydrochloric acid or dilute sulphuric acid, the pH value of regulator solution, makes
(I)be transformed into its ammonium salt crystallization to separate out, thus obtain 2-acyl group benzothiazole inorganic acid salt derivative.
Agents useful for same of the present invention all commercially.
Beneficial effect of the present invention is: 2-acyl group benzothiazole derivant of the present invention synthetic method cheaper starting materials is easy to get, reaction conditions is gentle, easy and simple to handle, synthetic yield is high, be conducive to suitability for industrialized production, the benzothiazole derivant having antibacterial, an antiviral isoreactivity for preparation provides a new approach.
Embodiment
Below by embodiment, the present invention will be further elaborated, but and do not mean that content limitation of the present invention is in embodiment.
embodiment 1r
1=H, R
2=CH
3time, the preparation of 2-ethanoyl benzothiazole derivant
Benzothiazole (0.135 g, 1 mmol) and diethyl phosphite (0.690 g, 5 mmol) are joined in the there-necked flask of 50 mL, in oil bath, is heated to 90 DEG C stirs 10 min; Then add the peroxy tert-butyl alcohol aqueous solution (1.287 g, 10 mmol) of mass percent 70%, continue reaction at this temperature, TLC detects.After completion of the reaction, be extracted with ethyl acetate (15 ' 3 mL), merge organic phase, after anhydrous sodium sulfate drying, silica gel column chromatography is separated, and obtains target compound, productive rate 85%.
The spectral data of target compound is as follows:
1H NMR (400 MHz, CDCl
3) d: 2.86 (s, 3H, 11-H), 7.56 (td,
J= 7.6, 1.3 Hz, 1H,5-H), 7.61 (td,
J= 8.0, 1.3 Hz, 1H,6-H), 8.01 (d,
J= 8.0 Hz, 1H,7-H), 8.22 (d,
J= 7.8 Hz, 1H,4-H).
13C NMR (100 MHz, CDCl
3) d: 26.2 (11-C), 122.5 (7-C), 125.5 (4-C), 127.0 (6-C), 127.7 (5-C), 137.5 (8-C), 153.6 (9-C), 166.5 (2-C), 193.2 (10-C).。
embodiment 2r
1=H, R
2=CH
2cH
3time, the preparation of 2-propionyl benzothiazole derivant
Benzothiazole (0.135 g, 1 mmol) and di-n-propyl phosphite (0.830 g, 5 mmol) are joined in the there-necked flask of 50 mL, in oil bath, is heated to 80 DEG C stirs 10 min; Then add the peroxy tert-butyl alcohol aqueous solution (1.287 g, 10 mmol) of mass percent 70%, continue reaction at this temperature, TLC detects.After completion of the reaction, be extracted with ethyl acetate (15 ' 3 mL), merge organic phase, after anhydrous sodium sulfate drying, silica gel column chromatography is separated, and obtains target compound, productive rate 75%.
The spectral data of target compound is as follows:
1H NMR (400 MHz, CDCl
3) d: 1.31 (t,
J= 7.3 Hz, 6H,12-H), 3.32 (q,
J= 7.3 Hz, 4H,11-H), 7.54 (t,
J= 7.4 Hz, 1H,5-H) , 7.59 (t,
J= 7.2 Hz, 1H,6-H), 7.99 (d,
J= 7.8 Hz, 1H,7-H), 8.19 (d,
J= 8.1 Hz, 1H,4-H).
13C NMR (100 MHz, CDCl
3) d: 7.89 (12-C), 32.1 (11-C), 122.5 (7-C), 125.3 (4-C), 126.9 (6-C), 127.6 (5-C), 137.2 (8-C), 153.6 (9-C), 166.4 (2-C), 196.0 (10-C). 。
embodiment 3r
1=NO
2, R
2=CH
3time, the preparation of 6-nitro-2-ethanoyl benzothiazole derivant
(1) synthesis of 6-nitrobenzene thiazole
Benzothiazole (18.2 mL, 0.17 mol) is placed in the low-temp reaction bath of-5 DEG C, drips the 46 mL vitriol oils under agitation, after dropwising, continue stirring 0.5 h; Dropwise added by 18.2 mL nitrosonitric acids, temperature remains on less than 5 DEG C; Add rear continuation stirring 0.5 h, slowly return to stirring at room temperature 2 h.Reaction mixture is poured onto in the frozen water of 400 mL, is placed in refrigerator and solid is all separated out.Suction filtration, is washed to washings in neutral, dries solid, with ethyl alcohol recrystallization, obtain faint yellow solid 6-nitrobenzene thiazole 20.8 g.Productive rate 68 %.
1H NMR (400 MHz, CDCl
3) δ：9.28 (s, 1H, H-2), 8.93 (d, J = 2.2 Hz, 1H, H-7), 8.42 (dd, J = 9.3, 2.2 Hz, 1H, H-5), 8.26 (d, J = 9.3 Hz, 1H, H-4).
(2) 6-nitro-2-ethanoyl benzothiazole derivant
6-nitrobenzene thiazole (0.180 g, 1 mmol) and diethyl phosphite (0.690 g, 5 mmol) are joined in the there-necked flask of 50 mL, in oil bath, is heated to 90 DEG C stirs 10 min; Then add the peroxy tert-butyl alcohol aqueous solution (1.287 g, 10 mmol) of mass percent 70%, continue reaction at this temperature, TLC detects.After completion of the reaction, be extracted with ethyl acetate (15 ' 3 mL), merge organic phase, after anhydrous sodium sulfate drying, silica gel column chromatography is separated, and obtains target compound, productive rate 85%.
The spectral data of target compound is as follows:
1H NMR (400 MHz, CDCl
3) d: 2.86 (s, 3H, 11-H), 8.31 (d,
J= 9.1, 1H ,4-H), 8.42 (dd,
J= 9.1, 2.2 Hz, 1H,5-H), 8.93 (d,
J= 2.2 Hz, 1H,7-H).
13C NMR (100 MHz, CDCl
3) d: 26.2 (11-C), 119.1 (7-C), 122.1 (5-C), 126.0 (4-C), 137.5 (8-C), 146.6 (6-C), 156.9 (9-C), 171.4 (2-C), 192.4 (10-C).
embodiment 4r
1=Br, R
2=CH
3time, the preparation of 6-bromo-2-ethanoyl benzothiazole derivant
(1) synthesis of 6-aminobenzothiazole
6-nitrobenzene thiazole (4.8 g, 26.6 mmol) is joined in the mixed solution of 3.8 mL concentrated hydrochloric acids and 150mL 80% ethanol, then adds iron powder (6.0 g, 107 mmol).The ultrasonic wave this system being placed in 100W reacts 40 min, and raw material reaction is complete.Iron powder is crossed and is filtered by rapid column chromatography, removes solvent under reduced pressure, the solid with ethyl acetate obtained and the extraction of 10% aqueous sodium carbonate, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, (ethyl acetate: sherwood oil, 1: 2 (v: v)) obtain faint yellow solid 6-aminobenzothiazole 3.5 g, productive rate 85% then to use silicagel column column chromatography for separation.
1H NMR (400 MHz, CDCl
3) δ：8.70 (s, 1H, H-2), 7.89 (d, 1H, J = 8.9 Hz, H-4), 7.16 (d, 1H, J = 2.3 Hz, H-7), 6.87 (dd, 1H, J = 8.9, 2.3 Hz, H-5), 3.86 (bs, 2H, NH
2).
(2) synthesis of 6-bromo benzothiazole
6-aminobenzothiazole (1 g, 6.6 mmol) is joined in 1 mL water and the hydrobromic mixed solution of 15 mL.Under condition of ice bath, Sodium Nitrite (0.51 g, 7.3 mmol) is dissolved in 10 mL water, is then slowly added drop-wise in above-mentioned system, continues in ice bath, stir 0.5 h.Cuprous bromide (1.1 g, 7.7 mmol) is dissolved in 15 mL Hydrogen bromides.And then join in above-mentioned system, be warming up to 80 DEG C of reaction 2h.Be cooled to 0 DEG C after reacting completely, the aqueous sodium hydroxide solution dropwise adding 40 % makes system be neutral.Be extracted with ethyl acetate, after anhydrous sodium sulfate drying, decompression steams solvent.Then (ethyl acetate: sherwood oil, 1: 5 (v: v)) obtain pale solid 6-bromo benzothiazole 1.975 g, productive rate 69% to use silicagel column column chromatography for separation.
1H NMR (400 MHz, CDCl
3) δ: 7.59 (dd, J = 8.7 Hz, J = 2.1 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 8.95 (s, 1H).
(3) synthesis of 6-bromo-2-ethanoyl benzothiazole derivant
6-bromo benzothiazole (0.213 g, 1 mmol) and diethyl phosphite (0.690 g, 5 mmol) are joined in the there-necked flask of 50 mL, in oil bath, is heated to 90 DEG C stirs 10 min; Then add metachloroperbenzoic acid (1.72 g, 10 mmol), continue reaction at this temperature, TLC detects.After completion of the reaction, be extracted with ethyl acetate (15 ' 3 mL), merge organic phase, after anhydrous sodium sulfate drying, silica gel column chromatography is separated, and obtains target compound, productive rate 85%.
The spectral data of target compound is as follows:
1H NMR (400 MHz, CDCl
3) d: 2.81 (s, 3H, 11-H), 7.66 (d,
J= 8.8 Hz, 1H,5-H) , 8.01 (d,
J= 8.8 Hz, 1H,4-H), 8.10 (s, 1H,7-H).
13C NMR (100 MHz, CDCl
3) d: 26.1 (11-C), 121.9(6-C), 125.0 (7-C), 126.5 (4-C), 130.7 (5-C), 138.9(8-C), 152.3 (9-C), 166.9 (2-C), 192.8 (10-C). 。
embodiment 5r
1=Br, R
2=-CH (CH
3)
2time, the preparation of 6-bromo-2-isobutyryl benzothiazole derivant
6-bromo benzothiazole (0.213 g, 1 mmol) and phosphorous acid diisobutyl ester (0.97 g, 5 mmol) are dissolved in the there-necked flask of 50 mL filling alcohol solvent, in oil bath, are heated to 90 DEG C stir 10 min; Then add metachloroperbenzoic acid (1.72 g, 10 mmol), react at this temperature, TLC detects.After completion of the reaction, be extracted with ethyl acetate (15 ' 3 mL), merge organic phase, after anhydrous sodium sulfate drying, silica gel column chromatography is separated, and obtains target compound, productive rate 85%.
The spectral data of target compound is as follows:
1H NMR (400 MHz, CDCl
3) d: 1.33 (d,
J= 6.9 Hz, 6H, 12-H), 3.94 (m, 1H, 11-H), 7.65 (d,
J= 8.8 Hz, 1H,5-H) , 8.01 (d,
J= 8.8 Hz, 1H, 4-H), 8.10 (s, 1H, 7-H).
13C NMR (100 MHz, CDCl
3) d: 18.6 (12-C), 36.4 (11-C), 121.8 (6-C), 124.9 (7-C), 126.4 (4-C), 130.6 (5-C), 138.9 (8-C), 152.4 (9-C), 166.5 (2-C), 198.8 (10-C)。
Claims (4)
1. the preparation method such as formula the benzothiazole derivant of 2-acyl group (I) Suo Shi, it is characterized in that, synthesize as follows: first substituted benzothiazole derivatives and hydrogen dialkyl phosphite are dissolved in alcohol solvent or not and use solvent, then add superoxide, react at 60-90 DEG C; After reaction terminates, be cooled to room temperature, through extraction, dry, pressure reducing and steaming solvent, obtains general formula (I) 2-acyl group benzothiazole derivant crude product;
Described superoxide is peroxy tert-butyl alcohol or metachloroperbenzoic acid; Described hydrogen dialkyl phosphite is diethyl phosphite, di-n-propyl phosphite or phosphorous acid diisobutyl ester;
Wherein R
1represent the monosubstituted of one of following group: hydrogen base, nitro, amino, kharophen, cyano group, halogen, C1-3 alkyl; R
2represent the monosubstituted of one of following group: C1-5 alkyl.
2. the preparation method of 2-acyl group benzothiazole derivant as claimed in claim 1, is characterized in that, R
1select H ,-NO
2, Br-,-CH
3,-C
2h
5; R
2choosing-CH
3,-C
2h
5,-CH
2cH
2cH
3,-CH (CH
3)
2.
3. the preparation method of 2-acyl group benzothiazole derivant as claimed in claim 1, is characterized in that, the mol ratio that described reaction raw materials replaces benzothiazole, hydrogen dialkyl phosphite and superoxide is 1: 5: 10.
4. the preparation method of 2-acyl group benzothiazole derivant as claimed in claim 1, it is characterized in that, temperature of reaction selects 90 DEG C.
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|---|---|---|---|---|
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| CN1657529A (en) * | 2004-02-20 | 2005-08-24 | 中国科学院上海药物研究所 | 2-substituted imine thia zlidine derivative its preparation technology and medicinal composition |
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