CN102351702B - Synthesis method of hypoglycemic drug molecule TAPA (2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester) - Google Patents
Synthesis method of hypoglycemic drug molecule TAPA (2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester) Download PDFInfo
- Publication number
- CN102351702B CN102351702B CN201110237472.5A CN201110237472A CN102351702B CN 102351702 B CN102351702 B CN 102351702B CN 201110237472 A CN201110237472 A CN 201110237472A CN 102351702 B CN102351702 B CN 102351702B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- tri
- alkoxy
- acid
- washing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Relating to drug molecules with a hypoglycemic function, the invention provides a synthesis method of hypoglycemic drug molecule TAPA. The method comprises the steps of: converting the raw material of 2, 3, 4-trialkoxybenzaldehyde 1 into 3-(2, 3, 4-trialkoxy) phenylpropionic acid 2 with Meldrum acid; under the action of polyphosphoric acid, subjecting 2 to intramolecular acylation so as to obtain corresponding hydrindone 3; subjecting 3 and a Grignard reagent to an addition reaction, then conducting acidifying elimination so as to obtain hydrindene 4, carrying out pyrolysis to 4 under the effect of organic base so as to directly obtain 2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic acid 5; and finally in the presence of thionyl chloride, reacting 5 with anhydrous alcohol, thus obtaining the target product 2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester (TATP). According to the method of the invention, each step of operation is easy to separate, the route is short, the yield is high, and the reagents are all cheap reagents in common use. Thus, the method provided in the invention is suitable for mass production.
Description
Technical field
The present invention relates to have the drug molecule of function of blood sugar reduction, especially contain 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] synthetic method of acetic ester (TAPA) structural compounds.
Background technology
Diabetes are a kind of sugar being caused by insulin deficit, protein and lipodystrophy disease, and pathogenesis is complicated, have become the third-largest disease of harm humans health.In recent years, due to the change of growth in the living standard, dietary structure, rhythm of life and the few moving factors such as mode of life of sitting that day is becoming tight, global onset diabetes rate rapid development more.According to the World Health Organization, estimate, by 2025, global maturity-onset diabetes patient's number will increase to 300,000,000, and diabetes mellitus in China patient number will reach 4,000 ten thousand, and incidence trend is quite severe, has become the Social Events that threatens people ' s health.At present, the medicine for the treatment of diabetes mainly contains sulphur urine class, biguanides, thiazolidinediones and alpha-glucosidase inhibitor etc., the shortcomings such as yet these antidiabetic medicines still exist clinically, and curative effect is shorter, side effect is large, treatment cost is higher, therefore the antidiabetic medicine of researching and developing novel texture is very urgent, and has important economic benefit and social benefit.
2-[(2; 3; 4-tri-alkoxy-6-acyl group) phenyl] the drug molecule TAPA of acetic ester structure has good physiologically active (referring to Chinese patent CN101891618A); especially 2-[(2; 3; 4-trimethoxy-6-capryloyl) phenyl] ethyl acetate (TAPA1) can activate adenylic acid (AMP) activated protein kinase (AMPK); and on cell biological test experiments, proved that it can reach with 1% drug level the ability that improves equally AMPK α phosphonic acids level with N1,N1-Dimethylbiguanide; can be used as antidiabetic drug candidate, there is the application prospect of good antidiabetic medicine.
R
1the alkyl of=C1~C5, R
2the alkyl of=C1~C10, R
3the alkyl of=C1~C5
The applicant is in China invention CN101891618A; from the 2-[(2 that synthesized of an intermediate high yield, 3,4-tri-alkoxy-6-acyl group) phenyl] the drug molecule TAPA of acetic ester structure; but its route is longer, wherein also to uses and there is highly toxic perosmic anhydride (OsO
4) reagent is oxidized to the adjacent glycol of cis by two keys, these weak points have limited a large amount of synthetic and application of TAPA, therefore all require further improvement.
Summary of the invention
Object of the present invention aim to provide a class with 2,3,4-tri-alkoxy phenyl aldehyde for raw material, method is easy, efficiency and the higher hypoglycemic drug molecule 2-[(2 of productive rate, 3,4-trimethoxy-6-acyl group) phenyl] synthetic method of acetic ester (TAPA).
Hypoglycemic drug molecule TAPA of the present invention is 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] acetic ester, its structural formula is as follows:
R
1the alkyl of=C1~C5, R
2the alkyl of=C1~C10, R
3the alkyl of=C1~C5
The synthetic route of hypoglycemic drug molecule TAPA of the present invention is as follows:
R
1the alkyl of=C1~C5, R
2the alkyl of=C1~C10, R
3the alkyl of=C1~C5
The synthetic method of hypoglycemic drug molecule TAPA of the present invention comprises the following steps:
1) by 2,2-dimethyl-1,3-diox-4,6-diketone (Meldrum acid) is dissolved in triethylammonium formate (TEAF) solution, makes 0.2~1.0mol/L solution, add again 2, after 3,4-tri-alkoxy phenyl aldehyde reaction, reactant is obtained to 3-(2 after acidifying, extraction, washing, dry, concentrated, purifying, 3,4-tri-alkoxy) phenylpropionic acid;
2), by 3-(2,3,4-tri-alkoxy) phenylpropionic acid and polyphosphoric acid (PPA) reacting by heating, after reactant is cooling, through extraction, washing, after dry, concentrated, purifying, obtain hydrindenone;
3) hydrindenone is dissolved in haloalkane solvent, makes 0.10~0.30mol/L solution, add Grignard reagent R
2after MgX reaction, reactant is through cooling, acidifying, and extraction, washing, obtain hydrogenation indenes after dry, concentrated, purifying, at Grignard reagent R
2in MgX, R
2=C1~C10 alkyl, X=Cl, Br, I;
4) hydrogenation indenes is dissolved in haloalkane solvent, makes 0.01~0.10mol/L solution, be filled with after ozone gas, add after organic bases reaction, after acidifying, extraction, washing, dry, concentrated, purifying, obtain 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] acetic acid;
5) by 2-[(2; 3; 4-tri-alkoxy-6-acyl group) phenyl] acetic acid is dissolved in absolute alcohol; make 0.1~0.5mol/L solution; add after sulfur oxychloride reaction, decompression is lower steams except excessive alcohol, obtains hypoglycemic drug molecule 2-[(2 after purifying again; 3,4-tri-alkoxy-6-acyl group) phenyl] acetic ester (TAPA).
In step 1) in, described by 2,2-dimethyl-1,3-diox-4,6-diketone (Meldrum acid) is dissolved in triethylammonium formate (TEAF) solution, can be by 2,2-dimethyl-1 at 0~120 ℃, 3-diox-4,6-diketone (Meldrum acid) is dissolved in triethylammonium formate (TEAF) solution; Described 2,2-dimethyl-1,3-diox-4, the consumption of 6-diketone preferably 2,3,1.0~1.2 times of 4-tri-alkoxy phenyl aldehyde mole number; The concentration of described reactant is 0.5~0.7mol/L preferably; The reagent of described acidifying can be selected mineral acid etc., and described mineral acid is hydrochloric acid preferably, and described acidifying is preferably acidified to pH=1.0~2.0; Described extraction is optional to be extracted with ethyl acetate; Described washing can be selected saturated sodium-chloride washing; Described dry anhydrous sodium sulphate or the anhydrous magnesium sulfates etc. can selected are dry.
In step 2) in, the temperature of described reaction can be 0~100 ℃; The consumption of described polyphosphoric acid is 17~20 times of 3-(2,3,4-tri-alkoxy) phenylpropionic acid weight preferably; Described cooling employing adds frozen water cooling; Described extraction is optional to be extracted with ethyl acetate; Described washing can be selected saturated sodium-chloride washing; Described dry anhydrous sodium sulphate or the anhydrous magnesium sulfates etc. can selected are dry.
In step 3) in, the described temperature that hydrindenone is dissolved in haloalkane solvent can be-20~40 ℃; The described Grignard reagent R that adds
2mgX can add Grignard reagent R in protection of inert gas
2mgX; Described halogenated hydrocarbon solvent can be selected from the halohydrocarbon of C1~C4 etc., preferably methylene dichloride or trichloromethane etc.; The concentration of described hydrindenone is 0.15~0.20mol/L preferably; Described Grignard reagent consumption is 3~4 times of hydrindenone mole number preferably; The reagent of described acidifying can be selected mineral acid, and described mineral acid is hydrochloric acid preferably, and described acidifying is preferably acidified to pH=1.0~2.0; Preferably 0~5 ℃ of the temperature of described acidifying; Described extraction can be selected dichloromethane extraction; Described washing can be selected saturated sodium-chloride washing; Described dry anhydrous sodium sulphate or the anhydrous magnesium sulfates etc. can selected are dry.
In step 4) in, the described temperature that hydrogenation indenes is dissolved in haloalkane solvent can be-100~50 ℃; Described halogenated hydrocarbon solvent can be selected from the halohydrocarbon of C1~C4 etc., preferably methylene dichloride or trichloromethane etc.; The concentration of described hydrogenation indenes is 0.03~0.05mol/L preferably; Described organic bases can be selected triethylamine or 2,6-lutidine or pyridine etc., and the consumption of described organic bases is 1.5~2.0 times of hydrogenation indenes mole number preferably; The reagent of described acidifying can be selected mineral acid, hydrochloric acid preferably, and described acidifying is preferably acidified to pH=1.0~2.0; Described extraction can be selected dichloromethane extraction; Described washing can be selected saturated sodium-chloride washing; Described dry anhydrous sodium sulphate or the anhydrous magnesium sulfates etc. can selected are dry.
In step 5) in, described by 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] temperature that is dissolved in absolute alcohol of acetic acid can be-20~40 ℃, described 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] the concentration 0.2~0.3mol/L preferably of acetic acid; The consumption of described sulfur oxychloride is 2-[(2 preferably, 3,4-tri-alkoxy-6-acyl group) phenyl] 1.0~1.5 times of acetic acid mole number.
The present invention for raw material, is first converted into 3-(2,3,4-tri-alkoxy) phenylpropionic acid with Meldrum acid with 2,3,4-tri-alkoxy phenyl aldehyde; Under polyphosphoric acid effect, 3-(2,3,4-tri-alkoxy) phenylpropionic acid acidylate in molecule obtains corresponding hydrindenone; Hydrindenone and Grignard reagent addition again acidifying elimination obtain hydrogenation indenes, and the cracking under organic bases effect of hydrogenation indenes and ozone gas directly obtains 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] acetic acid; Finally under sulfur oxychloride exists, 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] acetic acid reacts with absolute alcohol and obtains target product 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] acetic ester TAPA.Each step operation is separated simple, and route is shorter, and productive rate is higher, and reagent is conventional cheap reagent, is applicable to a large amount of production.
Embodiment
Below by embodiment, the present invention is further illustrated.
Embodiment 1
Step 1 is synthesized 3-(2,3,4-trimethoxy) phenylpropionic acid
By 2,2-dimethyl-1,3-diox-4,6-diketone (Meldrum acid) (13.2g, 91.7mmol) be dissolved in triethylammonium formate solution (135mL), make 0.7mol/L solution, then add 2,3,4-TMB (15.0g, 76.4mmol).Reactant is cooled to 0 ℃ after 95~100 ℃ of heated and stirred 5h, stirs the lower 6mol/L of using hcl acidifying to pH=1.After separatory, water is extracted with ethyl acetate (15mL * 3), merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.After filtration, concentrated, purifying obtains 3-(2,3,4-trimethoxy) phenylpropionic acid (compound 2, R
1=CH
3), productive rate 76%.White solid, M.p.75~77 ℃; IR (film): v
max=3434,2971,2936,2830,1709,1495,1468,1416,1277,1098,1051cm
-1;
1h-NMR (400MHz, CDCl
3) δ 2.64 (t, J=7.8Hz, 2H, Ar-CH
2), 2.89 (t, J=7.8Hz, 2H, CH
2cOOH), 3.84 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 3.90 (s, 3H, OCH
3), 6.60 (d, J=8.5Hz, 1H, ArH), 6.85 (d, J=8.5Hz, 1H, ArH);
13c-NMR (100MHz, CDCl
3) δ 25.1,34.8,55.9,60.7,60.8,107.1,123.7,126.0,142.2,151.9,152.5,179.4; MS (ESI): m/z 263 (M+Na
+); Ultimate analysis: calculated value (C
12h
16o
5): C, 59.99; H, 6.71. measured value: C, 59.61; H, 6.87.
Synthetic 4,5, the 6-of step 2 trimethoxy-2,3-bihydrogen-1-indenone
3-(2,3,4-trimethoxy) phenylpropionic acid (15.0g, 62.4mmol) and polyphosphoric acid (287g) are stirred and spent the night at 55 ℃.Under cooling, add frozen water 500mL, after separatory, water is extracted with ethyl acetate (150mL * 3), merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.After filtration, concentrated, purifying obtains 4,5,6-trimethoxy-2,3-bihydrogen-1-indenone (compound 3, R
1=CH
3), productive rate 80%.White solid, M.p.84~86 ℃; IR (film): v
max=3436,2928,2843,1709,1601,1473,1421,1347,1317,1279,1236,1206,1132,1094,1030cm
-1;
1h-NMR (400MHz, CDCl
3) δ 2.68 (t, J=5.6Hz, 2H, Ar-CH
2), 3.05 (t, J=5.6Hz, 2H, CH
2cO), 3.89 (s, 3H, OCH
3), 3.96 (s, 3H, OCH
3), 3.97 (s, 3H, OCH
3), 7.03 (s, 1H, ArH);
13c-NMR (100MHz, CDCl
3) δ 22.4,36.1,56.2,60.6,61.1,100.6,132.5,141.6,147.6,150.0,154.2,206.0; MS (ESI): m/z 245.1 (M+Na
+).
The synthetic 1-of step 3 n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes
4,5,6-trimethoxy-2,3-bihydrogen-1-indenone (10g, 45.0mmol) is dissolved in dry methylene chloride (200mL), under nitrogen atmosphere, under 0 ℃ of stirring, drip n-heptyl magnesium bromide Grignard reagent (2.0M, 68.0mL), add rear room temperature and continue to stir 3h to reacting completely.Cooling lower dropping 6mol/L hydrochloric acid (100mL), stirs 1h.After separatory, dichloromethane extraction for water (50mL * 3), merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.After filtration, concentrated, purifying obtains 1-n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes (compound 4, R
1=CH
3, R
2=n-C
7h
15), productive rate 78%.Yellow oil, IR (film): v
max=3438,2928,2854,1574,1464,1415,1115,1040cm
-1;
1h-NMR (400MHz, CDCl
3) δ 0.92 (t, J=5.3Hz, 3H, CH
3), 1.25-1.50 (m, 8H, (CH
2)
4), 1.65-1.75 (m, 2H, CH
2c
5h
11), 2.51 (t, J=6.8Hz, 2H, CH
2c
6h
13), 3.35 (s, 2H, ArCH
2) 3.90 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.02 (s, 3H, OCH
3), 6.18 (s, 1H, CH=C), 6.72 (s, 1H, ArH);
13c-NMR (100MHz, CDCl3) δ 14.0,22.6,27.6,27.9,29.1,29.4,29.5,31.8,35.3,56.3,60.1,61.0,98.7,127.3,139.2,141.8,144.2,149.3,153.0; MS (ESI) m/z 327.2 (M+Na
+, 100%); Ultimate analysis: calculated value (C
19h
28o
3): C, 74.96; H, 9.27. measured value: C, 74.92; H, 9.08.
Step 4 is synthesized 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid
1-n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes (5.0g, 16.4mmol) be dissolved in dry methylene dichloride (328mL), at-78 ℃, pass into ozone gas to system and become after basket, add again triethylamine (5.0mL, 33.0mmol), stirred overnight at room temperature.Add after hcl acidifying, after separatory, dichloromethane extraction for water (50mL * 3), merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.Filter, concentrated, purifying obtains 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid (compound 5, R
1=CH
3, R
2=n-C
7h
15), productive rate 60%.White solid, M.p.105~109 ℃; IR (film): v
max=3434,2959,2930,2850,1703,1677,1597,1405,1334,1246,1226,1188,1142,1106,1053cm
-1;
1h-NMR (400MHz, CDCl
3) δ 0.87 (t, J=6.9Hz 3H, CH
3), 1.20-1.40 (m, 8H, (CH
2)
4), 1.60-1.75 (m, 2H, CH
2c
5h
11), 2.89 (t, J=6.6Hz, 2H, ArCOCH
2), 3.85-3.95 (m, 11H, 3OCH
3, CH
2cOOH), 7.05 (s, 1H, ArH);
13c-NMR (100MHz, CDCl
3) δ 14.0,22.6,24.4,29.1,29.2,31.6,32.4,40.9,56.2,60.8,61.1,108.5,121.4,133.2,145.5,152.0,152.9,176.4,203.8; MS (ESI): m/z 375.2 (M+Na
+, 100%); Ultimate analysis, calculated value (C
19h
28o
6): C, 64.75; H, 8.01. measured value: C, 64.84; H, 7.78.
Step 5 is synthesized 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] ethyl acetate
2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid (12.9g, 36.4mmol) is dissolved in dehydrated alcohol (120mL), drips sulfur oxychloride (3.5mL) under 0 ℃ of stirring, and reaction mixture is at room temperature stirred and spent the night.Under decompression, boil off excess ethyl alcohol, after purifying, obtain 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] ethyl acetate (compound TAPA1, R
1=CH
3, R
2=n-C
7h
15, R
3=C
2h
5), productive rate 96%.White solid, M.p.50~52 ℃; IR (film): v
max=3437,2931,2856,1737,1681,1494,1454,1403,1334,1163,1138,1117,1030cm
-1;
1h-NMR (400MHz, CDCl
3) δ 0.83-0.91 (m, 3H, CH
3), 1.20-1.50 (m, 11H, (CH
2)
4, CH
3), 1.50-1.85 (m, 2H, CH
3cH
2), 2.85 (t, J=7.6Hz, 2H, COCH
2), 3.82-3.95 (m, 11H, 3OCH
3, ArCH
2), 4.15 (q, J=7.2Hz, 2H, OCH
2cH
3), 7.05 (s, 1H, ArH);
13c-NMR (100MHz, CDCl
3) δ 14.0,14.2,22.6,24.4,29.1,29.2,31.7,31.9,41.0,56.2,60.6,60.8,61.1,108.5,121.8,133.6,145.1,151.8,152.8,172.1,203.1; MS (ESI): m/z403.2 (M+Na
+, 100%); Ultimate analysis, calculated value (C
21h
32o
6): C, 66.29; H, 8.48. measured value: C, 66.16; H, 8.72.
Embodiment 2
Step 1 is synthesized 3-(2,3,4-trimethoxy) phenylpropionic acid
By 2,2-dimethyl-1,3-diox-4,6-diketone (Meldrum acid) (76.4mmol) is dissolved in triethylammonium formate solution, makes 0.5mol/L solution, then adds 2,3,4-TMB (76.4mmol), is cooled to 0 ℃ after reacting completely under uniform temp, stir lower to hcl acidifying, after separatory, water is extracted with ethyl acetate, and merges organic phase, with saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying.After filtration, concentrated, purifying obtains 3-(2,3,4-trimethoxy) phenylpropionic acid (compound 2, R
1=CH
3), productive rate 75%.
Synthetic 4,5, the 6-of step 2 trimethoxy-2,3-bihydrogen-1-indenone
3-(2,3,4-trimethoxy) phenylpropionic acid (62.4mmol) and polyphosphoric acid (255g) are stirred and spent the night at 80 ℃.Under cooling, add frozen water 500mL, after separatory, water is extracted with ethyl acetate, and merges organic phase, with saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying.After filtration, concentrated, purifying obtains 4,5,6-trimethoxy-2,3-bihydrogen-1-indenone (compound 3, R
1=CH
3), productive rate 78%.
The synthetic 1-of step 3 n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes
4,5,6-trimethoxy-2,3-bihydrogen-1-indenone (45.0mmol) is dissolved in dry methylene chloride (200mL), under nitrogen atmosphere, under 0 ℃ of stirring, drip n-heptyl magnesium chloride Grignard reagent (136mmol), add rear room temperature and continue to stir 3h to reacting completely.Cooling lower dropping hcl acidifying, stirs 1h.After separatory, water dichloromethane extraction, merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.After filtration, concentrated, purifying obtains 1-n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes (compound 4, R
1=CH
3, R
2=n-C
7h
15), productive rate 75%.
Step 4 is synthesized 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid
1-n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes (16.4mmol) is dissolved in dry methylene dichloride (328mL), at-78 ℃, passes into ozone gas to system and becomes after basket, then add pyridine (33.0mmol), stirred overnight at room temperature.Add after hcl acidifying, after separatory, water dichloromethane extraction, merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.Filter, concentrated, purifying obtains 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid (compound 5, R
1=CH
3, R
2=n-C
7h
15), productive rate 65%.
Step 5 is synthesized 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] ethyl acetate
2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid (36.4mmol) is dissolved in dehydrated alcohol (180mL), drips sulfur oxychloride (3.0mL) under 0 ℃ of stirring, and reaction mixture is at room temperature stirred and spent the night.Under decompression, boil off excess ethyl alcohol, after purifying, obtain 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] ethyl acetate (compound TAPA1, R
1=CH
3, R
2=n-C
7h
15, R
3=C
2h
5), productive rate 94%.
Embodiment 3
Step 1 is synthesized 3-(2,3,4-trimethoxy) phenylpropionic acid
By 2,2-dimethyl-1,3-diox-4,6-diketone (Meldrum acid) (84.0mmol) is dissolved in triethylammonium formate solution, makes 0.6mol/L solution, then adds 2,3,4-TMB (76.4mmol), is cooled to 0 ℃ after reacting completely under uniform temp, stir lower to hcl acidifying, after separatory, water is extracted with ethyl acetate, and merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.After filtration, concentrated, purifying obtains 3-(2,3,4-trimethoxy) phenylpropionic acid (compound 2, R
1=CH
3), productive rate 78%.
Synthetic 4,5, the 6-of step 2 trimethoxy-2,3-bihydrogen-1-indenone
3-(2,3,4-trimethoxy) phenylpropionic acid (62.4mmol) and polyphosphoric acid (300g) are stirred and spent the night at 65 ℃.Under cooling, add frozen water 500mL, after separatory, water is extracted with ethyl acetate, and merges organic phase, with saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying.After filtration, concentrated, purifying obtains 4,5,6-trimethoxy-2,3-bihydrogen-1-indenone (compound 3, R
1=CH
3), productive rate 76%.
The synthetic 1-of step 3 n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes
4,5,6-trimethoxy-2,3-bihydrogen-1-indenone (45.0mmol) is dissolved in dry trichloromethane (200mL), under nitrogen atmosphere, under 0 ℃ of stirring, drip n-heptyl magnesium iodide Grignard reagent (136mmol), add rear room temperature and continue to stir 3h to reacting completely.Cooling lower dropping hcl acidifying, stirs 1h.After separatory, water dichloromethane extraction, merges organic phase, with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.After filtration, concentrated, purifying obtains 1-n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes (compound 4, R
1=CH
3, R
2=n-C
7h
15), productive rate 75%.
Step 4 is synthesized 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid
1-n-heptyl-4,5,6-trimethoxy-3-hydrogen-indenes (16.4mmol) is dissolved in dry trichloromethane (540mL), at-78 ℃, pass into ozone gas to system and become after basket, then add 2,6-lutidine (26.2mmol), stirred overnight at room temperature.Add after hcl acidifying, after separatory, water dichloromethane extraction, merges organic phase, with saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying.Filter, concentrated, purifying obtains 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid (compound 5, R
1=CH
3, R
2=n-C
7h
15), productive rate 63%.
Step 5 is synthesized 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] ethyl acetate
2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] acetic acid (36.4mmol) is dissolved in dehydrated alcohol (146mL), drips sulfur oxychloride (4.0mL) under 0 ℃ of stirring, and reaction mixture is at room temperature stirred and spent the night.Under decompression, boil off excess ethyl alcohol, after purifying, obtain 2-[(2, the positive capryloyl of 3,4-trimethoxy-6-) phenyl] ethyl acetate (compound TAPA1, R
1=CH
3, R
2=n-C
7h
15, R
3=C
2h
5), productive rate 97%.
Claims (5)
1. the synthetic method of hypoglycemic drug molecule TAPA, is characterized in that comprising the following steps:
1) by 2,2-dimethyl-1,3-diox-4,6-diketone is dissolved in triethylammonium formate solution, makes 0.2~1.0mol/L solution, add again 2, after 3,4-tri-alkoxy phenyl aldehyde reaction, reactant is obtained to 3-(2 after acidifying, extraction, washing, dry, concentrated, purifying, 3,4-tri-alkoxy) phenylpropionic acid; Described by 2,2-dimethyl-1,3-diox-4,6-diketone is dissolved in triethylammonium formate solution, be at 0~120 ℃ by 2,2-dimethyl-1,3-diox-4,6-diketone is dissolved in triethylammonium formate solution; Described 2,2-dimethyl-1,3-diox-4, the consumption of 6-diketone is 1.0~1.2 times of 2,3,4-tri-alkoxy phenyl aldehyde mole number; The concentration of described reactant is 0.5~0.7mol/L;
The reagent of described acidifying is mineral acid, and described mineral acid is hydrochloric acid, and described acidifying is to be acidified to pH=1.0~2.0; Described extraction choosing is extracted with ethyl acetate; Saturated sodium-chloride washing is selected in described washing; Described dry select anhydrous sodium sulphate or anhydrous magnesium sulfate drying;
2), by 3-(2,3,4-tri-alkoxy) phenylpropionic acid and polyphosphoric acid reacting by heating, after reactant is cooling, through extraction, washing, after dry, concentrated, purifying, obtain hydrindenone;
3) hydrindenone is dissolved in haloalkane solvent, make 0.10~0.30mol/L solution, add after Grignard reagent R2MgX reaction, reactant is through cooling, acidifying, extraction, washing, obtain hydrogenation indenes after dry, concentrated, purifying, in Grignard reagent R2MgX, R2=C1~C10 alkyl, X=Cl, Br, I; The reagent of described acidifying is selected hydrochloric acid, and described acidifying is to be acidified to pH=1.0~2.0; The temperature of described acidifying is 0~5 ℃; Dichloromethane extraction is selected in described extraction; Saturated sodium-chloride washing is selected in described washing; Described dry select anhydrous sodium sulphate or anhydrous magnesium sulfate drying;
4) hydrogenation indenes is dissolved in haloalkane solvent, makes 0.01~0.10mol/L solution, be filled with after ozone gas, add after organic bases reaction, after acidifying, extraction, washing, dry, concentrated, purifying, obtain 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] acetic acid; The described temperature that hydrogenation indenes is dissolved in haloalkane solvent is-100~50 ℃; Described halogenated hydrocarbon solvent is selected from methylene dichloride or trichloromethane; The concentration of described hydrogenation indenes is 0.03~0.05mol/L; Described organic bases is selected triethylamine or 2,6-lutidine or pyridine, and the consumption of described organic bases is 1.5~2.0 times of hydrogenation indenes mole number; The reagent of described acidifying is selected hydrochloric acid, and described acidifying is to be acidified to pH=1.0~2.0; Dichloromethane extraction is selected in described extraction; Saturated sodium-chloride washing is selected in described washing; Described dry select anhydrous sodium sulphate or anhydrous magnesium sulfate drying;
5) by 2-[(2; 3; 4-tri-alkoxy-6-acyl group) phenyl] acetic acid is dissolved in absolute alcohol; make 0.1~0.5mol/L solution; add after sulfur oxychloride reaction, decompression is lower steams except excessive alcohol, obtains hypoglycemic drug molecule 2-[(2 after purifying again; 3,4-tri-alkoxy-6-acyl group) phenyl] acetic ester.
2. the synthetic method of hypoglycemic drug molecule TAPA as claimed in claim 1, is characterized in that in step 2) in, the temperature of described reaction is 0~100 ℃; The consumption of described polyphosphoric acid is 17~20 times of 3-(2,3,4-tri-alkoxy) phenylpropionic acid weight.
3. the synthetic method of hypoglycemic drug molecule TAPA as claimed in claim 1, is characterized in that in step 2) in, described cooling employing adds frozen water cooling; Described extraction choosing is extracted with ethyl acetate; Saturated sodium-chloride washing is selected in described washing; Described dry select anhydrous sodium sulphate or anhydrous magnesium sulfate drying.
4. the synthetic method of hypoglycemic drug molecule TAPA as claimed in claim 1, is characterized in that in step 3), and the described temperature that hydrindenone is dissolved in haloalkane solvent is-20~40 ℃; The described Grignard reagent R2MgX that adds adds Grignard reagent R2MgX in protection of inert gas; Described halogenated hydrocarbon solvent is selected from methylene dichloride or trichloromethane; The concentration of described hydrindenone is 0.15~0.20mol/L; Described Grignard reagent consumption is 3~4 times of hydrindenone mole number.
5. the synthetic method of hypoglycemic drug molecule TAPA as claimed in claim 1, it is characterized in that in step 5), described by 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] temperature that is dissolved in absolute alcohol of acetic acid is-20~40 ℃, described 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] concentration of acetic acid is 0.2~0.3mol/L; The consumption of described sulfur oxychloride is 2-[(2,3,4-tri-alkoxy-6-acyl group) phenyl] 1.0~1.5 times of acetic acid mole number.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110237472.5A CN102351702B (en) | 2011-08-18 | 2011-08-18 | Synthesis method of hypoglycemic drug molecule TAPA (2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester) |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110237472.5A CN102351702B (en) | 2011-08-18 | 2011-08-18 | Synthesis method of hypoglycemic drug molecule TAPA (2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester) |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102351702A CN102351702A (en) | 2012-02-15 |
CN102351702B true CN102351702B (en) | 2014-08-13 |
Family
ID=45575377
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110237472.5A Expired - Fee Related CN102351702B (en) | 2011-08-18 | 2011-08-18 | Synthesis method of hypoglycemic drug molecule TAPA (2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester) |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102351702B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102220170B1 (en) * | 2018-01-17 | 2021-02-25 | 성균관대학교산학협력단 | Ketide compounds, method for manufacturing, and use for treating diabetes thereof |
BR112021005274A2 (en) | 2018-09-22 | 2021-06-15 | Torrent Pharmaceuticals Limited | methods for producing pyrazole compounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101891618A (en) * | 2010-06-23 | 2010-11-24 | 厦门大学 | 2-[(2,3,4-trialkoxy-6-acyl) phenyl] acetic ester as well as preparation method and application thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003902860A0 (en) * | 2003-06-06 | 2003-06-26 | Daicel Chemical Industries, Ltd | Benzimidazole compounds |
CN101407459B (en) * | 2008-11-18 | 2013-03-27 | 厦门大学 | Monohydroxy-2-acyl phenylacetate, and preparation and use thereof |
CN102010336B (en) * | 2010-11-03 | 2013-09-25 | 中国科学院上海有机化学研究所 | (4R)-4-methyl-2-carbonyl valerate compound, synthesizing method and application |
-
2011
- 2011-08-18 CN CN201110237472.5A patent/CN102351702B/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101891618A (en) * | 2010-06-23 | 2010-11-24 | 厦门大学 | 2-[(2,3,4-trialkoxy-6-acyl) phenyl] acetic ester as well as preparation method and application thereof |
Non-Patent Citations (5)
Title |
---|
Masahiro Miura等.Synthesis, X-ray Analysis, and Acidolysis of exo-and endo-1-Methylindene Ozonides.《J.Am.Chem.Soc.》.1983,第105卷(第8期), |
Michael B. Smith等.臭氧化.《高等有机化学》.2010,(第1版), * |
Synthesis, X-ray Analysis, and Acidolysis of exo-and endo-1-Methylindene Ozonides;Masahiro Miura等;《J.Am.Chem.Soc.》;19830430;第105卷(第8期);第2414-2426页 * |
一锅法N,N-二甲基-4-氨基吡啶催化合成蒎酮酸酯;于静等;《有机化学》;20110731;第31卷(第7期);第1091-1094页 * |
于静等.一锅法N N-二甲基-4-氨基吡啶催化合成蒎酮酸酯.《有机化学》.2011 |
Also Published As
Publication number | Publication date |
---|---|
CN102351702A (en) | 2012-02-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW201323409A (en) | Method of producing 4,4-difluoro-3,4-dihydroisoquinoline derivative | |
CN107473962A (en) | A kind of preparation method of (R) 2 (methylenedioxy phenoxy of 4 chlorine 2) octyl propionate root resistance agent | |
CN102351702B (en) | Synthesis method of hypoglycemic drug molecule TAPA (2-[(2, 3, 4-trialkoxy-6-acyl) phenyl] acetic ester) | |
CN102382001A (en) | Synthesis method for ortho amino aromatic formic acid aryl ester derivatives | |
Liu et al. | Synthesis and anthelmintic activity of osthol analogs against Dactylogyrus intermedius in goldfish | |
CN111747921A (en) | Preparation method and medical application of daphnetin derivative | |
CN110577547B (en) | Synthesis method of biotin intermediate | |
CN109438315A (en) | A kind of preparation method of capillary | |
CN110272400B (en) | Synthesis method of 2-trifluoromethyl substituted furan compound and derivative thereof | |
CN104086596A (en) | Phosphorescent iridium complex, and preparation method and application thereof | |
JP5715247B2 (en) | Compounds for inhibiting type 5 phosphodiesterase and methods for their preparation | |
JP3241735B2 (en) | Optically pure 4-aryl-2-hydroxytetronic acid | |
CN103450092B (en) | Synthesis method of metronidazole-sulfanilamide derivatives | |
CN101665418A (en) | Methods for preparing E-3,5-dimethoxy-4'-oxhydryl diphenylethene and derivative thereof | |
EP3428154A1 (en) | 4-sulfur pentafluoride phenol compound and preparation method therefor, and preparation method for sulfur pentafluoride substituted benzopyran compound | |
CN101781311A (en) | Novel preparation method of platelet aggregation inhibition compound | |
CN108218847B (en) | Aryloxy phenoxy alkanoic acid derivative and medical application thereof | |
CN111072606B (en) | Octahydrobenzofuran derivative, preparation method and application thereof | |
CN103709092B (en) | The preparation method of Mitiglinide Calcium | |
CN114989075B (en) | Preparation method of etoricoxib intermediate | |
CN109824536A (en) | A kind of preparation method of Otilonium Bromide | |
CN103242128B (en) | Preparation method of 9,10-dihydrophenanthrene derivatives | |
CN106699648A (en) | 2-(4-aryloxy phenoxy)montanic acid naphthalene ester compound and application thereof | |
CN117304022A (en) | Method for synthesizing rosmarinic acid and analogues thereof | |
CN104628551A (en) | Preparation method of 2,5-dimethylphenylacetic acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140813 Termination date: 20210818 |
|
CF01 | Termination of patent right due to non-payment of annual fee |