CN102627624B

CN102627624B - 4-(4-aminobenzene sulfonamide) phenylacetic acid derivative and preparation method and application thereof

Info

Publication number: CN102627624B
Application number: CN201210125184.5A
Authority: CN
Inventors: 杨大成; 晏菊芳; 杨艳; 陈欣; 范莉; 杨龙
Original assignee: Southwest University
Current assignee: Southwest University
Priority date: 2012-04-25
Filing date: 2012-04-25
Publication date: 2014-03-19
Anticipated expiration: 2032-04-25
Also published as: CN102627624A

Abstract

The invention discloses a 4-(4-aminobenzene sulfonamide) phenylacetic acid derivative with a general formula shown as the accompanying drawing. The 4-(4-aminobenzene sulfonamide) phenylacetic acid derivative structurally comprises a benzene sulfonamide structural unit and a phenylacetic acid structural unit. According to in-vitro antidiabetic activity determination results, the compounds have a certain activity of stimulating peroxisome proliferator activated receptors (PPARs). The PPAR relative stimulating rate of partial compounds (taking pioglitazone as a reference) exceeds 58 percent and reaches 81.79 percent high. The compounds can be used for preparing antidiabetic drugs and can also be used as pilot molecules of novel antidiabetic drugs for deep research. The invention additionally provides a method for preparing the compounds through multiple lines, the method is simple and efficient and the yield is high.

Description

4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives and its preparation method and application

Technical field

The invention belongs to chemistry and pharmaceutical field, relate to a class equal amido phenenyl acid derivative, also relate to the preparation method of this analog derivative and the application in pharmacy field.

Background technology

Diabetes (diabetes mellitus, DM) are a kind of endocrine and metabolic disorders diseases of complexity, have become one of three large non-infectious chronic diseases that whole world M & M is the highest.Diabetic subject's number of China in 2010 occupies the whole world first.At present, conventional oral anti-type 2 diabetes mellitus medicine clinically, is mainly divided into 4 classes according to the mode of action: (1) sugared conditioning agent, as alpha-glucosidase inhibitor, aldose reductase inhibitor; (2) insulin secretion stimulators, as sulfonylurea and Lie Nai class (glitinides); (3) euglycemic agent, as biguanides and thiazolidinediones (thiazolidinediones, TZDs); (4) incretin synergistic agent, as glucagon kind polypeptide-1 (glucagon-like peptide 1, GLP-1) and dipeptidyl peptidase-4 (dipeptidyl peptidase-IV, DPP-4) inhibitor etc.In addition, hypoglycemic oral traditional Chinese medicine is also widely used at home as golden Stilbene Siofor, YUQUAN WAN, ginseng Stilbene Siofor etc.Although antidiabetic drugs is of a great variety, result for the treatment of is each has something to recommend him, but generally can not effectively improve the disorders of lipid metabolism of diabetes accompanying, and there is the problems such as side effect of life-time service, as biguanides easily causes gastrointestinal reaction and lactic acidosis, sulfonylureas easily causes hypoglycemia, and Thiazolidinediones life-time service can cause body weight increase, oedema, low-density lipoprotein cholesterol level rising and liver toxicity etc.Therefore, the research of the antidiabetic medicine of new and effective low toxicity is still significant.

Toluylic acid (phenylacetic acid, PA) is important industrial chemicals, and itself also has anticancer isoreactivity.The p-hydroxyphenylaceticacid being synthesized by toluylic acid, amphetamine, chlorophenyl acetic acid ethyl ester and Efaproxiral (efaproxira) etc. are important medicine or pesticide intermediates.Phenylacetic acid derivatives also has good biological activity as Actarit, lumiracoxib, Ibuprofen BP/EP, diclofenac, Ka Motate, guanfacine, Methylphenidylacetate, penicillin, ceforanide, clopidogrel, M 9834 and Azoxystrobin etc.In these derivatives, all contain toluylic acid or phenylacetyl structural unit.In recent years, GlaxoSmithKline company and Merck company find that respectively phenylacetic acid derivatives GW-3965 and L-165461 have good anti-diabetic activity.This seminar also finds, some para-amino benzoic acid derivative, m-aminophenyl glycine derivative and p-nitrophenyl alanine derivatives have good anti-diabetic activity.

Sulfa drugs is class exploitation synthetic antibacterial drug early, and the bacterium that is widely used in prevention and the treatment mankind and other animals infects, and has in addition diuresis, anticancer, anti-inflammatory analgesic isoreactivity.Bibliographical information in recent years, some compound that contains benzsulfamide structural unit shows the activity of Inhibit HIV-1 Protease, antagonism α 1-adrenoceptor, and some molecule that contains sulfanilamide (SN), Sulfamethoxazole (SMZ) or Sulphadiazine Sodium (SD) structural unit that this seminar reacts synthetic by Mannich also shows good anti-diabetic activity.

Summary of the invention

In view of this, the object of the invention is to benzsulfamide to be connected with toluylic acid structural unit, design and synthesize the compound of a class formation novelty, expectation therefrom finds to have guide's molecule of high anti-diabetic activity.

For achieving the above object, the invention provides following technical scheme:

1.4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives, has following general formula:

In formula, R ¹for hydrogen or C1-C6 alkyl, R ²for hydrogen or R ³cO base, R ³for C2-C5 alkyl or the C1-C5 alkyl that replaced by halogen, but R ¹and R ²can not be hydrogen simultaneously.

Further, R ¹for hydrogen or C1-C4 alkyl, R ³for C2-C3 alkyl or the C1-C3 alkyl that replaced by fluorine or chlorine.

Further, R ¹for hydrogen or C1-C4 straight chained alkyl, R ³for C2-C3 straight chained alkyl or the C1-C3 straight chained alkyl that replaced by chlorine.

Further, R ³for n-propyl, chloromethyl, 2-chloroethyl or 3-chloropropyl.

Further, R ¹for C1-C4 straight chained alkyl, R ²for R ³cO base, R ³for chloromethyl, 2-chloroethyl or 3-chloropropyl.

Further, R ¹for methyl, R ³for chloromethyl; Or, R ¹for ethyl, R ³for chloromethyl or 2-chloroethyl; Or, R ¹for n-propyl, R ³for chloromethyl.

2. the preparation method of 4-described in (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, comprises the following steps:

A. by equal amido phenenyl acid with to acetamido benzene sulfonyl halogen, coupling makes intermediate compound I M1;

B. intermediate compound I M1 deacetylation is made to intermediate compound I M2;

C. by intermediate compound I M2 and carboxylic acid halides R ³cOX carries out acylation reaction, makes R ¹for hydrogen, R ²for R ³the 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM1;

D. by intermediate compound I M2 and alcohol R ¹oH carries out esterification, makes R ²for hydrogen, R ¹4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C6 alkyl;

Or, by compound TM1 and alcohol R ¹oH is at SOCl ₂under effect, carry out esterification and de-R ³cO radical reaction, makes R ²for hydrogen, R ¹4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C6 alkyl;

Or, by intermediate compound I M1 and alcohol R ¹oH is at SOCl ₂under effect, carry out esterification and deacetylation, make R ²for hydrogen, R ¹4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C6 alkyl;

E. by Compound I M3 and carboxylic acid halides R ³cOX carries out acylation reaction, makes R ¹for C1-C6 alkyl, R ²for R ³the 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM2;

In above-mentioned reaction formula, R ¹, R ²and R ³definition identical with aforementioned definitions, X is halogen.

Further, the preparation method of described 4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives comprises the following steps:

A. by equal amido phenenyl acid and para-acetylaminobenzene sulfonyl chloride at K ₂cO ₃for coupling under acid binding agent, the acetone condition that is solvent makes intermediate compound I M1;

B. intermediate compound I M1 deacetylation under the condition of alkalescence, temperature 60-70 ℃ is made to intermediate compound I M2;

C. by intermediate compound I M2 and acyl chlorides R ³cOCl is at K ₂cO ₃for carrying out acylation reaction under acid binding agent, the acetone condition that is solvent, make R ¹for hydrogen, R ²for R ³the 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM1;

D. by intermediate compound I M2 and alcohol R ¹oH is at SOCl ₂under effect, temperature 60-85 ℃ carries out esterification, makes R ²for hydrogen, R ¹4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C4 alkyl;

Or, by compound TM1 and alcohol R ¹oH is at SOCl ₂under effect, temperature 60-85 ℃ carries out esterification and de-R ³cO radical reaction, makes R ²for hydrogen, R ¹4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C4 alkyl;

Or, by intermediate compound I M1 and alcohol R ¹oH is at SOCl ₂under effect, temperature 60-85 ℃ carries out esterification and deacetylation, makes R ²for hydrogen, R ¹4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C4 alkyl;

E. by Compound I M3 and acyl chlorides R ³cOCl is at K ₂cO ₃for carrying out acylation reaction under acid binding agent, the acetone condition that is solvent, make R ¹for C1-C4 alkyl, R ²for R ³the 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM2.

3. 4-described in (the 4-aminobenzene sulfonamide base) application of phenylacetic acid derivatives in preparing antidiabetic medicine.

Further, described antidiabetic medicine is peroxisome proliferation-activated receptors (PPAR) agonist class antidiabetic medicine.

Beneficial effect of the present invention is: the present invention is connected benzsulfamide with toluylic acid structural unit, designed and synthesized 4-(the 4-aminobenzene sulfonamide base) phenylacetic acid derivatives of a class formation novelty, In Vitro Anti diabetic activity measurement result shows, these compounds all have certain PPAR agonist activity, wherein the relatively exciting rate of PPAR of part of compounds (take pioglitazone as reference) surpasses 58%, be up to 81.79%, these compounds can be used for preparing antidiabetic medicine, and the guide's molecule that also can be used as novel antidiabetic thing is further furtherd investigate.The present invention also provides the method for preparing these compounds by many routes, succinct efficient, yield is high.

Accompanying drawing explanation

In order to make the object, technical solutions and advantages of the present invention clearer, below in conjunction with accompanying drawing, the present invention is described in further detail, wherein:

Fig. 1 is the yield comparison diagram that IM2, TM1 and IM1 are separately converted to IM3.

Fig. 2 be IM2 and IM3 be separately converted to TM1 and TM2 yield comparison diagram (with R ¹for X-axis).

Fig. 3 be IM2 and IM3 be separately converted to TM1 and TM2 yield comparison diagram (with R ³for X-axis).

Fig. 4 is that the structure of IM2, IM3, TM1 and TM2 and PPAR agonist activity graph of a relation are (with R ²for X-axis).

Fig. 5 is that the structure of IM2, IM3, TM1 and TM2 and PPAR agonist activity graph of a relation are (with R ¹for X-axis).

Embodiment

Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.

Detecting instrument and the main agents in preferred embodiment, used are as follows: AV-300 type NMR spectrometer with superconducting magnet (Bruker, USA; TMS is interior mark), HR ESI-FTICR MS (Varian 7.0T, USA), the accurate micro melting point apparatus (Beijing Fu Kai Instrument Ltd.) of X-6 type; Equal amido phenenyl acid (CP, Deng Guan Chemical Co., Ltd.), p-acetaminobenzenesulfonyl chloride (CP, Shanghai Da Rui fine chemicals company limited), all the other reagent are commercially available chemical pure or analytical pure product.

The preparation of embodiment 1, intermediate compound I M1

In reaction flask, add successively equal amido phenenyl acid (4-APA), K ₂cO ₃and suitable quantity of water, stirring and dissolving, ice bath is cooling, drips the acetone soln of para-acetylaminobenzene sulfonyl chloride (ASC), 4-APA, K ₂cO ₃with the molar ratio of ASC be 1: 2.1: 1.2-1.5, dropwising recession except ice bath, stirring at room reaction, tlc (TLC) monitoring reaction process.After reaction finishes, vacuum rotary steam is removed acetone, obtains faint yellow turbid solution, suction filtration, and filter cake washes with water, drains, and obtains crude product.Crude product is put in 20mL2N KOH to stirring and dissolving 0.5h, suction filtration, filter residue washes with water, and washing lotion and filtrate merge, and ice bath is cooling, slowly drip dense HCl, have a large amount of solids to separate out, regulate pH=2～3 (with no longer include solid separate out be as the criterion), standing, suction filtration, filter cake washes with water, drain, water or alcohol disperse again, and vacuum-drying, obtains intermediate compound I M1.Part experiment condition and the results are shown in Table 1.

Preparation condition and the result of table 1IM1

IM1 4-(4-acetamido benzene sulfonamido) toluylic acid: m.p.118.6～118.9 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 2.05 (s, 3H, H-15), 3.91 (s, 2H, H-2), 7.08 (d, 2H, J=7.8Hz, H-5), 7.18 (d, 2H, J=7.8Hz, H-4), 7.65～7.72 (m, 4H, H-9, H-10), 10.25 (s, 1H, H-12), 10.31 (s, 1H, H-7), 12.27 (s, 1H, H-14); ¹³cNMR (75MHz, DMSO-d ₆) δ: 22.14,40.29,118.99,119.64,120.72,127.01,128.38,129.32,133.23,137.74,143.59,169.47.

The preparation of embodiment 2, intermediate compound I M2

In reaction flask, add successively IM1 and certain density KOH solution, stirring and dissolving, is warming up to 60-65 ℃ of temperature control stirring reaction, and TLC monitors reaction process.After reaction finishes, ice bath is cooling, slowly drips dense HCl, has a large amount of solids to separate out, regulate pH=4～5 (with no longer include solid separate out be as the criterion), suction filtration, filter cake washes with water, drying at room temperature obtains crude product.Crude product is disperseed with 0.2N HCl, suction filtration, filter cake washes with water, and vacuum-drying obtains intermediate compound I M2.Part experiment condition and the results are shown in Table 2.

Preparation condition and the result of table 2IM2

IM2 4-(4-aminobenzene sulfonamide base) toluylic acid: m.p.121.4～122.7 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 3.43 (s, 2H, H-2), 5.96 (s, 2H, H-12), 6.52 (d, 2H, J=7.8Hz, H-5), 6.98 (d, 2H, J=7.8Hz, H-4), 7.06 (d, 2H, J=7.8Hz, H-10), 7.37 (m, 2H, J=7.8Hz, H-9), 9.81 (s, 1H, H-7), 12.15 (s, 1H, H-13); ¹³c NMR (75MHz, DMSO-d ₆) δ: 40.29,113.03,119.90,124.95,129.11,130.31,130.57,137.32,153.20,173.17.

The preparation of embodiment 3,4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM1

In reaction flask, add successively IM2, K ₂cO ₃0.70g (5mmol) and acetone 8mL, stirring and dissolving, ice bath is cooling, drips acyl chlorides R ³cOCl, finishes, temperature control stirring reaction, and TLC monitors reaction process.After reaction finishes, revolve to steam and remove acetone, add suitable quantity of water to stir, drip 2N HCl adjust pH=2～3 (with no longer include solid separate out be as the criterion), standing, suction filtration, filter cake washes with water, drying at room temperature obtains crude product.By the mixed solvent recrystallization (sample for analysis is further used column chromatography purification) such as DCM-sherwood oil, EA-sherwood oil for crude product, obtain compound TM1.The experiment condition of part TM1 and the results are shown in Table 3, yield is relatively shown in Fig. 2, Fig. 3.

Preparation condition and the result of table 3 part TM1

TM1-a 4-(4-(2-chloracetyl amido) benzene sulfonamido) toluylic acid: m.p.119.1～123.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 3.44 (s, 2H, H-2), 4.27 (s, 2H, H-15), 7.01 (d, 2H, J=7.8Hz, H-5), 7.09 (d, 2H, J=7.8Hz, H-4), 7.65～7.71 (m, 4H, H-9, H-10), 10.16 (s, 1H, H-12), 10.65 (s, 1H, H-7), 12.25 (s, 1H, H-14); ¹³c NMR (75MHz, DMSO-d ₆) δ: 40.29,43.95,119.50,120.54,128.46,130.54,131.17,134.33,136.62,142.71,165.70,173.08; HR MS C ₁₆h ₁₄clN ₂o ₅s calculated value is 381.0317, and measured value is 381.0313.

TM1-b 4-(4-(3-chlorine propionamido-) benzene sulfonamido) toluylic acid: m.p.119.0～121.3 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 2.84 (t, 2H, J=6.0Hz, H-15), 3.44 (s, 2H, H-2), 3.86 (t, 2H, J=5.7Hz, H-16), 7.00 (d, 2H, J=7.8Hz, H-5), 7.10 (d, 2H, J=7.8Hz, H-4), 7.68～7.74 (m, 4H, H-9, H-10), 10.11 (s, 1H, H-12), 10.42 (s, 1H, H-7), 12.19 (s, 1H, H-14); ¹³c NMR (75MHz, DMSO-d ₆) δ: 31.11,40.20,40.96,119.18,120.53,128.39,130.51,131.14,133.77,136.59,143.12,169.12,173.05; HR MSC ₁₇h ₁₇clN ₂naO ₅s calculated value is 419.0439, and measured value is 419.0431.

TM1-c 4-(4-(4-neoprene amide group) benzene sulfonamido) toluylic acid: m.p.122.1～124.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 1.98～2.08 (m, 2H, H-16), 2.47 (m, 2H, H-15), 3.43 (s, 2H, H-2), 3.65～3.69 (t, 2H, J=6.0Hz, H-17), 6.99 (d, 2H, J=8.1Hz, H-5), 7.09 (d, 2H, J=8.1Hz, H-4), 7.68～7.72 (m, 4H, H-9, H-10), 10.11 (s, 1H, H-12), 10.34 (s, 1H, H-7), 12.19 (s, 1H, H-14); ¹³c NMR (75MHz, DMSO-d ₆) δ: 22.17,28.15,33.82,39.75,119.18,120.53,128.39,130.51,131.14,133.78,136.59,143.12,169.12,173.05; HR MS C ₁₈h ₁₉clN ₂naO ₅s calculated value is 433.0595, and measured value is 433.0601.

TM1-d 4-(4-amide-based small benzene sulfonamido) toluylic acid: m.p.105.2～107.5 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.89 (t, 3H, J=7.2Hz, H-17), 1.55～1.62 (m, 2H, H-16), 2.29 (t, 2H, J=6.9Hz, H-15), 3.43 (s, 2H, H-2), 6.99 (d, 2H, J=7.8Hz, H-5), 7.09 (d, 2H, J=7.8Hz, H-4), 7.65～7.72 (m, 4H, H-9, H-10), 10.11 (s, 1H, H-12), 10.21 (s, 1H, H-7), 12.15 (s, 1H, H-14); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.98,18.81,38.77,40.30,119.05,120.42,128.31,130.49,131.06,133.44,136.73,143.52,172.29,173.09; HR MS C ₁₈h ₁₉n ₂o ₅s calculated value is 375.1020, and measured value is 375.1024.

With reference to above-described embodiment, adopt other carboxylic acid halides R ³cOX (R ³for C2-C5 alkyl or the C1-C5 alkyl that replaced by halogen), can make R of the present invention ¹for hydrogen, R ²for R ³other 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM1.

The preparation of embodiment 4,4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3

IM3 is prepared with following 3 routes:

Route A: add alcohol R in reaction flask ¹oH 5mL, ice bath stirs, completely cooling after, drip SOCl ₂1.5mmol, dropwises recession except ice bath, and stirring at room 10min, adds IM2, is warming up to 65～80 ℃ of temperature control stirring reactions, and TLC monitors reaction process.After reaction finishes, revolve to steam and remove alcohol, add suitable quantity of water, stirring at room, drips saturated Na ₂cO ₃solution, has a large amount of solids to separate out, adjust pH=7～8 (with no longer include solid separate out be as the criterion), standing, suction filtration, filter cake washes with water, drying at room temperature obtains crude product.By methylene dichloride for crude product (DCM)-sherwood oil, ethyl acetate (EA)-mixed solvent recrystallizations such as sherwood oil, obtain Compound I M3.

Route B: add alcohol R in reaction flask ¹oH 7mL, ice bath stirs, completely cooling after, drip SOCl ₂2.0mmol, dropwises recession except ice bath, and stirring at room 10min, adds TM1, and after 15min is stirred in continuation, temperature control reacts, and TLC monitors reaction process.After reaction finishes, underpressure distillation, except desolventizing, adds water 20mL and DCM 20mL, mixes saturated Na ₂cO ₃solution regulates pH to 7～8, and stratification, collects respectively water layer and organic layer, and water layer with DCM extraction 2 times (each 20mL), merges organic layer, anhydrous Na again ₂sO ₄dry, suction filtration, filtrate decompression distillation, except desolventizing, obtains crude product.By DCM-sherwood oil mixed solvent recrystallization for crude product, obtain Compound I M3.

Route C: the TM1 in route B is replaced with IM1, and all the other operations are identical with route B, obtain Compound I M3.

The experiment condition of part IM3 and the results are shown in Table 4, the total recovery of route A/B/C is relatively shown in Fig. 1.

Preparation condition and the result of table 4 part IM3

IM3-a 4-(4-aminobenzene sulfonamide base) methyl phenylacetate: m.p.124.1～126.9 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 3.54 (s, 2H, H-2), 3.57 (s, 3H, H-13) 5.98 (s, 2H, H-12), 6.52 (d, 2H, J=7.5Hz, H-10), 6.99 (d, 2H, J=7.8Hz, H-5), 7.08 (d, 2H, J=7.8Hz, H-4), 7.38 (d, 2H, J=7.5Hz, H-9), 9.86 (s, 1H, H-7); ¹³cNMR (75MHz, DMSO-d ₆) δ: 39.78,52.07,113.02,119.83,124.85,129.10,129.55,130.33,137.62,153.21,172.03; HR MS C ₁₅h ₁₆n ₂naO ₄s calculated value is 343.0723, and measured value is 343.0730;

IM3-b 4-(4-aminobenzene sulfonamide base) Phenylacetic acid ethylester: m.p.115.6～117.8 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 1.15 (t, 3H, J=7.2Hz, H-14), 3.52 (s, 2H, H-2), 4.00～4.07 (q, 2H, J=6.9Hz, H-13), 5.96 (s, 2H, H-12), 6.52 (d, 2H, J=7.5Hz, H-10), 6.99 (d, 2H, J=7.8Hz, H-5), 7.08 (d, 2H, J=7.8Hz, H-4), 7.38 (d, 2H, J=7.5Hz, H-9), 9.83 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 14.46,39.98,60.63,113.01,119.87,124.81,129.12,129.76,130.31,137.58,153.17,171.58; HR MS C ₁₆h ₁₈n ₂naO ₄s calculated value is 357.0880, and measured value is 357.0881.

IM3-c 4-(4-aminobenzene sulfonamide base) n-propyl phenylacetate: m.p.109.4～110.6 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.81 (t, 3H, J=7.2Hz, H-15), 1.47～1.59 (m, 2H, H-14), 3.53 (s, 2H, H-2), 3.95 (t, 2H, J=6.6Hz, H-13), 5.96 (s, 2H, H-12), 6.52 (d, 2H, J=7.5Hz, H-10), 7.00 (d, 2H, J=7.8Hz, H-5), 7.08 (d, 2H, J=7.8Hz, H-4), 7.37 (d, 2H, J=7.5Hz, H-9), 9.82 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 10.61,21.91,40.04,66.06,112.98,119.91,124.83,129.09,129.82,130.28,137.55,153.23,171.60; HR MSC ₁₇h ₂₀n ₂naO ₄s calculated value is 371.1036, and measured value is 371.1028.

IM3-d 4-(4-aminobenzene sulfonamide base) butyl phenylacetate: m.p.106.4～108.8 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.83 (t, 3H, J=7.2Hz, H-16), 1.21～1.30 (m, 2H, H-15), 1.43～1.55 (m, 2H, H-14), 3.54 (s, 2H, H-2), 3.98 (t, 2H, J=6.3Hz, H-13), 5.94 (s, 2H, H-12), 6.52 (d, 2H, J=7.5Hz, H-10), 7.08 (d, 2H, J=7.8Hz, H-5), 7.16 (d, 2H, J=7.8Hz, H-4), 7.38 (d, 2H, J=7.5Hz, H-9), 9.83 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.91,18.95,30.53,40.06,64.29,112.99,119.91,124.92,129.08,129.78,130.26,137.65,153.21,171.54; HR MS C ₁₈h ₂₂n ₂naO ₄s calculated value is 385.1192, and measured value is 385.1189.

With reference to above-described embodiment, adopt other alcohol R ¹oH (R ¹for C1-C6 alkyl), can make R of the present invention ²for hydrogen, R ¹other 4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3 for C1-C6 alkyl.

The preparation of embodiment 5,4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM2

Raw material IM2 in TM1 preparation method is replaced with IM3, and all the other operations are identical with the preparation of TM1, obtain compound TM2.The experiment condition of part TM2 and the results are shown in Table 5, yield is relatively shown in Fig. 2, Fig. 3.

Preparation condition and the result of table 5 part TM2

TM2-a 4-(4-(2-chloracetyl amido) benzene sulfonamido) methyl phenylacetate: m.p.135.0～137.4 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 3.56 (s, 2H, H-2), 3.57 (s, 3H, H-14), 4.27 (s, 2H, H-15), 7.02 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.18 (s, 1H, H-12), 10.64 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 39.75,43.93,52.08,119.47,120.57,128.43,130.45,130.51,134.32,136.86,142.75,165.78,171.98; HR MS C ₁₇h ₁₇clN ₂naO ₅s calculated value is 419.0439, and measured value is 419.0444.

TM2-b 4-(4-(3-chlorine propionamido-) benzene sulfonamido) methyl phenylacetate: m.p.148.7～150.8 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 2.83 (t, 2H, J=5.7Hz, H-15), 3.57 (m, 5H, H-2, H-14), 3.86 (t, 2H, J=5.4Hz, H-16), 7.00 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.15 (s, 1H, H-12), 10.43 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 39.67,39.97,40.89,52.04,119.21,120.55,128.39,130.45,130.49,133.83,136.84,143.08,169.20,172.02; HR MS C ₁₈h ₁₉clN ₂naO ₅s calculated value is 433.0595, and measured value is 433.0600.

TM2-c 4-(4-(4-neoprene amide group) benzene sulfonamido) methyl phenylacetate: m.p.164.8～166.1 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 1.97～2.06 (m, 2H, H-16), 2.47 (m, 2H, H-15), 3.56 (s, 2H, H-2), 3.57 (s, 3H, H-14), 3.68 (t, 2H, J=6.9Hz, H-17), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.14 (s, 1H, H-12), 10.33 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 22.17,28.14,33.82,39.75,52.07,119.07,120.48,128.30,130.35,130.46,133.47,136.93,143.50,171.37,171.99; HR MS C ₁₉h ₂₁clN ₂naO ₅s calculated value is 447.0752, and measured value is 447.0751.

TM2-d 4-(4-amide-based small benzene sulfonamido) methyl phenylacetate: m.p.160.5～162.3 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.89 (t, 3H, J=7.2Hz, H-17), 1.53～1.65 (m, 2H, H-16), 2.29 (t, 2H, J=6.9Hz, H-15), 3.55 (s, 2H, H-2), 3.57 (s, 3H, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.65～7.73 (m, 4H, H-9, H-10), 10.13 (s, 1H, H-12), 10.22 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.98,18.80,22.14,40.03,52.01,119.06,119.58,120.74,126.88,128.32,129.28,133.40,137.95,143.56,172.31; HR MS C ₁₉h ₂₂n ₂naO ₅s calculated value is 413.1142, and measured value is 413.1147.

TM2-e 4-(4-(2-chloracetyl amido) benzene sulfonamido) Phenylacetic acid ethylester: m.p.129.1～131.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 1.14 (t, 3H, J=6.6Hz, H-15), 3.53 (s, 2H, H-2), 4.00～4.07 (m, 2H, H-14), 4.27 (s, 2H, H-16), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.18 (s, 1H, H-12), 10.66 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 14.37,43.90,60.63,66.88,119.47,120.61,128.43,130.45,130.57,134.34,136.83,142.72,165.72,171.46; HR MSC ₁₈h ₁₉clN ₂naO ₅s calculated value is 433.0595, and measured value is 433.0603.

TM2-f 4-(4-(3-chlorine propionamido-) benzene sulfonamido) Phenylacetic acid ethylester: m.p.144.6～145.7 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 1.14 (t, 3H, J=6.6Hz, H-15), 2.84 (t, 2H, J=6.0Hz, H-16), 3.53 (s, 2H, H-2), 3.86 (t, 2H, J=6.0Hz, H-17), 4.00～4.07 (m, 2H, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.13 (s, 1H, H-12), 10.42 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 14.43,39.73,39.97,40.95,60.59,119.15,120.55,128.41,130.45,130.52,133.79,136.94,143.24,169.14,171.49; HR MS C ₁₉h ₂₁clN ₂naO ₅s calculated value is 447.0752, and measured value is 447.0755.

TM2-g 4-(4-(3-neoprene amide group) benzene sulfonamido) Phenylacetic acid ethylester: m.p.115.2～117.3 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 1.13 (t, 3H, J=6.6Hz, H-15), 1.95～2.02 (m, 2H, H-17), 2.46 (m, 2H, H-18), 3.51 (s, 2H, H-2), 3.67 (t, 2H, J=6.6Hz, H-16), 3.98～4.05 (m, 2H, H-14), 6.99 (d, 2H, J=7.5Hz, H-5), 7.08 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.12 (s, 1H, H-12), 10.33 (s, 1H, H-7); ¹³cNMR (75MHz, DMSO-d ₆) δ: 14.44,28.12,33.87,39.97,45.32,60.64,119.06,120.51,128.30,129.01,130.42,133.44,136.95,143.46,171.39,171.50; HR MS calculated value is C ₂₀h ₂₃clN ₂naO ₅s461.0908, measured value is 461.0911.

TM2-h 4-(4-amide-based small benzene sulfonamido) methyl phenylacetate: m.p.134.7～136.6 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.89 (t, 3H, J=7.2Hz, H-18), 1.14 (t, 3H, J=6.6Hz, H-15), 1.53～1.65 (m, 2H, H-17), 2.29 (t, 2H, J=6.9Hz, H-16), 3.53 (s, 2H, H-2), 4.00～4.07 (m, 2H, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.65～7.73 (m, 4H, H-9, H-10), 10.13 (s, 1H, H-12), (10.22 s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.97,14.44,38.78,39.97,45.32,60.63,119.01,120.44,128.32,129.01,130.42,133.40,136.95,143.54,171.41,171.27; HR MS C ₂₀h ₂₄n ₂naO ₅s calculated value is 427.1298, and measured value is 427.1292.

TM2-i 4-(4-(2-chloracetyl amido) benzene sulfonamido) n-propyl phenylacetate: m.p.115.6～118.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.79 (t, 3H, J=7.5Hz, H-16), 1.46～1.55 (m, 2H, H-15), 3.56 (s, 2H, H-2), 3.94 (t, 2H, J=6.6Hz, H-14), 4.26 (s, 2H, H-17), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.14 (s, 1H, H-12), 10.33 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 10.53,21.89,40.04,43.91,66.06,119.45,120.62,128.42,130.45,130.64,134.26,136.78,142.78,165.71,171.52; HR MS C ₁₉h ₂₁clN ₂naO ₅s calculated value is 447.0752, and measured value is 447.0759.

TM2-j 4-(4-(3-chlorine propionamido-) benzene sulfonamido) n-propyl phenylacetate: m.p.99.6～101.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.78 (t, 3H, J=7.5Hz, H-16), 1.47～1.54 (m, 2H, H-15), 2.83 (t, 2H, J=7.2Hz, H-17), 3.52 (s, 2H, H-2), 3.84 (t, 2H, J=5.1Hz, H-18), 3.92 (t, 2H, J=6.6Hz, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.09 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.14 (s, 1H, H-12), 10.33 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 10.53,21.89,39.93,40.21,40.85,66.06,119.17,120.70,128.30,130.37,130.61,133.89,136.91,143.19,169.14,171.48; HR MS C ₂₀h ₂₃clN ₂naO ₅s calculated value is 461.0908, and measured value is 461.0907.

TM2-k 4-(4-(4-neoprene amide group) benzene sulfonamido) n-propyl phenylacetate: m.p.102.7～104.7 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.80 (t, 3H, J=7.5Hz, H-16), 1.46～1.58 (m, 2H, H-15), 1.97～2.05 (m, 2H, H-18), 2.47 (m, 2H, H-17), 3.54 (s, 2H, H-2), 3.68 (t, 2H, J=6.6Hz, H-19), 3.94 (t, 2H, J=6.6Hz, H-14), 7.00 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.64～7.72 (m, 4H, H-9, H-10), 10.12 (s, 1H, H-12), 10.33 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 10.56,21.89,28.12,33.83,40.07,45.31,66.06,119.03,120.54,128.30,129.00,130.41,133.42,136.92,143.46,171.41,171.53; HRMS C ₂₁h ₂₅clN ₂naO ₅s calculated value is 475.1065, and measured value is 475.1060.

TM2-l 4-(4-amide-based small benzene sulfonamido) n-propyl phenylacetate: m.p.128.7～130.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.79 (t, 3H, J=7.5Hz, H-16), 0.89 (t, 3H, J=7.2Hz, H-19), 1.46～1.55 (m, 2H, H-15), 1.55～1.64 (m, 2H, H-18), 2.29 (t, 2H, J=7.2Hz, H-17), 3.54 (s, 2H, H-2), 3.94 (t, 2H, J=6.6Hz, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.64～7.72 (m, 4H, H-9, H-10), 10.12 (s, 1H, H-12), 10.22 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 10.55,13.90,18.80,21.88,38.75,40.01,66.05,118.97,120.46,128.30,130.42,130.48,133.42,136.92,143.46,171.52,172.27; HR MS C ₂₁h ₂₆n ₂naO ₅s calculated value is 441.1455, and measured value is 441.1447.

TM2-m 4-(4-(2-chloracetyl amido) benzene sulfonamido) butyl phenylacetate: m.p.92.5～93.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.83 (t, 3H, J=7.2Hz, H-17), 1.18～1.30 (m, 2H, H-16), 1.45～1.54 (m, 2H, H-15), 3.53 (s, 2H, H-2), 3.98 (t, 2H, J=6.3Hz, H-14), 4.26 (s, 2H, H-18), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.66～7.73 (m, 4H, H-9, H-10), 10.16 (s, 1H, H-12), 10.64 (s, 1H, H-7); ¹³cNMR (75MHz, DMSO-d ₆) δ: 13.88,18.92,30.51,40.02,40.93,64.28,119.14,120.53,128.39,130.44,130.54,133.77,136.86,143.13,169.14,171.49; HR MS C ₂₀h ₂₃clN ₂naO ₅s calculated value is 461.0908, and measured value is 461.0905.

TM2-n 4-(4-(3-chlorine propionamido-) benzene sulfonamido) butyl phenylacetate: m.p.86.3～87.5 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.82 (t, 3H, J=7.2Hz, H-17), 1.18～1.31 (m, 2H, H-16), 1.45～1.54 (m, 2H, H-15), 2.84 (t, 2H, J=6.0Hz, H-18), 3.53 (s, 2H, H-2), 3.86 (t, 2H, J=6.3Hz, H-19), 3.99 (t, 2H, J=6.6Hz, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.11 (d, 2H, J=7.5Hz, H-4), 7.67～7.73 (m, 4H, H-9, H-10), 10.14 (s, 1H, H-12), 10.42 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.41,18.80,26.57,35.81,39.93,40.85,64.28,119.02,120.50,128.27,129.02,130.39,133.31,136.93,143.45,171.37,171.57; HR MS C ₂₁h ₂₅clN ₂naO ₅s calculated value is 475.1065, and measured value is 475.1058.

TM2-o 4-(4-(4-neoprene amide group) benzene sulfonamido) butyl phenylacetate: m.p.71.3～73.4 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.83 (t, 3H, J=7.2Hz, H-17), 1.18～1.30 (m, 2H, H-16), 1.45～1.52 (m, 2H, H-15), 1.97～2.08 (m, 2H, H-19), 2.47 (m, 2H, H-18), 3.53 (s, 2H, H-2), 3.68 (t, 2H, J=6.3Hz, H-20), 3.99 (t, 2H, J=6.9Hz, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.65～7.73 (m, 4H, H-9, H-10), 10.12 (s, 1H, H-12), 10.33 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.81,18.83,27.77,30.51,33.86,39.90,45.30,64.28,119.02,120.50,128.27,129.02,130.39,133.31,136.93,143.45,171.37,171.57; HR MS C ₂₂h ₂₇clN ₂naO ₅s calculated value is 489.1221, and measured value is 489.1216.

TM2-p 4-(4-amide-based small benzene sulfonamido) butyl phenylacetate: m.p.72.9～75.2 ℃; ¹h NMR (300MHz, DMSO-d ₆) δ: 0.82 (t, 3H, J=7.2Hz, H-17), 0.89 (t, 3H, J=7.8Hz, H-20), 1.18～1.30 (m, 2H, H-16), 1.45～1.55 (m, 2H, H-15), 1.55～1.65 (m, 2H, H-19), 2.29 (t, 2H, J=7.2Hz, H-18), 3.53 (s, 2H, H-2), 3.98 (t, 2H, J=6.9Hz, H-14), 7.01 (d, 2H, J=7.5Hz, H-5), 7.10 (d, 2H, J=7.5Hz, H-4), 7.64～7.73 (m, 4H, H-9, H-10), 10.12 (s, 1H, H-12), 10.22 (s, 1H, H-7); ¹³c NMR (75MHz, DMSO-d ₆) δ: 13.87,13.96,18.75,18.92,30.53,38.78,40.02,64.28,118.98,120.42,128.30,130.42,130.38,133.31,136.96,143.53,171.45,172.30; HR MS C ₂₂h ₂₈n ₂naO ₅s calculated value is 455.1611, and measured value is 455.1618.

With reference to above-described embodiment, adopt other carboxylic acid halides R ³cOX (R ³for C2-C5 alkyl or the C1-C5 alkyl that replaced by halogen), can make R of the present invention ¹for C1-C6 alkyl, R ²for R ³other 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM2.

Total synthetic route of the present invention has following 3:

Route A: with coupling makes IM1 to acetamido benzene sulfonyl halogen, IM1 deacetylation makes IM2 by equal amido phenenyl acid, and IM2 esterification makes IM3, and IM3 acylations makes TM2;

Route B: with coupling makes IM1 to acetamido benzene sulfonyl halogen, IM1 deacetylation makes IM2 by equal amido phenenyl acid, and IM2 acylations makes TM1, TM1 SOCl ₂/ alcohol legal system obtains IM3, and IM3 acylations makes TM2;

Route C: equal amido phenenyl acid and para-acetylaminobenzene sulfonyl chloride coupling are made to IM1, IM1 SOCl ₂/ alcohol method directly makes IM3, and IM3 acylations makes TM2.

In route B, contriver once wanted to use SOCl ₂/ alcohol method is directly prepared TM2 (route B ') from TM1, but experiment finds, TM1 SOCl ₂the synthetic TM2 of/alcohol method is also unsuccessful, and that obtain is not TM2 but IM3.As can be seen from Figure 1, along with alcohol carbochain R ¹growth, the yield that TM1 is converted into IM3 is first to raise and reduce, the yield of propyl ester is the highest, ethyl ester takes second place, methyl esters is minimum.The mechanism of deacylated tRNA base and esterification is all addition-elimination course, and theoretically, methyl alcohol the most easily reacts, but the yield of methyl esters is minimum, and this is probably relevant with the solvability of methyl esters; Propyl ester yield is the highest, and nucleophilie nucleus ability that may be stronger with propyl alcohol, poor solvability are relevant; The solvability of butyl ester is minimum, but its sterically hindered maximum is unfavorable for completing of esterification, so its yield is lower than propyl ester and ethyl ester.Generally speaking, as the R of TM1 ³during for chloropropyl (TM1-c), IM3 yield is the highest, as the R of TM1 ³iM3 yield minimum (except propyl ester) during for chloroethyl (TM1-b).Above-mentioned the results show, SOCl ₂/ alcohol system can a step realize aliphatic carboxylic acid esterification and N-aryl fatty amide deacylated tRNA base.

In route C, contriver be take IM1 as raw material, SOCl ₂/ alcohol is reaction reagent, directly prepares IM3, and a step realizes the esterification of carboxyl and removing of ethanoyl.In experiment, temperature of reaction and SOCl have been investigated ₂with the molar ratio of IM1 on the impact of reacting.Found that, when temperature of reaction is 75～80 ℃, SOCl ₂with the molar ratio of IM1 be 2.0: 1 o'clock, reaction effect is best, and yield is higher; Work as SOCl ₂be increased at 2.5: 1 o'clock with the molar ratio of IM1, reaction yield does not have material alterations, but Reaction time shorten a little illustrates SOCl ₂consumption speed of reaction is had to impact, but be not principal element.

From Fig. 1, can also find, the total recovery of the synthetic IM3 of pass course A is along with R ¹the growth of carbochain becomes to increase progressively trend, and the total recovery of the synthetic IM3 of pass course B is along with R ¹the growth of carbochain first increases and successively decreases, and the total recovery of the synthetic IM3 of pass course C is along with R ¹the growth of carbochain and successively decreasing.Therefore, at synthetic IM3 and TM2 (R ¹for methyl or ethyl) time, route C is better than route A or B, and at synthetic IM3 and TM2 (R ¹for propyl group or butyl) time, although route C does not preponderate on yield, with respect to route A or B, adopt the synthetic TM2 of route C more succinct efficient, the purity of crude product is also better, in industrial application, more preponderates.

The linked reaction of acyl chlorides and aromatic amine, suitable solvent is the most important.Generally speaking, the selection of solvent take can fine dissolving raw material, be conducive to product separation, reaction is fast, impurity is few and security good etc. be selection foundation.The present invention has tried out acetonitrile, acetone, DCM and THF etc., finds to make solvent with acetone, by IM2 and R ³the yield that TM1 is prepared in COCl coupling is very high, and the purity of crude product is fine, only need can obtain sterling by high yield (> 90%) through simple aftertreatment.IM3 is the esterification products of IM2, and experiment shows that the solvability of IM3 in acetone is also fine, with K ₂cO ₃make acid binding agent, IM3 and R ³the large multipotency of linked reaction of COCl completes in 5h, and impurity is few, the height that the yield of TM2 has (90% left and right), slightly low (80% left and right) having.Reaction for yield in 80% left and right, attempt rising temperature of reaction to 30～35 ℃, found that, in carbochain, chloride person's reaction yield does not rise counter falling, not chloride person's yield does not have considerable change, analyzes reason, may be that after rising temperature, the reactive behavior of α-Cl or β-Cl strengthens, by product increases (on TLC plate, impure point increases), causes yield to reduce.

Acidylate experiment (IM2 and IM3 are separately converted to TM1 and TM2) result (Fig. 2-3) shows, yield TM1 > TM2 may be main relevant with the solvability of product; Work as R ¹during for identical group, along with R ³the growth of carbochain, reaction yield reduces, and total order is CH ₂cl > C ₂h ₄cl > n-C ₃h ₆cl > n-C ₃h ₇speed of response may mainly be subject to the impact of the reactive behavior of acyl chlorides own: volume larger (sterically hindered larger), chlorine atom are more away from carbonyl (sucting electronic effect weakens), speed of response is slower, and reaction yield except with reacting finisheding degree mutually outside the Pass, also relevant with the solvability of product, be that composite factor determines; Work as R ³during for identical group, R ¹for the yield of methyl is higher than ethyl, reacting finisheding degree is main determining factor, and R ¹for the yield of propyl group or butyl changes, be obviously composite factor in action.

The PPAR determination of activity of embodiment 6,4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives

HepG2 cell is inoculated in to 96 orifice plates, 1.5 * 10 ⁴individual/hole, with the low sugar DMEM substratum that contains 100U/mL Streptomycin sulphate and penicillin, is 37 ℃, CO in temperature ₂gas volume fraction is overnight incubation under 5% condition, according to transfection reagent specification sheets, carry out plasmid transfection, transfection plasmid comprises the plasmid phRL-TK with PPAR response element and Photinus pyralis LUC reporter gene, after transfection 24h, use the substratum that contains testing sample instead, each testing sample is established two multiple holes, set up blank (cell of untransfected) simultaneously, negative control (the cell of transfection, do not add testing sample) and the positive control (cell of transfection, add pioglitazone), after continuing to cultivate 24h, by luciferase reporter gene detection kit (Promega), detect uciferase activity, according to the chemiluminescence intensity L value detecting, calculate exciting rate: exciting rate (%)=[(L1 _sample-L1 _blank)/(L1 _negative-L1 _blank)]/[(L2 _sample _product-L2 _blank)/(L2 _negative-L2 _blank)] * 100%, the chemiluminescence intensity that wherein L1 is Photinus pyralis LUC, L2 is the chemiluminescence intensity of internal reference renilla luciferase.The active detected result of PPAR of part 4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives is in Table 6.The structure of IM2, IM3, TM1 and TM2 and PPAR agonist activity graph of a relation are shown in Fig. 4, Fig. 5.

The PPAR of table 6 part 4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives is active

As can be seen from Table 6,4-(4-aminobenzene sulfonamide base) phenylacetic acid derivatives IM3-a～IM3-d, TM1-a～TM1-d and TM2-a～TM2-p show PPAR agonist activity more or less, wherein the relative exciting rate of the PPAR of TM2-a, TM2-e, TM2-f and TM2-i (be take pioglitazone as reference, its activity is 100%) reach more than 58%, be respectively 58.22%, 66.43%, 70.29%, 81.97%.

Experimental study also finds, except the listed 4-of table 6 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, other 4-of the present invention (4-aminobenzene sulfonamide base) phenylacetic acid derivatives also all shows PPAR agonist activity more or less.From table 6 and Fig. 4-5, can find out, the general sequence of the relatively exciting rate of PPAR is TM2 > IM3 > TM1, show amino in 4-(4-aminobenzene sulfonamide base) toluylic acid molecule and carboxyl all modification person's (TM2) activity be better than amino or carboxyl modification person (IM3 separately, TM1), amino and carboxyl is not the indispensable pharmacophoric group of bioactive molecule, and in TM2, R ³with the activity integral body of halogen atom, be better than and be not with halogen atom person, overall activity shows as XCH ₂> X (CH ₂) ₃> X (CH ₂) ₂, illustrate that halogen atom may be another important factor that determines this quasi-molecule activity.

Finally explanation is, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by with reference to above-described embodiment, invention has been described, but those of ordinary skill in the art is to be understood that, can to it, make various changes in the form and details, and not depart from the spirit and scope of the present invention that appended claims limits.

Claims

2. 4-according to claim 1 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that R ¹for hydrogen or C1-C4 alkyl, R ³for C2-C3 alkyl or the C1-C3 alkyl that replaced by fluorine or chlorine.

3. 4-according to claim 2 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that R ¹for hydrogen or C1-C4 straight chained alkyl, R ³for C2-C3 straight chained alkyl or the C1-C3 straight chained alkyl that replaced by chlorine.

4. 4-according to claim 3 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that R ³for n-propyl, chloromethyl, 2-chloroethyl or 3-chloropropyl.

5. 4-according to claim 4 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that R ¹for C1-C4 straight chained alkyl, R ²for R ³cO base, R ³for chloromethyl, 2-chloroethyl or 3-chloropropyl.

6. 4-according to claim 5 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that R ¹for methyl, R ³for chloromethyl; Or, R ¹for ethyl, R ³for chloromethyl or 2-chloroethyl; Or, R ¹for n-propyl, R ³for chloromethyl.

7. the preparation method of 4-claimed in claim 1 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that, comprises the following steps:

C. by intermediate compound I M2 and carboxylic acid halides R ³cOCl carries out acylation reaction, makes R ¹for hydrogen, R ²for R ³the 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM1;

E. by Compound I M3 and carboxylic acid halides R ³cOCl carries out acylation reaction, makes R ¹for C1-C6 alkyl, R ²for R ³the 4-of CO base (4-aminobenzene sulfonamide base) phenylacetic acid derivatives TM2;

In above-mentioned reaction formula, X is halogen.

8. the preparation method of 4-according to claim 7 (4-aminobenzene sulfonamide base) phenylacetic acid derivatives, is characterized in that, comprises the following steps:

9. the 4-described in claim 1-6 any one (the 4-aminobenzene sulfonamide base) application of phenylacetic acid derivatives in preparing antidiabetic medicine.

10. application according to claim 9, is characterized in that, described antidiabetic medicine is peroxisome proliferation-activated receptors agonist class antidiabetic medicine.