* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1933, vol. 5, p. 61,64
[2] Journal of the American Chemical Society, 1958, vol. 80, p. 6420,6421
Reference：
[1] Monatshefte fuer Chemie, 1928, vol. 50, p. 107
8
[ 110-94-1 ]
[ 69134-53-8 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 339[2] Journal of the Chemical Society, 1925, vol. 127, p. 475
[3] Journal of the Chemical Society, 1921, vol. 119, p. 339[4] Journal of the Chemical Society, 1925, vol. 127, p. 475
9
[ 110-94-1 ]
[ 627-31-6 ]
Reference：
[1] Journal of the Chemical Society, 1965, p. 2438 - 2444
10
[ 544-13-8 ]
[ 110-94-1 ]
[ 39201-33-7 ]
Reference：
[1] Tetrahedron Letters, 1990, vol. 31, # 49, p. 7223 - 7226
[2] Tetrahedron Letters, 1988, vol. 29, # 21, p. 2589 - 2590
[3] Patent: US5908954, 1999, A,
11
[ 110-94-1 ]
[ 25561-30-2 ]
[ 354-38-1 ]
[ 55494-07-0 ]
[ 55982-15-5 ]
Reference：
[1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
12
[ 110-94-1 ]
[ 18107-18-1 ]
[ 1501-27-5 ]
Yield
Reaction Conditions
Operation in experiment
39%
With methanol In tetrahydrofuran; hexane
Example 21; Synthesis of 5-(4-((3,5-bis(trifluoromethyl)phenyl)(2-methyl-2H-tetrazol-5-yl)methyl)-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)pentan-1-ol (58); The synthetic scheme for the synthesis of compound (58) according to Example 21 is shown in FIG. 12. Step A; 5-Methoxy-5-oxopentanoic acid (54); TMSCHN2 (2.0 M hexanes, 3.8 mL) was added to a solution of glutaric acid (1.0 g, 7.6 mmol) in 4:1 THF/MeOH (75 mL). The solution was stirred and then the volatiles were removed in vacuo. The crude product was purified was purified by column chromatography (Biotage 40M, with 5:9 EtOAc/hexanes) to afford 5-methoxy-5-oxopentanoic acid (54) as a colorless oil (430 mg, 39percent).
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 485, p. 258,279
23
[ 67-56-1 ]
[ 110-94-1 ]
[ 1119-40-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
Cooling
PCl3 (8 ml) was added batchwise to a solution of glutaric acid (13.2 g; 0.10 mol) in methanol (50 ml) under cooling and stirring. The solvent was removed from the reaction mixture under vacuum. The resulting residue was distilled off under vacuum. The amount of the resulting glutaric acid dimethyl ester with a boiling point of 110-112° C. was 14.7 (92percent).
Reference：
[1] Analytical Chemistry, 2004, vol. 76, # 16, p. 4765 - 4778
[2] Patent: US2016/31858, 2016, A1, . Location in patent: Paragraph 0143
[3] Recueil des Travaux Chimiques des Pays-Bas, 1899, vol. 18, p. 373
[4] Chem. Zentralbl., 1918, vol. 89, # I, p. 1144
[5] Recueil des Travaux Chimiques des Pays-Bas, 1926, vol. 45, p. 586
[6] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 212,214; engl.Ausg.S.219
[7] Recueil des Travaux Chimiques des Pays-Bas, 1899, vol. 18, p. 373
[8] Journal of the Chemical Society, 1934, p. 339[9] Journal of the Chemical Society, 1948, p. 640
[10] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3587 - 3593
[11] Patent: US2009/264674, 2009, A1, . Location in patent: Page/Page column 5-6
[12] Patent: US2013/303796, 2013, A1, . Location in patent: Paragraph 0027; 0028; 0034
[13] Green Chemistry, 2016, vol. 18, # 7, p. 2193 - 2200
[14] New Journal of Chemistry, 2018, vol. 42, # 15, p. 12745 - 12753
24
[ 110-94-1 ]
[ 616-38-6 ]
[ 1119-40-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 160℃; for 5 h; Autoclave; Green chemistry
General procedure: Into a stainless steel pressure microreactor of capacity 17 mL was charged 5 wt percent of zeolite NaY-Bf, 100 mmol of carboxylic acid, and 300–400 mmol of dimethyl carbonate, the reactor was hermetically closed, and the reaction mixture was heated at 180–200°C for 5 h. On completion of the reaction the reactor was cooled to room temperature, opened, the reaction mixture was filtered through a bed of Al2O3. Unreacted dimethyl carbonate was distilled off, the residue was distilled at atmospheric pressure or in a vacuum, or it was crystallized from ethanol.
Reference：
[1] Russian Journal of Organic Chemistry, 2017, vol. 53, # 2, p. 163 - 168[2] Zh. Org. Khim., 2017, vol. 53, # 2, p. 177 - 181,5
25
[ 110-94-1 ]
[ 18107-18-1 ]
[ 1119-40-0 ]
Reference：
[1] Patent: EP1544190, 2005, A1, . Location in patent: Page/Page column 8
[2] Journal of the American Chemical Society, 2009, vol. 131, # 4, p. 1382 - 1383
Reference：
[1] Helvetica Chimica Acta, 1995, vol. 78, # 6, p. 1419 - 1436
[2] Journal of Organic Chemistry, 1983, vol. 48, # 18, p. 3106 - 3108
[3] Bulletin de la Societe Chimique de France, 1937, vol. <5> 4, p. 1667
[4] Annales de Chimie (Cachan, France), 1878, vol. <5>14, p. 477;[5] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1881, p. 408
[6] Monatshefte fuer Chemie, 1928, vol. 50, p. 107
[7] Journal of Physical Chemistry, 1996, vol. 100, # 32, p. 13492 - 13497
[8] Journal of Chemical and Engineering Data, 2011, vol. 56, # 4, p. 800 - 810
[9] Patent: US2013/303796, 2013, A1, . Location in patent: Paragraph 0027; 0029; 0034
[10] Green Chemistry, 2016, vol. 18, # 7, p. 2193 - 2200
31
[ 110-94-1 ]
[ 623-81-4 ]
[ 818-38-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 485, p. 283
[2] Justus Liebigs Annalen der Chemie, 1931, vol. 485, p. 283
32
[ 98-52-2 ]
[ 110-94-1 ]
[ 124-04-9 ]
[ 110-15-6 ]
[ 10347-88-3 ]
Reference：
[1] Journal of applied chemistry of the USSR, 1984, vol. 57, # 10 pt 2, p. 2138 - 2142
33
[ 13756-54-2 ]
[ 7697-37-2 ]
[ 110-94-1 ]
[ 1461-96-7 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 870
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 2098
34
[ 110-94-1 ]
[ 100-39-0 ]
[ 54322-10-0 ]
Yield
Reaction Conditions
Operation in experiment
39%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 0 - 20℃;
Toa solution of glutaricacid (4.0 g, 30.27 mmol) in THF (40 mL) at 0 C were added benzylbromide (3.60 mL, 30.27mmol) and diazabicyclo [5.4.0]undec-7-ene (4.51 mL, 30.27mmol). After the reaction mixturewas stirred at room temperature overnight, water was added, extractedwith EtOAc, dried over dried over MgSO4, filtered and concentrated.The crude residue was purified by silica gel column chromatography (16percent EtOAcin hexene) to afford 9(2.62 g, 11.71 mmol, 39percent) as an oil.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3687 - 3695
35
[ 110-94-1 ]
[ 100-51-6 ]
[ 54322-10-0 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1963, vol. 33, p. 919 - 922[2] Zhurnal Obshchei Khimii, 1963, vol. 33, p. 934 - 938
[3] Patent: WO2008/96372, 2008, A2, . Location in patent: Page/Page column 16
With acidic cation exchange resin Amberlyst 70; at 50 - 160℃;Flow reactor; Green chemistry;
General procedure: Hexanedioic acid and methanol at a weight ratio of 1:5 were mixed at 50 C., and then introduced into the lower part of the vertical reactor at a liquid hourly space velocity (LHSV) of 6 hour-1. The reaction was performed at 130 to 175 C., as shown in Table 2. The reaction was performed at 115 C.. The esterized mixture was output from the upper part of the vertical reactor, and collected to be analyzed by gas photography. The acid value of the product was determined by titration, and the conversion rate and the selectivity were analyzed. The results were shown in Table 2.
With Candida antarctica lipase B; In cyclohexane; at 45.0℃; for 24.0h;
General procedure: A (nano)biocatalyst (10-200 mg/l mmol of dicarboxylic acid) wasintroduced into a 10 mL round-bottom flask. Next, decane (20 wt. % peracid, internal standard), solvent (0-2 mL/L mmol of acid), dicarboxylicacid (1.0 mmol) and alcohol (2.0-32.8 mmol) were successively added.The reaction mixture was then inserted into the thermostatic shaker(250 rpm) at 25-45 C and the reaction was carried out for 2-24 h.During the reaction, 10 mul of the samples (diluted with acetonitrile)were periodically collected to monitor the reaction progress by GC-FID.After the completion of the reaction, the (nano)biocatalyst was filteredand washed with 20 mL of cyclohexane. The filtrate was concentratedusing a rotary evaporator (7 mbar, 110 C, 6 h for di-n-butyl esters and5 mbar, 135 C, 8 h for 2-ethylhexanol esters) to remove cyclohexaneand alcohols. The esters were purified by column chromatographyusing Al2O3 as the stationary phase and CH2Cl2 as the eluent. NMRspectra are available in Supplementary Information (Figs S9-S24).
With phosgene; 4-cyclopentylaminopyridine; In octane;Reflux; Large scale;
Synthesis of Glutaryl Chloride Catalyzed by 4 - Cyclohexylaminopyridinin 200 g of glutaric acid, 3000 g of octane, and 1 g of 4-cyclohexylaminopyridine were charged into a reaction flask, and the mixture was heated to reflux. When the molar ratio of phosgene to glutaric acid to phosgene was 1:10, Stop phosgene. And the content of the glutaryl chloride is 97% or more by chemical titration, and the molar yield is 82%.
74.5%
With thionyl chloride;Reflux;
The mixture of 88ml SOCl2 and 53.0g glutaric acid was heated to reflux for non-irritating gas (HCl) release. After completion of the reaction the excess SOCl2 was removed by atmospheric distillation, then dealed by vacuum distillation to collect 121C/13mmHg distillate to give a colorless liquid with in a yield of 74.5%.
66.8%
With thionyl chloride; at 90℃; for 4.5h;
The glutaric acid c (95.0 g, 0.72 mol) and the SOCl2 (144 mL) were added into the 250 mL flask orderly, and the reflex condenser tube and the exhaust absorption device were installed. The solution was stirred at 90 for 4.5 h. The reaction equipment was changed from backflow to the vacuum distillation equipment. The product was purified by decompression distillation to yield colorless transparent liquid (80.8 g, 66.8%).
With thionyl chloride; N,N-dimethyl-formamide;Reflux;
General procedure: Method A (1b, 1d-f): A mixture of dicarboxylic acid (0.6 mmol), SOCl2 (10 mL) and two drops of dry DMF was refluxed for 4-6 h and then the excessive SOCl2 was removed under vacuum. The afforded chloride was added dropwise to a solution of sinomenine (329 mg, 1 mmol) and Et3N (1.5 mmol) in dry CH2Cl2 (10 mL) in an ice bath over 10 min. Then the ice bath was removed, the reaction solution was allowed to stir at ambient temperature overnight and then added with saturated NaHCO3 (5 mL). The organic layer was separated and then washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (EtOAc/MeOH/NH4OH, 37:2:1-17:2:1, v/v/v), affording the title compounds as a white solid.
With pyridine; thionyl chloride; for 3h;Reflux;
General procedure: Into round-bottom flask thionyl chloride (5 mL, 70 mmol), carboxylic acid (1 g) and pyridine (1 muL, 0.012 mmol) were added. Mixture was stirred and heated at reflux for 3 hours. Excess of thionyl chloride was evaporated under reduced pressure and the crude acyl chloride was used for further synthesis. The respective acyl chloride, 4-nitroaniline (2 mmol) and triethylamine (2 mmol) in DMF (15 mL) were heated at 50C for 18 hours. To precipitate the final product water was used. The solid was filtrated off under vacuum. Pure compounds were obtained by crystallization from a small amount of methanol
With oxalyl dichloride; In dichloromethane; at 20℃; for 24h;Inert atmosphere;
General procedure: The corresponding carboxylic or dicarboxylic acid (1.0 mmol) was dissolved in dry dichloromethane (5 ml) and oxalylchloride (0.17 ml, 2.0 mmol) was added under nitrogen atmosphere. The mixture was stirred for 24 hours at room temperature. After removing the solvent under reduced pressure, haloperidol(940 mg, 2.5 mmol), dichloromethane (10 ml) and DIPEA (0.41 ml, 2.5 mmol) were added. After being stirred for 19 hours at room temperature the reaction mixture was treated with water and extracted with dichloromethane. The organic layer was washed with NaHCO3 (saturated solution) and brine. After being dried over Na2SO4 the solvent was removed under reduced pressure to obtain the crude product. Purification was performed using flash chromatography with dichloromethane/methanol as a solvent system.
With thionyl chloride; at 80℃; for 8h;
General procedure: Glutaroylchloride, adipoyl chloride, pimeloyl chloride, suberoylchloride, azeloyl chloride, sebacoyl chloride and dodecanedioylchloride were synthesized from the parent diacids. Thealiphatic diacids were gently refluxed with thionyl chlorideat 80C for 8 h till a clear solution was obtained. The acidchloride solution was initially distilled under lower reducedpressure (100-150 mm Hg) to remove the excess of thionylchloride and was double distilled under reduced pressure (1-2mm Hg) at 150C to get pure acid chloride, prior to use.
With thionyl chloride; at 80℃; for 3.5h;
0.15mol glutaric acid was dissolved in 10mL of thionyl chloride,Slowly raise the temperature to 80 C,The reaction conditions in the condensation reflux 3.5h,Partial brown solution,Under reduced pressure to give glutaryl chloride.
With thionyl chloride; In toluene; at 0 - 80℃; for 9h;Inert atmosphere;
To the solution of glutaric acid S3 (22.0 g, 166.7 mmol, 1.0 equiv) in toluene (300 mL) was added SOCl2 (48.4 mL, 666.8 mmol, 4.0 equiv) dropwise at 0 C. The mixture was stirred at 80 C for 9 h and then concentrated in vacuo to give glutaryl dichloride, which was used directly in the next step without further purification. N,O-Dimethylhydroxylamine hydrochloride (40.6 g, 416.8 mmol, 2.5 equiv) and pyridine (107.2 mL, 1.33 mol, 8.0 equiv) were dissolved in CH2Cl2 (300 mL). After the addition of the above prepared crude glutaryl dichloride in CH2Cl2 (100 mL) at 0 C, the reaction mixture was stirred for 6 h and was quenched with water (100 mL) at 0 C. The mixture was extracted with CH2Cl2 (3 × 100 mL) and the combined organic layer was washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulted residue was purified by flash column chromatography on silica gel (ethyl acetate, Rf = 0.2) to afford the known compound 7[2] (24.0 g, 66 %) as a light yellow oil.
With thionyl chloride; at 60 - 70℃; for 4h;
A mixture of glutaric acid (1.00 g, 7.57 mmol) and thionyl chloride (4 ml_) was heated at 60-70 C for 4 hours. Excess thionyl chloride was removed via distillation to afford the desired compound as an oil. dH (400 MHz, CDCb) 3.02 (t, J 8.0, 4H, CH2), 2.08 (quin, J 8.0, 2H, CH2).
With toluene-4-sulfonic acid; In toluene;Heating / reflux;
Example 1: Preparation of pentanedioic acid monobenzyl esterGlutaric acid (200 g) was taken along with benzyl alcohol (160 g), p-toluene sulfonic acid (30 g) and toluene (1.0 L). The reaction mass was heated to reflux temperature and water (^ 26 ml) was collected by azeotropic distillation. Reaction completion was checked by TLC/HPLC for absence of benzyl alcohol. After reaction completion, the reaction mass was cooled to ambient temperature and demineralized water (1.0 L) was added and the reaction mass was stirred for 15 minutes. The organic layer was separated and washed with demineralized water (1.0 L).The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum to get the title compound as oil.
The resulting solution was filtered and analyzed by HPLC. After 4.0 h, the HPLC yield of 4-cyanobutyric acid and glutaric acid were 85.1percent and 8.2percent, respectively, with 5.7percent glutaronitrile remaining.
With oxygen; copper(II) nitrate; In acetonitrile; at 120℃; under 4500.45 Torr; for 7h;
In a 15 mL PTFE-lined reactor, 0.5 mmol of cyclohexanone was added.Weigh 0.1 mmol of copper nitrate as a catalyst, add 2 mL of solvent acetonitrile (substrate cyclohexanone concentration is 0.25 mol/L), charge oxygen to 0.6 MPa, raise the temperature to 120 C, stir the reaction for 7 h, after the reaction is over,Gas chromatography-mass spectrometry and high performance liquid chromatography to detect products as a variety of carboxylic acids,Adipic acid, glutaric acid and succinic acid were included, and the product carboxylic acid was quantitatively analyzed by high performance liquid chromatography.The conversion of the substrate and the yield of the product are shown in Table 1.
(S)-2,2'-dihydroxy-1,1'-binaphthyl-3-carbaldehyde[ No CAS ]
[ 1002101-64-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
General procedure: At first, (S)-2,20-dihydroxy-1,10-binaphthyl-3-carbaldehyde 4 (1 mmol), diacids (0.5 mmol), and a catalytic amount of dimethylaminopyridne DMAP (0.2 mmol) were dissolved in 10 mL of dry CH2Cl2 and stirred for 15 min at room temperature. The solution was cooled to 0 C and then added immediately to (1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCl) (1.5 mmol) under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature and stirred for 2 h. After completionof the reaction, as indicated by TLC, CH2Cl2 was removed under reduced pressure and the reaction mixture was diluted with EtOAc.The organic layer was washed with water dried over anhydrous Na2SO4 and then concentrated under reduced pressure to give the crude compound. Purification of the crude compound by column chromatography over silica gel using 20% EtOAc in hexaneas an eluent afforded pure binapthyl bis(hydroxylaldehydes) 5-7 as a yellow solid in 73-96% yield
With hydrogen; nitric acid;Ru-Sn-Re catalyst; In water; at 180℃; under 15001.5 - 112511 Torr; for 18h;
10 g of water, 5.0 g of the dicarboxylic acid mixture and 0.3 g of the Ru-Sn-Re catalyst prepared in Reference Example 1 were charged into a 100 ml autoclave made of Hastelloy, which was equipped with a magnetic induction type stirrer. The atmosphere in the autoclave was replaced by nitrogen at room temperature and, then, pressurized hydrogen gas was introduced into the autoclave to increase the internal pressure thereof to 2 MPa, and the internal temperature of the autoclave was elevated to 180 C. After the internal temperature of the autoclave reached 180 C., pressurized hydrogen gas was further introduced into the autoclave to increase the internal pressure thereof to 15 MPa, and then a hydrogenation reaction was performed under the above-mentioned internal pressure for 18 hours. After completion of the hydrogenation reaction, a hydrogenation reaction mixture containing a diol mixture was taken out from the autoclave, while leaving the catalyst in the autoclave. The diol mixture contained in the hydrogenation reaction mixture was analyzed by gas chromatography under the above-mentioned analysis conditions to determine the yields of the diols. As a result, it was found that the yields of 1,4-butanediol, 1,5-pentanediol and 1,6-hexanediol were 75%, 98% and 96%, respectively. [00215] Into the autoclave containing the catalyst therein were charged 5.0 g of the dicarboxylic acid mixture and 10 g of water, and a hydrogenation reaction was performed under substantially the same conditions as mentioned above to produce a diol mixture. This procedure for the hydrogenation of the dicarboxylic acid mixture was further repeated 6 times (i.e., 7 runs of the hydrogenation were performed). With respect to the catalyst used, the activity maintenance ratio (%) was calculated by the formula: {(total amount of 1,4-butanediol, 1,5-pentanediol and 1,6-hexanediol which were obtained in the 7th run of the hydrogenation)/(total amount of 1,4-butanediol, 1,5-pentanediol and 1,6-hexanediol which were obtained in the 1st run of the hydrogenation)}×100. When the activity maintenance ratio is less than 100%, it means that the catalytic activity is lowered. The results are shown in Table 1.
With hydrogenchloride; sodium sulfate;OsO4; In ethyl acetate; N,N-dimethyl-formamide; tert-butyl alcohol;
EXAMPLE 25 This example shows the oxidation of 2-cyclohexeneone using Condition A. 2-Cyclohexeneone (100 mg) was dissolved in DMF (10 mL), and OsO4 (0.12 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (2.56 g) was added in one portion and the reaction had a final volume (12 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (600 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (50 mL*3) and brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Glutaric acid was obtained in 92% GC yield. This product was not isolated.
9.75 g (2.5 molar equivalents) of the metformin free-base was stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at 40 C , and a solution of <n="24"/>3.98 g (1 molar equivalent) of glutaric acid in acetone- water was added dropwise thereto and stirred at 10 C . The produced crystal was filtered and dried in hot air, thus obtaining 11.24g (yield: 95.3%) of metformin glutarate.
95.3%
In water; acetone; at 10 - 40℃;Product distribution / selectivity;
(2); 9.75 g (2.5 molar equivalents) of the metformin free-base was stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at 40 C., and a solution of 3.98 g (1 molar equivalent) of glutaric acid in acetone-water was added dropwise thereto and stirred at 10 C. The produced crystal was filtered and dried in hot air, thus obtaining 11.24 g (yield: 95.3%) of metformin glutarate.
62.8%
In ethanol; at 10 - 20℃;Product distribution / selectivity;
9.75 g (2.5 molar equivalents) of metformin free-base was stirred in 100 ml of ethanol at room temperature, after which a solution of 3.98 g (1 molar equivalent) of glutaric acid in ethanol was added dropwise thereto and stirred at 10 "C . The produced crystal was filtered and dried in hot air, thus obtaining 7.41 g (yield: 62.8%) of metformin glutarate.
57.7%
With sodium hydroxide; In ethanol; at 70℃;Product distribution / selectivity;
10.0 g of metformin, 2.40 g of sodium hydroxide and 3.98 g of glutaric acid were stirred in 150 ml of ethyl alcohol at a temperature of 70 C , and then methylene chloride was added thereto. The produced inorganic salt was filtered and ethyl acetate was added to the filtered solution. The produced crystal was filtered and dried in hot air, thus obtaining 6.79 g (yield: 57.7%) of metformin glutarate.
43.8%
In methanol; at 40℃;Product distribution / selectivity;
10.0 g of the metformin free-base and 3.98 g of glutaric acid were stirred in 100 ml of methyl alcohol at a temperature of 40 C , and then ethyl acetate was added thereto. The produced crystal was filtered and dried in hot air, thus obtaining 5.15 g (yield: 43.8%) of metformin glutarate.
20.00 g (4 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 4.83 g (4 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 180 ml of chloroform-methylalcohol (15:1) and 8 ml of water at room temperature, and then produced salt was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in chloroform-methylalcohol (15:1) was added dropwise and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 11.39 g (yield: 96.9%) of metformin glutarate.
96.7%
12.5 g (2.5 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 3.02g (2.5 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 112.5 ml of tetrahydrofuran (THF) and 5 ml of water at room temperature, and then the produced inorganic salt was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in tetrahydrofuran-water was added dropwise and stirred at <n="23"/>10 C . The produced crystal was filtered and dried in hot air, thus obtaining 11.41 g (yield: 96.7%) of metformin glutarate
96.9%
Example 2; Preparation of Metformin Glutarate; 20.00 g (4 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 4.83 g (4 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 180 ml of chloroform-methylalcohol (15:1) and 8 ml of water at room temperature, and then produced salt was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in chloroform-methylalcohol (15:1) was added dropwise and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 11.39 g (yield: 96.9%) of metformin glutarate.
88.8 - 94.3%
12.5 g (2.5 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 3.02 g (2.5 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at room temperature, and then the produced inorganic salt was filtered. To the filtered solution, 3.98 g (1 molar equivalent) of glutaric acid in acetone-water was added dropwise and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 11.12g (yield: 94.3%) of metformin glutarate.; 12.5 g (2.5 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 3.02 g (2.5 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 56.25 ml of acetone and 5 ml of water, and then the produced inorganic salt was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in acetone- water was added dropwise and stirred at 10 C . The produced crystal was filtered and dried in hot air, thus obtaining 10.47 g (yield: 88.8%) of metformin glutarate.
70.8%
40.0 g of <strong>[1115-70-4]metformin hydrochloride</strong> and 9.67g of potassium hydroxide were stirred in a mixed solution of 180 ml of acetone and 8 ml of water at room temperature, and then the produced inorganic salt was filtered. To the filtered solution, a solution of 7.98 g of glutaric acid in acetone-water was added dropwise and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 16.7 g (yield: 70.8%) of metformin glutarate.
61.6%
Preparation of metformin glutarate 9.97 g (2 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 3.38 g (2 molar equivalents) were stirred in 180 ml of ethanol at 40 C , and then the produced inorganic salt was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in ethanol was added dropwise and stirred at 10 C , and then the produced crystal was filtered. The produced crystal was stirred in ethanol at 50 "C, and then stirred at 10 C for 5 hours. Then, the stirred solution was dried in hot air, thus obtaining 7.27 g (yield: 61.6%) of metformin glutarate.
49.1 - 52.9%
20 g (4 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 4.83 g (4 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 180 ml of acetonitrile and 8 ml of water at room temperature, and then the produced inorganic salt <n="21"/>was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in acetonitrile-water was added dropwise and stirred at room temperature. The produced crystal was filtered and dried in hot air, thus obtaining 6.24g (yield: 52.9%) of metformin glutarate.; 20 g (4 molar equivalents) of <strong>[1115-70-4]metformin hydrochloride</strong> and 4.83 g (4 molar equivalents) of sodium hydroxide were stirred in a mixed solution of 180 ml of acetonitrile and 8 ml of water at room temperature, and then the produced inorganic salt was filtered. To the filtered solution, a solution of 3.98 g (1 molar equivalent) of glutaric acid in acetonitrile-water was added dropwise and stirred at 10 C . The produced crystal was filtered and dried in hot air, thus obtaining 5.8g (yield: 49.1%) of metformin glutarate.
In tetrahydrofuran;Product distribution / selectivity;
176 mg of <strong>[71125-38-7]meloxicam</strong> was ground with 66 mg of glutaric acid and 400 muL of THF was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis.
In 2,2,2-trifluoroethanol; at 40℃; for 4h;Product distribution / selectivity;
[00219] <strong>[641571-10-0]Nilotinib</strong> base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40C to obtain a mixture. The mixture was stirred and added to a solution of glutaric acid (0.037g, 0.28mmol) in TFE (1 niL) at 40C. The resulting clear solution was stirred for about 4 h at 40C. The solution was subsequently cooled to 5C. The mixture was kept at 5C overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered to give <strong>[641571-10-0]Nilotinib</strong> glutarate form I.
In methanol; water; N,N-dimethyl-formamide; at 110.0℃; for 72.0h;
General procedure: A mixture of Zn(NO3)2 (0.15 mmol), 1,3-dpb and glu2- (0.1 mmol) was dissolved in 8 ml of DMF-MeOH-H2O (1 : 1 : 2, v/v). The final mixture was placed in a Parr Teflon-lined stainless steel vessel (15 ml) and heated at 110 C for3 days, colourless crystals were obtained (52% yield based on 1,3-dpb). IR (KBr, gamma/cm-1): 3425 (m), 3068 (w), 2848 (w), 2359 (m), 1580 (s), 1515 (s), 1394 (s), 1226 (s), 1156 (w), 1056 (s), 964 (w), 852 (w), 757 (m), 674 (m), 536 (m). Found (%): C, 59.06; H, 4.13; N, 6.41. Calc. for C21H18N2O4Zn (%): C, 58.96; H, 4.24; N, 6.55.
General procedure: The umifenovir base was obtained from umifenovir hydrochloridemonohydrate by placing 10 g (18.8 mmol) of umifenovirhydrochloride monohydrate in 200 mL deionized water followedby heating and stirring. After complete dissolution 0.75 g(18.8 mmol) NaOH solution in deionized water was added to theumifenovir hydrochloride solution. The precipitate of umifenovirwas filtered and air dried.Umifenovir base (0.500 g, 1.05 mmol) and 1.05 mmol acid (salicylicacid 0.145 g, gentisic acid 0.160 g, glutaric acid 0.139 g andmaleic acid 0.122 g) were dissolved in 20 mL of hot ethyl acetateand allowed to crystallize.
With Oxone; 2-iodo-3,4,5,6-tetramethylbenzoic acid; In water; acetonitrile; at 60℃; for 24.0h;Green chemistry;
General procedure: In a typical experiment, a round bottom flask containing 4-6mL of acetonitrile/water mixture (1:1) was charged with 0.5-1.0mmol of the diol, 5mol% of TetMe-IA, and oxone (2equiv). The resulting mixture was stirred at rt for benzylic diols and at 45C for aliphatic diols. At the end of the reaction, as judged from TLC analysis, little water was added to dissolve the inorganic salts, and the organic matter was extracted with EtOAc at least two times. The combined extract was dried over anhydrous Na2SO4, concentrated in vacuo to obtain the crude product, which was subjected to silica-gel column chromatography using ethyl acetate/pet ether to isolate the pure product.
N1,N5-bis(dibenzo[b,d]furan-3-yl)glutaramide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0℃; for 0.25h;
Example 3 Synthesis of the compound 3S (N1,N5-bis(dibenzo[b,d]furan-3-yl) glutarammideI) In a flask are introduced 366 mg of 1a (3-amminodibenzofuran, 2.0 mmol), 1 b (132 mg of glutaric acid, 1.0 mmol), 135 mg of HOBT (1.0 mmol), 10 ml of dichloromethane and 0:14 ml of triethylamine (1.0 mmol). The solution is cooled to 0 C. with an ice bath and 206 mg of DCC is added (1.0 mmol). It is left under stirring for 15 minutes and then the ice bath is removed. After a short time a white precipitate of cyclohexylurea forms, it is left under stirring for another 3 h, then filtered on gooch and the solvent is evaporated at reduced pressure. The crude is purified by column chromatography (eluent EtOAc: hexane 25:75), the pure product 1c is obtained with a yield of 80%. For the synthesis of the other derivatives it is sufficient to work in excess of glutaric acid in such a way as to isolate the mono-amidified product. Then we proceed with the next reaction in the same conditions but using a 3-amminodibenzofuran or an appropriately substituted 3-aminodibenzothiophene
To a 10 mL glass peptide synthesis vessel was added Rink Amide AM resin (0.60 g, 0.31 mmol)and DMF (4 mL). The mixture was gently agitated with a wrist-action Burrel shaker for 1h andthen filtered. A 20% solution of piperidine in DMF (4 mL) was added and the mixture wasagitated for 30 min. The resin was filtered and then washed with DMF (3 × 4 mL). 7-N-(Fluorenylmethoxycarbonyl)aminocoumarin-4-acetic acid1 (0.40 g, 0.91 mmol), HOBt.H2O (140mg, 0.95 mmol) and DMF (4 mL) was added to the resin followed by DIC (144 muL, 0.93 mmol).The mixture was agitated for 24h, filtered and then washed with DMF (3 × 4mL), THF (3 × 4mL)and MeOH (3 × 4mL) respectively.General Procedure for Coupling the First Fmoc-Amino Acid to the ACC-ResinTo a 10 mL glass peptide synthesis vessel was added ACC-resin (0.31 mmol) and DMF (4 mL).The mixture was gently agitated with a wrist-action Burrel shaker for 1h and then filtered. A 20%solution of piperidine in DMF (4 mL) was added and the mixture was agitated for 30 min. Theresin was filtered and then washed with DMF (3 × 4 mL). In a separate scintillation vial wereadded Fmoc-amino acid (1.32 mmol), HOBt (200 mg, 1.32 mmol), DMF (4 mL) and DIC (200 muL,1.29 mmol). After a preactivation time of 5 min, the mixture was added to the resin and agitatedovernight. The resin was filtered and washed with DMF (3 × 4 mL).Representative Synthesis of a Di-peptide -ACCAs a representative example, the synthesis of N-suc-L-Phe-Gly-ACC is described. To a 10 mLglass peptide synthesis vessel was added Fmoc-Gly-ACC-resin (0.1 mmol) and DMF (3 mL). The mixture was gently agitated for 1h and then filtered. A 20% solution of piperidine in DMF (3mL) was added and the mixture was agitated for 30 min. The resin was filtered and then washedwith DMF (3 × 3 mL). In a separate scintillation vial were added Fmoc-L-Phe-OH (190 mg, 0.5mmol), HOBt (76 mg, 0.5 mmol), DMF (3 mL) and DIC (76 muL, 0.5 mmol). After a preactivationtime of 5 min, the mixture was added to the resin and agitated for 5h. The resin was filtered andwashed with DMF (3 × 4 mL). A 20% solution of piperidine in DMF (3 mL) was added and themixture was agitated for 30 min. The resin was filtered and then washed with DMF (3 × 3 mL).Succinic anhydride (100 mg, 1.0 mmol), DMF (3mL) and DIPEA (150 muL, 0.9 mmol) were addedand the mixture was agitated overnight, filtered and then washed with DMF (3 × 4 mL). Asolution of TFA:iPr3SiH:H2O (95:2.5:2.5, 3 mL) was added and the mixture was agitatedovernight. The resin was filtered and washed with TFA (2 × 3 mL). The combined filtrate wasconcentrated and the residue was washed with ether (3 × 3 mL) to give suc-L-Phe-Gly-ACC aspale yellow solid (32 mg, 62%). Amino terminus of some peptides was capped as the acetylderivative. This was accomplished by premixing AcOH (5 equiv), HOBt (5 equiv) and DIC (5equiv) in DMF and adding the mixture to the resin. The resulting mixture was agitated for 5h,filtered, and then washed with DMF. For ACC-peptides 11-18, the amino terminus was coupledwith the corresponding dicarboxylic acid as follows: In a separate scintillation vial were addeddicarboxylic acid (5 equiv), HOBt (5 equiv), DMF and DIC (5 equiv). After a pre-activation time of5 min, the mixture was added to the resin and agitated overnight. The resin was filtered andwashed with DMF (3 × 4 mL). The purification of all ACC-peptides was performed either bysimply washing the solid thoroughly with ether or by reverse-phase HPLC (ACN/H2O-0.1% TFA,15 - 60% for 20 min, 20 mL/min, 254 nm detection for 22.5 min). Purity check for all ACCpeptideswas completed by analytical reverse-phase HPLC (ACN/H2O-0.1% TFA, 10 - 60% for20 min, 1 mL/min, 254 nm detection for 23 min). Retention times are indicated as tR.
N,N'-bis-[2-(1,3-benzimidazol-2-yl)ethyl]pentanediamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.9%
Carbonyldiimidazole (23.4 g; 0.145 mol) was added to a solution of glutaric acid (8 g; 0.06 mol) in anhydrous tetrahydrofuran (500 ml) and stirred for 2 hours. Then benzimidazolyl ethylamine (21.6 g; 0.133 mol) was added to the reaction mixture. The resulting solution was stirred for 3 hours and allowed to stand at room temperature. The residue of the product was separated, washed with water, and dried. The yield was 21 g (82.9%). Rf 0.21 (2). M.p. 170-170.5 C. [M]+419. 1H-NMR (DMSO): delta, m.d.: 1.61-1.76 (m, 2H, CH2), 1.95-2.07 (t, 2H, CH2), 2.9-3.0 (t, 4H, 2CH2), 3.45-3.55 (quint, 4H, 2CH2), 7.06-7.14 (m, 4H, Ar), 7.39-7.54 (m, 4H, Ar), 7.98-8.08 (t, 2H, Ar), 11.6-12.7 (s, 2H, NH). HPLC under condition B: an individual peak at a retention time of 26.6 min.
With palladium 10% on activated carbon; W(OTf)6; hydrogen; acetic acid; at 150℃; under 15001.5 Torr; for 12h;
General procedure: Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10percent, 26.5mg, 0.025mmol, 0.5molpercent) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2molpercent). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699percent yield measured propionic acid, purity of the product was 99percent. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the substrate used was 2 mmol, And add lmL of acetic acid as solvent, the reaction temperature is 150 ° C, the hydrogen pressure is 2MPa, the yield is 40percent The purity of the product is 99percent. The product was subjected to nuclear magnetic identification using the manner described in the present invention, The NMR data for the product are as follows:
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one glutaric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.5%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
Initially, ET and GL were milled separately (Retsch Planetary Ball Mill PM 100 with 10 steel 0.5-cm balls, speed 300rpm, time 15min) and then sieved using 122-, 102- and 88-mum mesh sieves. The final fine was used for all experiments. To obtain the cocrystal (<strong>[938-73-8]ethenzamide</strong>:glutaric acid 1:1; 100mg of ET and 79.93mg of GL) to be used as a reference sample, the neat grinding method (with 10 steel 0.5-cm balls, speed 300rpm and time 1h) was applied.
N,N’-bis({4-[(6-methoxyquinolin-8-yl)amino]pentyl})pentanediamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
General procedure: PQdiphosphate(0.349 g, 0.766mmol) and TEA (0.428 mL, 3.211mmol) were stirred in dichloromethane (15 mL) to obtain PQ base.Dicarboxylicacid (succinic,fumaric, maleic,glutaric,adipic,pimelic,suberic, oritaconicacid) (0.333mmol) was activated using HATU (0.279, 0.733mmol) in the presence ofHuenig?sbase (DIEA) (0.255 mL, 1.465mmol) in dichloromethane (10 mL). After 15 min, a solution of PQ base was added to a solution of correspondingdicarboxylicacid and stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and extracted with brine (3 × 30 mL), dried over anhydrous sodiumsulfateand evaporated. The crude product was purified by column chromatography (mobile phase cyclohexane/ethyl acetate/methanol 1:1:0.5).
General procedure: To a stirred solution of dicarboxylic acids (3.0 eq.) in DCM (10 vol.) was added oxalyl chloride (6.5 eq.) and DMF (catalytic amount) at 0 C. Stirring was continued at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was added to 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5d, 1.0 eq.) in THF (5 vol.). The reaction mixture was stirred for 45 min at 80 C. After completion of the reaction (monitored by TLC) the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash using 7- 9% MeOH in DCM as eluent to afford title compound (3 lai-3la3, yield: 55-60 %).
5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-5-oxopentanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: To a stirred solution of succinic acid (680mg, 5.8mmol) in DMF (10mL) was added anhydrous DCM (150mL). Then the mixture was cooled to 0C, NMM (1.16g, 11.5mmol), VHL-1 (1.0g, 2.3mmol), HOAT (63mg, 0.46mmol) and EDCI.HCl (530mg, 2.8mmol) were added sequentially. The solution was purged and refilled with nitrogen. The resulting mixture was stirred at room temperature for 12h. The reaction mixture was quenched with water (1mL). After concentration, the residue was purified reverse phase ISCO (C18) to afford the desired compound s-4a (4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid) (s-4a) (0.82g, 65% yield) as a white solid.
Chemistry
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Material Science
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110K+ Compounds
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