* 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.
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
8
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 1455-77-2 ]
[ 120-89-8 ]
[ 849585-22-4 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 71-30-7 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 56-06-4 ]
[ 66224-66-6 ]
[ 57-13-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
[ 18588-61-9 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
9
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 1455-77-2 ]
[ 120-89-8 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 71-30-7 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 57-13-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
10
[ 77287-34-4 ]
[ 23147-58-2 ]
[ 1455-77-2 ]
[ 120-89-8 ]
[ 849585-22-4 ]
[ 73-40-5 ]
[ 110-15-6 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 57-13-6 ]
[ 302-72-7 ]
[ 18588-61-9 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
11
[ 4553-62-2 ]
[ 110-15-6 ]
[ 123-56-8 ]
[ 29553-51-3 ]
Yield
Reaction Conditions
Operation in experiment
96 %Chromat.
With phosphoric acid In water at 270℃; for 2 h;
Example 5 Preparation of a Mixture of Imides From Pure MGN and From Bio-Sourced Succinic Acid [0169] In a 100 mL reactor, are introduced 23 g of 2-methyl-glutaronitrile and then 25 g of succinic acid obtained by fermentation are added. Stirring is applied and 0.1 g of 85percent ortho-phosphoric acid are added. The reaction medium is heated up to 270° C. and these conditions are maintained for 2 hours. By GC analysis, the following results are obtained: [0170] TT percent (MGN)=98percent [0171] RR percent (MGI)=96percent [0172] RR percent (succinimide)=97percent
Reference:
[1] Doklady Akademii Nauk SSSR, 1955, vol. 102, p. 113,115[2] Chem.Abstr., 1956, p. 4899
13
[ 220819-23-8 ]
[ 83-73-8 ]
[ 110-15-6 ]
[ 443-48-1 ]
[ 13182-87-1 ]
Reference:
[1] Scientia Pharmaceutica, 1998, vol. 66, # 4, p. 309 - 324
14
[ 110-15-6 ]
[ 72-14-0 ]
[ 116-43-8 ]
Reference:
[1] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
15
[ 77287-34-4 ]
[ 23147-58-2 ]
[ 1455-77-2 ]
[ 849585-22-4 ]
[ 328-42-7 ]
[ 110-15-6 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 66-22-8 ]
[ 56-06-4 ]
[ 57-13-6 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
16
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 1455-77-2 ]
[ 120-89-8 ]
[ 849585-22-4 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 71-30-7 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 56-06-4 ]
[ 66224-66-6 ]
[ 57-13-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
[ 18588-61-9 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
17
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 120-89-8 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 110-15-6 ]
[ 144-62-7 ]
[ 127-17-3 ]
[ 56-06-4 ]
[ 57-13-6 ]
[ 18588-61-9 ]
[ 18514-52-8 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
18
[ 13357-09-0 ]
[ 110-15-6 ]
[ 443-48-1 ]
[ 13182-87-1 ]
Reference:
[1] European Journal of Medicinal Chemistry, 1998, vol. 33, # 9, p. 675 - 683
19
[ 220819-20-5 ]
[ 130-26-7 ]
[ 110-15-6 ]
[ 443-48-1 ]
[ 13182-87-1 ]
Reference:
[1] Scientia Pharmaceutica, 1998, vol. 66, # 4, p. 309 - 324
20
[ 220819-23-8 ]
[ 83-73-8 ]
[ 110-15-6 ]
[ 443-48-1 ]
[ 13182-87-1 ]
Reference:
[1] Scientia Pharmaceutica, 1998, vol. 66, # 4, p. 309 - 324
21
[ 110-15-6 ]
[ 79-03-8 ]
[ 765-69-5 ]
Reference:
[1] Organic Letters, 2017, vol. 19, # 15, p. 3958 - 3961
[2] Journal of Organic Chemistry, 1982, vol. 47, # 23, p. 4491 - 4498
[3] Organic Syntheses, 1992, vol. 70, p. 226 - 226
22
[ 77287-34-4 ]
[ 156-81-0 ]
[ 849585-22-4 ]
[ 617-48-1 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 108-53-2 ]
[ 71-30-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
[ 18514-52-8 ]
Yield
Reaction Conditions
Operation in experiment
0.18 mg
With ferric sulfate nonahydrate In water at 80℃; for 24 h;
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
General procedure: To model the chemical environment on the outer side of thetubular structures, NH2CHO (200 μL) was mixed with thesodium silicate solution (2.0 mL) in the presence of preformedMSH [ZnCl2, FeCl2·4H2O, CuCl2·2H2O, Fe2(SO4)3·9H2O,and MgSO4] (2.0percent w/w) at 80 °C for 24 h. In two selectedcases [FeCl2 and Fe2(SO4)3·9H2O], NH2CHO (200 μL) wasmixed with the sodium silicate solution (2.0 mL) in the presence of selected growing MSH (starting from 2.0percent w/w ofthe corresponding salt’s pellet) at 80 °C for 24 h. For the innerenvironment, NH2CHO (200 μL) was mixed with distilledwater (2.0 mL) in the presence of selected MSH (2.0percent w/w) at80 °C for 24 h. The reaction of NH2CHO (10percent v/v) with thesodium silicate solution (pH 12) without MSH membranes wasalso analyzed under similar experimental conditions. Theproducts were analyzed by gas chromatography associatedwith mass spectrometry (GC-MS) after treatment with N,Nbis-trimethylsilyl trifluoroacetamide in pyridine (620 μL) at 60°C for 4 h in the presence of betulinol (CAS Registry Number473-98-3) as the internal standard (0.2 mg). Mass spectrometrywas performed by the following program: injection temperature280 °C, detector temperature 280 °C, gradient 100 °C for 2min, and 10 °C/min for 60 min. To identify the structure of theproducts, two strategies were followed. First, the spectra werecompared with commercially available electron mass spectrumlibraries such as NIST (Fison, Manchester, U.K.). Second, GCMSanalysis was repeated with standard compounds. Allproducts have been recognized with a similarity index (SI)greater than 98percent compared to that of the reference standards.The analysis was limited to products of ≥1 ng/mL, and theyield was calculated as micrograms of product per startingformamide. For further experimental details, see the SupportingInformation.
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
27
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 120-89-8 ]
[ 849585-22-4 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 71-30-7 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 56-40-6 ]
[ 18588-61-9 ]
[ 18514-52-8 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
28
[ 77287-34-4 ]
[ 51953-18-5 ]
[ 1455-77-2 ]
[ 120-89-8 ]
[ 73-40-5 ]
[ 328-42-7 ]
[ 2491-15-8 ]
[ 110-15-6 ]
[ 71-30-7 ]
[ 120-73-0 ]
[ 144-62-7 ]
[ 113-00-8 ]
[ 127-17-3 ]
[ 66-22-8 ]
[ 66224-66-6 ]
[ 57-13-6 ]
[ 56-40-6 ]
[ 302-72-7 ]
Reference:
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
29
[ 110-15-6 ]
[ 25561-30-2 ]
[ 354-38-1 ]
[ 40309-57-7 ]
[ 55982-15-5 ]
Reference:
[1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
30
[ 110-15-6 ]
[ 75-65-0 ]
[ 15026-17-2 ]
Reference:
[1] Chemistry and Physics of Lipids, 2002, vol. 119, # 1-2, p. 51 - 68
[2] Chemical Communications, 1999, # 9, p. 823 - 824
31
[ 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
32
[ 110-15-6 ]
[ 67-63-0 ]
[ 924-88-9 ]
Yield
Reaction Conditions
Operation in experiment
97%
at 80℃; for 0.133333 h; Microwave irradiation
General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5–2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester.
Reference:
[1] Synthetic Communications, 2014, vol. 44, # 16, p. 2386 - 2392
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2004, vol. 179, # 6, p. 1187 - 1191
[3] Journal of Organic Chemistry, 1983, vol. 48, # 18, p. 3106 - 3108
[4] Journal of the Chemical Society, 1948, p. 631
33
[ 7664-93-9 ]
[ 110-15-6 ]
[ 598-10-7 ]
Reference:
[1] Chemische Berichte, 1911, vol. 44, p. 1024[2] Chem. Zentralbl., 1912, vol. 83, # II, p. 1365
Reference:
[1] J. Gen. Chem. USSR (Engl. Transl.), 1963, vol. 33, p. 919 - 922[2] Zhurnal Obshchei Khimii, 1963, vol. 33, p. 934 - 938
38
[ 110-15-6 ]
[ 100-51-6 ]
[ 103-50-4 ]
[ 103-43-5 ]
[ 103-40-2 ]
Reference:
[1] Russian Journal of General Chemistry, 2008, vol. 78, # 10, p. 1920 - 1923
39
[ 110-15-6 ]
[ 123-11-5 ]
[ 43212-67-5 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1948, p. 567,569
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 633,637
40
[ 110-15-6 ]
[ 2216-51-5 ]
[ 77341-67-4 ]
Reference:
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1902, vol. 34, p. 721[2] Chem. Zentralbl., 1903, vol. 74, # I, p. 162
[3] Journal of the American Pharmaceutical Association (1912-1977), 1938, vol. 27, p. 753
41
[ 110-15-6 ]
[ 2216-51-5 ]
[ 77341-67-4 ]
[ 34212-59-4 ]
Reference:
[1] Journal of the American Pharmaceutical Association (1912-1977), 1938, vol. 27, p. 753
42
[ 67-56-1 ]
[ 124-41-4 ]
[ 123-25-1 ]
[ 110-15-6 ]
[ 6289-46-9 ]
Reference:
[1] Monatshefte fuer Chemie, 1911, vol. 32, p. 77
43
[ 1492-23-5 ]
[ 110-15-6 ]
[ 2185-03-7 ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
at 50℃; for 2 h;
2 g (9.12 mmol) of O-succinyl-L-homoserine was dissolved in 10 ml (120 mmol, 13.2 equivalents) of concentrated hydrochloric acid, and the solution was allowed to react at 50° C. for 2 hours, and then cooled at room temperature for 3 hours. The precipitated solid was filtered, thereby obtaining 0.7 g (5.9 mmol) of succinic acid (SA) crystal (purity: 65percent). The filtrate was concentrated and recrystallized with anhydrous ethanol to yield 1.2 g (8.72 mmol) of homoserine lactone hydrochloride (purity: 95percent). 1H NMR (300 MHz, DMSO) δ 8.83 (2H, brs), 4.46 (1H, t, J=8.8 Hz), 4.36-4.24 (2H, m), 2.61-2.51 (1H, m), 2.30 (1H, t, J=10.3 Hz): Homoserine lactone hydrochloride 1H NMR (300 MHz, D2O) δ 4.36 (1H, t, J=9.0 Hz), 4.29 (2H, q, J=9.0 Hz), 2.69-2.60 (1H, m), 2.36-2.21 (1H, m): Homoserine lactone hydrochloride 1H NMR (300 MHz, D2O) δ 2.47 (4H, s): Succinic acid
The 40.50g (0.15mol) of doxylamine and 17.7g (0.15mol) of succinic acid was added 250ml flask and 130ml of acetone was heated at reflux until the solid dissolved, stirring was continued 1H; The acetone was distilled off and then 80ml of isopropyl propyl ether, ultrasound 10min, remove the upper isopropyl ether, spin dry and add 80ml of acetone, stirred at 0 °C crystallization, filtration to give the crude product. The crude product was recrystallized twice from acetone (crude 1g: Acetone 1.2ml), 80percent yield, with a purity of 99.88percent, the largest single hetero 0.07percent.
181.8 g
at 60℃;
The step S1 prepared 136g of N, N- dimethyl-2- [1-phenyl-1- (2-pyridyl) ethoxy] ethylamine were dissolved in a mixed solution of isopropanol 20-30 ° C and ethyl acetate (the volume ratio of 1: 1) was added with stirring 59.5g of succinic acid, warmed to 60 ° C, the reaction was stirred for 0.5 hours and then slowly cooled to 0-5 ° C, crystallization was stirred for 3-5 hours, under nitrogen in filtration, using 100ml of isopropanol and filter cake were washed with 200ml of ethyl acetate, the filter cake p> 0.08,45-50 ° C for 6-8 hours and dried under reduced pressure to yield N, N- dimethyl-2- [1 - phenyl-1- (2-pyridinyl) ethoxy] ethanamine succinate white solid 181.8g, content of 99.99percent,, the maximum absorption wavelength 262nm, 93percent yield, m.p. 105-106.5 ° C, total yield 91percent, as shown in FIG HPLC purity 99.93percent, as shown in FIG GC purity 99.90percent, MS data shown in Figure 1, MS: 271.2 [M + H]
Reference:
[1] Patent: CN103524403, 2016, B, . Location in patent: Paragraph 0055-0057
[2] Patent: CN105237467, 2016, A, . Location in patent: Paragraph 0048-0050
45
[ 110-15-6 ]
[ 676-47-1 ]
Reference:
[1] Journal of Organic Chemistry, 2014, vol. 79, # 7, p. 3152 - 3158
With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃;
To succinic acid (3 0 g, 25 42 mmol, 1 OO equiv) m THF (50 mL) was added a solution of 1- hydroxypyrrohdine-2,5-dione (64 g, 55 65 mmol, 2 20 eqmv) This was followed by the addition of a solution of DCC (11 5 g, 55 83 mmol, 2 20 equiv) in THF (50 mL) dropwise with stirring at O0C The resulting solution was stirred overnight at room temperature The reaction progress was monitored by LCMS The solids were collected by filtration and the filtrate was concentrated to give the crude product The resulting solids were washed with THF and ethanol This resulted in 2 4 g (27percent) of bis(2,5- dioxopyrrohdin-1-yl) succinate as a white solid.
Reference:
[1] Patent: WO2010/78449, 2010, A2, . Location in patent: Page/Page column 291
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 785 - 789[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1078 - 1081
[4] Chemical Papers, 2016, vol. 70, # 4, p. 505 - 514
[5] Patent: WO2016/205488, 2016, A1, . Location in patent: Paragraph 0264
48
[ 110-15-6 ]
[ 88495-63-0 ]
Reference:
[1] European Journal of Organic Chemistry, 2002, # 1, p. 113 - 132
With sulfuric acid; at 79.84℃; for 24h;Product distribution / selectivity;
EXAMPLE 9; Succinate recovery from fermentation products After demonstration of the process concept using pure succinate salts, a set of solids obtained from fermentation were subjected to theacidification/esterification process in EtOH. Characteristics of these solids are listed in Table 7.; Because of the high glucose content in sample labeled as W-l, a plasticlike sticky solid was obtained after drying. Melting of glucose made difficult water removal under experimental conditions. For this reason, dispersion and dissolution of particles within the reactive media was difficult. Other solids were dried without major difficulties and particle size reduction was conducted until fine-brownish dusts were obtained. Solids from batch 924-24m corresponded to crude SA obtained in the acid form because acidification was carried out in the aqueous broth before evaporation. In this case the amount of H2SO4 added was the required to catalyze esterification reaction (1 wt % of total solution).Acidification conditions for fermentation solids are listed in Table 8 and results are summarized in Table 9. Experiments ("runs") 21 and 22 were carried out in 2L batch reactors to evaluate the process in bench scale. In these runs reaction was performed under total reflux to avoid EtOH losses.; Even with excess of H2SO4, recovery of succinate and acetate species during ; acidification of solid W-1 was lower than that obtained with pure salts.After 2 h, around 40% recovery of succinate species was achieved compared with 80% in pure salts. However, after 24 h, comparable results with those obtained for pure solids are observed. This indicates that transport limitations are playing an important role in the process due to difficulties observed in dissolution of solids W-l. Figures 6A and 6B show the evolution of the recovery process in run 9 with Figure 6A showing succinate species and Figure 6B showing acetate species.Recovery on Runs 12 to 22 was in general lower compared with pure salts. In these experiments sulfuric acid loading was calculated only with respect to SA, therefore when stoichiometric ratio was used molar loading was about 86 % of the required to acidify all the acid species. This might explain the low recovery in experiments 12, 15 and 18. Remarkably, succinate esters were also produced during the process, confirming that H2SO4 acts as a catalyst before being consumed in salt acidification.Increasing H2SO4 loading enhances recovery as observed in experiments 13, 16 and 19 but temperature is still low to promote esterification. Operating at higher temperatures (333 and 383 K) similar recoveries to those obtained with pure salts were achieved as noticed in runs 20 and 21. In bench scale experiments with succinate salts and with crude SA (runs 21 y 22) high recovery and high conversion to MES and DES were obtained verifying feasibility of the process in a big scale. Evolution of succinate recovery in bench scale experiments is presented Figures 7A and 7B.
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;
To succinic acid (3 0 g, 25 42 mmol, 1 OO equiv) m THF (50 mL) was added a solution of 1- hydroxypyrrohdine-2,5-dione (64 g, 55 65 mmol, 2 20 eqmv) This was followed by the addition of a solution of DCC (11 5 g, 55 83 mmol, 2 20 equiv) in THF (50 mL) dropwise with stirring at O0C The resulting solution was stirred overnight at room temperature The reaction progress was monitored by LCMS The solids were collected by filtration and the filtrate was concentrated to give the crude product The resulting solids were washed with THF and ethanol This resulted in 2 4 g (27%) of bis(2,5- dioxopyrrohdin-1-yl) succinate as a white solid.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetone; at 25℃; for 24.0h;
General procedure: NHS-Cn was prepared as described by Chen et al. (2011) with a small modification; end-bit binary acid (15 mmol each; C2, C3, C4, C5, C6, C8, C10, C14) and NHS (40 mmol) were dissolved in acetone (25 mL), and then EDC (30 mmol) was added to the solution. The clear mixture was gently stirred at 25C for 24 h. After the acetone was removed by rotary evaporation under reduced pressure, the residue was washed several times with deionised water and then dried under vacuum at 50C. The crosslinker thus prepared was characterised by the 1H NMR and FT-IR spectra.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;
[0264] To a solution of diacid la (2 mmol) and hydroxysuccinimide (0.55 g, 4.8 mmol) in 30 mL of DMF was added EDC (0.75 g, 4.8 mmol) over 4 min. The reaction mixture was stirred for 22 h and the solvent was removed under reduced pressure. The residue was taken up in EtOAc (150 mL) and transferred to a separatory funnel. The organic phase was washed (I N HCl, brine, sat. NaHC03, brine), dried (Na2S04), filtered, and concentrated to afford the product as a white solid, which was used without additional purification or characterization.
1-(4-nitro-2-trifluoromethylphenyl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With PPA; at 85℃; for 20h;
a) 10 g (48.51 mmol) 4-Nitro-2- (trifluoromethyl)-aniline, 5.73 g (48.51 mmol) succinic acid and 60 g polyphosphoric acid are combined and heated to 85 C under stirring for 20 h. The reaction mixture is stirred into water (500 ml), the formed precipitate is removed by filtration, rinsed with water and dried. Yield : 13.57g (97 %)
92%
With polyphosphoric acid; at 80℃; for 12h;
General procedure: A mixture of aniline (1.0 g, 10.75 mmol), succinic acid (1.26 g, 10.75 mmol) and 86%polyphosphoric acid (10 g) was heated at 80 C for 12 h. After cooling, H2O (50 ml) wasadded and the precipitate was filtered off, washed several times with H2O and dried. 1-Phenyl-pyrrolidine-2,5-dione 1b is obtained as an almost colorless solid. Yield(%) = 94.
DIETHYL SUCCINATE EXAMPLE The reactive distillation experiment for esterification of succinic acid used a prereactor at 120C to produce Feed 1 stream from the prereactor stream as shown in Figure 47. The prereactor feed constitutes a 10:1 molar ratio of ethanol to succinic acid. The stream Feed 1 represents an equilibrium mixture. In the reactive distillation column, the conversion of residual succinic acid (SA) from Feed 1 is about 45%. Monoethyl succinate (MES) is also about 50% converted in the RD column to produce additional diethyl succinate, the desired final product. The results of this Example shown in Table 9 illustrate the capability of reactive distillation to produce diethyl succinate from succinic acid. Table 9 Results of Succinic Acid Esterification via Reactive Distillation (All values are species flow rates in g/min) Species Prereactor Feed 1 Feed 2 Distillate Bottoms Succinic acid 4.1 0.2 0 0 0.119 Monoethyl succinate 1.03 0 0 0.514 Diethyl succinate 4.73 0 0 5.39 EtOH 15.9 12.66 15 19.42 8.05 Water 1.29 0 1.36 0 Diethyl ether 0.096 0 0.10 0 TOTAL 20.0 20.0 15.0 20.9 14.1
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; water; at 60℃;Product distribution / selectivity;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
In ethanol; at 20 - 60℃;Product distribution / selectivity;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
In ethanol; water; at 4 - 60℃;Product distribution / selectivity;
EXAMPLE 16; Formation of Hemi-Succinate Salt; About 40 to 50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 ml of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR.; Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200 C., and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60 C.
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemi-succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethyl acetate; at 20℃;Product distribution / selectivity;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
In acetone; at 20℃;Product distribution / selectivity;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
In water; isopropyl alcohol; at 4 - 60℃;Product distribution / selectivity;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 10. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60 C. or ambient temperature (where a clear solution formed, stirring continued at 4 C.). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. TABLE 10 Physical Crystallinity LOD, % Solvent T, C. Appearance and FormTdecomposition 1H-NMR EtOH:H2O 60 SAM to FFP Excellent A 1.1 2.31 (2H, (1:0.05) 203.7 succinate) 3.86 (Hbz)IPA:H2O 60 SAM to FFP Excellent 4.6 2.31 (2H, (1:0.05) HA succinate) 3.85 (Hbz) EtOH Ambient FFP to SAM Excellent A 1.1 2.31 (2H, to FFP 194.6 succinate) 3.85 (Hbz) IPA Ambient FFP Good 2.8 + 4.6 1.02 (~3H, IPA) SA (90.6) (2- 2.32 (2H, step) succinate) 155.83.88 (Hbz) Acetone Ambient FFP Good B 1.5 + 1.3 (2- 2.31 (2H, step) succinate) 162.33.86 (Hbz) AcOEt Ambient FFP Good B 1.3 + 2.9 - 154.5 EtOH 60 SAM to FFP Excellent A - -EtOH:H2O 60 SAM to FFP Excellent A 1.0 2.31 (2H, (1:0.025) 197.3 succinate) 3.85 (Hbz)EtOH:H2O 60 SAM to FFP Excellent A - - (1:0.05) Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200 C., and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60 C.
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemisuccinate isopropanol hemisolvate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 20℃;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide hemisuccinate monohydrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; isopropyl alcohol; at 60℃;
About 40-50 mg of N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3- yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base monohydrate was suspended in 1 mL of a solvent as listed in Table 16. A stoichiometric amount of succinic acid was subsequently added to the suspension. The mixture was stirred at either 60C or ambient temperature (where a clear solution formed, stirring continued at 4C). Solids were collected by filtration and analyzed by XRPD, TGA and in some instances 1H-NMR. <n="30"/>- 29 -Table 16[0085] Four distinctly different hemi-succinate salts were isolated: a monohydrate (form A) (ethanol at ambient), a hemi-solvate of isopropanol (form SA) (isopropyl alcohol), and two unsolvated forms A and B. Form A displays higher crystallinity, minimal weight loss up to 200C, and higher decomposition temperature. In addition, it could be synthesized reproducibly, as demonstrated in ethanol and ethanol and water at 60C.
The desvenlafaxine 263g (1mol, 1.0eq) succinic acid and 124g (1.05mol, 1.05eq) was added a reaction flask. Isopropanol 1.84L (7v / w), purified water 526mL (2v / w).Was stirred warmed to reflux, stirred for 1H insulation, heating was stopped. Natural cooling to 0 ~ 10 C, crystallization was stirred for 4.5 h, filtered off with suction, the filter cake was rinsed with a small amount of isopropanol once, the filter cake was transferred to a vacuum oven, to control the temperature 40 ~ 50 C dried in vacuo 6h, to give a white. The solid 385g, 96.5% yield, 99.83% purity.
With water; In cyclohexane; at 68℃; for 2h;Product distribution / selectivity;
Example 1; ODV and succinic acid were charged to a reaction flask containing cyclohexane. Water was added to the above mixture. The resulting suspension was heated at 68C for two hours under stirring. The reaction mixture was allowed to cool to 25C and then filtered. The solid product was dried at 600C under vacuum until a constant weight was obtained. The 1H-NMR indicated formation of ODV succinate. The TGA, shown in Figure 3, indicated that the ODV succinate salt formed was a hydrate. The XRPD and DSC analysis data, shown in Figures 1 and 2 respectively, confirmed that the product obtained was the novel ODV succinate hydrate form of the present invention.
With water; In N,N-dimethyl-formamide; acetone; at 68℃; for 1.5h;Product distribution / selectivity;
Example 2; ODV was charged to a reaction flask containing a mixture of N, N- dimethylformamide and acetone. To this stirred mixture, succinic acid was added, followed by water. The resulting mixture was heated at 68C for around 90 minutes. The reaction mixture was cooled to 25C and then filtered. The solid product was dried at 600C under vacuum until a constant weight was obtained. The 1H-NMR indicated formation of ODV succinate. The TGA indicated that the ODV succinate salt formed was a hydrate. The XRPD and DSC analysis data confirmed that the product obtained was the novel ODV succinate hydrate form of the present invention and that it was identical with that obtained by following example 1.
In tetrahydrofuran;Product distribution / selectivity;
176 mg of <strong>[71125-38-7]meloxicam</strong> was ground with 30 mg of succinic 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 isopropyl alcohol; at 40℃; for 2h;Product distribution / selectivity;
Example 18; Preparation of Rasagiline Succinate Form IRasagiline base (1.78 g) was dissolved in 2-propanol (7.6 mL). Succinic acid (1.23 g) was added and the mixture was stirred for 2 h at 40 C. The mixture was allowed to cool to ambient temperature and stirred for 24 hours at this temperature. The mixture was filtered and dried under vacuum at 40 C. Yield 2.08 g.Analytical data: XRD: Form I, see FIG. 15. IR: see FIG. 16.
With dihydrogen peroxide;methyltrioxorhenium(VII); In dichloromethane; water; acetonitrile; at 20℃;
Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below.
With dihydrogen peroxide;methyltrioxorhenium(VII); In ethanol; water; at 20℃;
Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below.
With sulfuric acid; at 29.84℃; for 6h;Product distribution / selectivity;
EXAMPLE 9; Succinate recovery from fermentation products After demonstration of the process concept using pure succinate salts, a set of solids obtained from fermentation were subjected to theacidification/esterification process in EtOH. Characteristics of these solids are listed in Table 7.; Because of the high glucose content in sample labeled as W-l, a plasticlike sticky solid was obtained after drying. Melting of glucose made difficult water removal under experimental conditions. For this reason, dispersion and dissolution of particles within the reactive media was difficult. Other solids were dried without major difficulties and particle size reduction was conducted until fine-brownish dusts were obtained. Solids from batch 924-24m corresponded to crude SA obtained in the acid form because acidification was carried out in the aqueous broth before evaporation. In this case the amount of H2SO4 added was the required to catalyze esterification reaction (1 wt % of total solution).Acidification conditions for fermentation solids are listed in Table 8 and results are summarized in Table 9. Experiments ("runs") 21 and 22 were carried out in 2L batch reactors to evaluate the process in bench scale. In these runs reaction was performed under total reflux to avoid EtOH losses.; Even with excess of H2SO4, recovery of succinate and acetate species during ; acidification of solid W-1 was lower than that obtained with pure salts.After 2 h, around 40% recovery of succinate species was achieved compared with 80% in pure salts. However, after 24 h, comparable results with those obtained for pure solids are observed. This indicates that transport limitations are playing an important role in the process due to difficulties observed in dissolution of solids W-l. Figures 6A and 6B show the evolution of the recovery process in run 9 with Figure 6A showing succinate species and Figure 6B showing acetate species.Recovery on Runs 12 to 22 was in general lower compared with pure salts. In these experiments sulfuric acid loading was calculated only with respect to SA, therefore when stoichiometric ratio was used molar loading was about 86 % of the required to acidify all the acid species. This might explain the low recovery in experiments 12, 15 and 18. Remarkably, succinate esters were also produced during the process, confirming that H2SO4 acts as a catalyst before being consumed in salt acidification.Increasing H2SO4 loading enhances recovery as observed in experiments 13, 16 and 19 but temperature is still low to promote esterification. Operating at higher temperatures (333 and 383 K) similar recoveries to those obtained with pure salts were achieved as noticed in runs 20 and 21. In bench scale experiments with succinate salts and with crude SA (runs 21 y 22) high recovery and high conversion to MES and DES were obtained verifying feasibility of the process in a big scale. Evolution of succinate recovery in bench scale experiments is presented Figures 7A and 7B.
With sulfuric acid; at 29.84℃; for 24h;Product distribution / selectivity;
EXAMPLE 9; Succinate recovery from fermentation products After demonstration of the process concept using pure succinate salts, a set of solids obtained from fermentation were subjected to theacidification/esterification process in EtOH. Characteristics of these solids are listed in Table 7.; Because of the high glucose content in sample labeled as W-l, a plasticlike sticky solid was obtained after drying. Melting of glucose made difficult water removal under experimental conditions. For this reason, dispersion and dissolution of particles within the reactive media was difficult. Other solids were dried without major difficulties and particle size reduction was conducted until fine-brownish dusts were obtained. Solids from batch 924-24m corresponded to crude SA obtained in the acid form because acidification was carried out in the aqueous broth before evaporation. In this case the amount of H2SO4 added was the required to catalyze esterification reaction (1 wt % of total solution).Acidification conditions for fermentation solids are listed in Table 8 and results are summarized in Table 9. Experiments ("runs") 21 and 22 were carried out in 2L batch reactors to evaluate the process in bench scale. In these runs reaction was performed under total reflux to avoid EtOH losses.; Even with excess of H2SO4, recovery of succinate and acetate species during ; acidification of solid W-1 was lower than that obtained with pure salts.After 2 h, around 40% recovery of succinate species was achieved compared with 80% in pure salts. However, after 24 h, comparable results with those obtained for pure solids are observed. This indicates that transport limitations are playing an important role in the process due to difficulties observed in dissolution of solids W-l. Figures 6A and 6B show the evolution of the recovery process in run 9 with Figure 6A showing succinate species and Figure 6B showing acetate species.Recovery on Runs 12 to 22 was in general lower compared with pure salts. In these experiments sulfuric acid loading was calculated only with respect to SA, therefore when stoichiometric ratio was used molar loading was about 86 % of the required to acidify all the acid species. This might explain the low recovery in experiments 12, 15 and 18. Remarkably, succinate esters were also produced during the process, confirming that H2SO4 acts as a catalyst before being consumed in salt acidification.Increasing H2SO4 loading enhances recovery as observed in experiments 13, 16 and 19 but temperature is still low to promote esterification. Operating at higher temperatures (333 and 383 K) similar recoveries to those obtained with pure salts were achieved as noticed in runs 20 and 21. In bench scale experiments with succinate salts and with crude SA (runs 21 y 22) high recovery and high conversion to MES and DES were obtained verifying feasibility of the process in a big scale. Evolution of succinate recovery in bench scale experiments is presented Figures 7A and 7B.
With sulfuric acid; at 30℃; for 2h;Product distribution / selectivity;
EXAMPLE 6; The same experimental procedure described in Example 4 was followed. Each tube was loaded with 4.13 g of sodium succinate hexahydrate, 23.74 g of anhydrous ethanol, and 2.1 g of sulfuric acid, which corresponds to a 40% molar excess of H2SO4 relative to that required for acidification. Results of reaction are presented in Table 3.
With sulfuric acid; at 30℃; for 6h;Cooling with ice;Product distribution / selectivity;
EXAMPLE 4; Because of challenges with both liquid and solid phases containing succinate species, and because water can be taken up and released in various forms, accurate results may be difficult to obtain under some conditions using the methods of Examples 1-3. Accordingly, a modified experimental procedure was adopted as described in this example to allow for accounting of the total recovery of succinic species in solid and liquid phases. Experimental ProceduresA set of test tubes was loaded substantially identically with reagents, stirred at substantially identical rates, with the contents removed from reaction at different times. In each tube, the entire contents comprise the sample. Every reactor was stopped at different time intervals to mimic sampling in a batch reaction. In this experiment, the two phases were analyzed independently.A solution of sulfuric acid in ethanol was prepared in a flask maintained in an ice bath to avoid heating and evaporation of the alcohol under mixing. Cappable 50 mL test tubes were charged with a defined amount of this solution (approx. 40 mL). Succinate salt was added to every tube at the stoichiometric amount to produce free succinic acid and sodium sulfate. The tubes were placed in a water bath (over a magnetic plate) at constant temperature, and mixed with magnetic stir bars. Each tube was taken out of the bath and quenched in ice at a different time in order to follow the kinetics of the reaction.After centrifugation, of each tube at 6000 rpm for 15 minutes, the liquid layer was removed, weighed, and collected for analysis. The solids were washed in the same tube with anhydrous ethanol to remove any remaining soluble succinic species, and were centrifuged again to collect, weigh, and analyze the supernatant liquid. Finally, the solids were dissolved in water for further analysis. Because of the limited solubility of calcium sulfate in water, the solids were mixed with an aqueous solution of H2SO4 to dissolve any succinate remaining, and the liquid phase analyzed.Following the experimental procedure described above, six test tubes were loaded with 4.13 g of sodium succinate hexahydrate23.70 g of anhydrous ethanol (C2H60), and 1.50 g of sulfuric acid (H2SO4). These quantities represent approximately the stoichiometric ratio for complete acidification to succinic acid and sodium sulfate. Those tubes were closed hermetically and placed simultaneously into the water bath at 30 C. One tube was removed from the bath at each of the following times of reaction: 15 min, 30 min, lh, 2h, 3h, and 6h; and was processed for analysis. Molar recovery was calculated with respect to the total moles of succinic species initially loaded as the sodium salt. Mole percentages of succinic acid (SA), monoethyl succinate (MES), and diethyl succinate (DES) recovered in the liquid phase, are listed in Table 1.
With sulfuric acid; at 79.84℃; for 24h;Product distribution / selectivity;
EXAMPLE 9; Succinate recovery from fermentation products After demonstration of the process concept using pure succinate salts, a set of solids obtained from fermentation were subjected to theacidification/esterification process in EtOH. Characteristics of these solids are listed in Table 7.; Because of the high glucose content in sample labeled as W-l, a plasticlike sticky solid was obtained after drying. Melting of glucose made difficult water removal under experimental conditions. For this reason, dispersion and dissolution of particles within the reactive media was difficult. Other solids were dried without major difficulties and particle size reduction was conducted until fine-brownish dusts were obtained. Solids from batch 924-24m corresponded to crude SA obtained in the acid form because acidification was carried out in the aqueous broth before evaporation. In this case the amount of H2SO4 added was the required to catalyze esterification reaction (1 wt % of total solution).Acidification conditions for fermentation solids are listed in Table 8 and results are summarized in Table 9. Experiments ("runs") 21 and 22 were carried out in 2L batch reactors to evaluate the process in bench scale. In these runs reaction was performed under total reflux to avoid EtOH losses.; Even with excess of H2SO4, recovery of succinate and acetate species during ; acidification of solid W-1 was lower than that obtained with pure salts.After 2 h, around 40% recovery of succinate species was achieved compared with 80% in pure salts. However, after 24 h, comparable results with those obtained for pure solids are observed. This indicates that transport limitations are playing an important role in the process due to difficulties observed in dissolution of solids W-l. Figures 6A and 6B show the evolution of the recovery process in run 9 with Figure 6A showing succinate species and Figure 6B showing acetate species.Recovery on Runs 12 to 22 was in general lower compared with pure salts. In these experiments sulfuric acid loading was calculated only with respect to SA, therefore when stoichiometric ratio was used molar loading was about 86 % of the required to acidify all the acid species. This might explain the low recovery in experiments 12, 15 and 18. Remarkably, succinate esters were also produced during the process, confirming that H2SO4 acts as a catalyst before being consumed in salt acidification.Increasing H2SO4 loading enhances recovery as observed in experiments 13, 16 and 19 but temperature is still low to promote esterification. Operating at higher temperatures (333 and 383 K) similar recoveries to those obtained with pure salts were achieved as noticed in runs 20 and 21. In bench scale experiments with succinate salts and with crude SA (runs 21 y 22) high recovery and high conversion to MES and DES were obtained verifying feasibility of the process in a big scale. Evolution of succinate recovery in bench scale experiments is presented Figures 7A and 7B.
With sulfuric acid; at 59.84℃; for 5h;Product distribution / selectivity;
EXAMPLE 9; Succinate recovery from fermentation products After demonstration of the process concept using pure succinate salts, a set of solids obtained from fermentation were subjected to theacidification/esterification process in EtOH. Characteristics of these solids are listed in Table 7.; Because of the high glucose content in sample labeled as W-l, a plasticlike sticky solid was obtained after drying. Melting of glucose made difficult water removal under experimental conditions. For this reason, dispersion and dissolution of particles within the reactive media was difficult. Other solids were dried without major difficulties and particle size reduction was conducted until fine-brownish dusts were obtained. Solids from batch 924-24m corresponded to crude SA obtained in the acid form because acidification was carried out in the aqueous broth before evaporation. In this case the amount of H2SO4 added was the required to catalyze esterification reaction (1 wt % of total solution).Acidification conditions for fermentation solids are listed in Table 8 and results are summarized in Table 9. Experiments ("runs") 21 and 22 were carried out in 2L batch reactors to evaluate the process in bench scale. In these runs reaction was performed under total reflux to avoid EtOH losses.; Even with excess of H2SO4, recovery of succinate and acetate species during ; acidification of solid W-1 was lower than that obtained with pure salts.After 2 h, around 40% recovery of succinate species was achieved compared with 80% in pure salts. However, after 24 h, comparable results with those obtained for pure solids are observed. This indicates that transport limitations are playing an important role in the process due to difficulties observed in dissolution of solids W-l. Figures 6A and 6B show the evolution of the recovery process in run 9 with Figure 6A showing succinate species and Figure 6B showing acetate species.Recovery on Runs 12 to 22 was in general lower compared with pure salts. In these experiments sulfuric acid loading was calculated only with respect to SA, therefore when stoichiometric ratio was used molar loading was about 86 % of the required to acidify all the acid species. This might explain the low recovery in experiments 12, 15 and 18. Remarkably, succinate esters were also produced during the process, confirming that H2SO4 acts as a catalyst before being consumed in salt acidification.Increasing H2SO4 loading enhances recovery as observed in experiments 13, 16 and 19 but temperature is still low to promote esterification. Operating at higher temperatures (333 and 383 K) similar recoveries to those obtained with pure salts were achieved as noticed in runs 20 and 21. In bench scale experiments with succinate salts and with crude SA (runs 21 y 22) high recovery and high conversion to MES and DES were obtained verifying feasibility of the process in a big scale. Evolution of succinate recovery in bench scale experiments is presented Figures 7A and 7B.
<strong>[122883-93-6]Ziprasidone</strong> and THF were added to a round-bottomed flask and maintained at a temperature of 60C while stirring the solution with a magnetic stirrer for 1 hour. Upon complete dissolution of ziprasidone into a solution, ten-time excess of succinic acid (in relation to ziprasidone) was added and the mixture was stirred for another 10 minutes. Then activated carbon was added and the entire mixture was stirred for half an hour at temperature of 60C. The hot solution was filtered through celite. The clear solution obtained was left overnight at room temperature. The precipitate was filtered off on a vacuum filter, and washed with water to remove excess succinic acid used for synthesis. The reaction product was dried at 40C. The reaction yield was ca. 90%.Examples of amounts used for synthesis:1 g <strong>[122883-93-6]Ziprasidone</strong> (2.4 mmol)2.83 g succinic acid (24.0 mmol),100 ml THF,0.2 g activated carbon.NMR for succinateBase: Acid = 1 :1 .71 H NMR (700 MHz, DMSO-d6): delta= 2.42 (s, 4H, 2x CH2COOH), 2.56-2.59 (m, 2H, CH2), 2.70-2.73 (m, 4H, 2xCH2), 2.84-2.87 (m, 2H, CH2), 3.46 (s, 2H, CH2), 3.46- 3.48 (m, 2H, CH2), 6.81 (s, 1 H, CHAr), 7.23 (s, 1 H, CHAr), 7.34 (t, 1 H, 3JHH= 7.9 Hz, CHAr), 7.56 (t, 1 H, 3JHH= 7.9 Hz, CHAr), 8.05 (d, 1 H, 3JHH= 7.9 Hz, CHAr), 8.06 (d, 1 H, 3JHH= 7.9 Hz, CHAr), 10.41 (s, 1 H, NH), 12.16 (bs, 2H, COOH).13C NMR (176 MHz, DMSO-d6): delta= 28.81 , 28.78, 35.32, 49.52, 52.30, 58.09, 66.98, 109.50, 121 .03, 124.12, 124.37, 125.21 , 126.82, 127.30, 127.83, 131 .22, 143.22, 151 .95, 163.46, 173.56, 176.23.
5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
In isopropyl alcohol; at 80℃; for 0.25h;
10.0g of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl was dissolved in 50ml of isopropanol at 80C to give a slightly yellow solution . 3.3g of succinic acid was added to the solution as a solid and dissolved, the solution was stirred for 15 minutes then cooled. A white solid precipitated from the solution at 30C to give a thick slurry. The solid was isolated by filtration and dried in a vacuum oven for a final yield of 10.8g of the succinic acid salt (81%).
In toluene; at 20 - 55℃;
Toluene (5 ml) and <strong>[202409-33-4]etoricoxib</strong> (1 g) were taken into a reaction flask, the mixture was heated at 50-55C, followed by the addition of succinic acid (0.45 g). The reaction mass was cooled to 20-25C and maintained for 2 hours. The solid obtained was filtered, washed with toluene (3 ml) and then dried at 50-55C for 1 hour to yield 1.2 g of crystalline <strong>[202409-33-4]etoricoxib</strong> succinate (Purity by HPLC: 99.27%).
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one succinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.9%
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%)
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5- yl)methyl)isoindoline-l,3-dione of Formula (I), 1000 ml methanol and 119 g methyl amine were added to RBF at 25C to 35C. The reaction was heated to 60C to 65C for 1-2 hours. To the reaction mass succinic acid (15g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50C and maintained for 30 minutes. The reaction mass was cooled to 25 to 35C and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml x 2) afforded succinate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-^xazolidin-3- yl)phenyl)morpholin-3-one of Formula (JS).
The mono ester was prepared in first step by taking equimolar proportion (0.025 mol) of acid and alcohol (malonic acid and ethanol for DEM, succinic acid and ethanol for DES, phthalic anhydride and 1-butanol for DBP,phthalic anhydride and 2-ethyl 1-hexanol for DOP) were taken in a round bottomed flask and the reaction mixture stirred at ?80Cfor DEM and DES, ?110C for DBP and ?140C for DOP for about10-15 min in absence of any catalyst and solvent. The dicarboxylic acid and anhydride get completely converted to the monoester,so that the acid concentration at this stage is taken as the ini-tial concentration.
With beta-nicotinamide adenine dinucleotide, reduced dipotassium salt; recombinant His6-tagged 6-hydroxy-3-succinoyl-pyridine 3-monooxygenase from Pseudomonas putida S16; FAD; oxygen; In aq. buffer; at 25℃;pH 8.0;Enzymatic reaction;Mechanism; Catalytic behavior;
To test the in vitro activity of His-HspB, HSP and NADH were mixed with the recombinant enzyme in air-saturated 20 mM Tris-HCl buffer (pH 8.0) at 25 C. The decrease in absorbance at 340 nm, which was monitored by using a UV-2550 spectrophotometer (Shimadzu, Kyoto, Japan)or a 96-well plate reader (VictorTM X3, 2030 Multilabel Reader, PerkinElmer Life Sciences), was used to calculate the enzymeactivity of HspB. The activity of His-HspB with 3-succinoylpyridine (SP) was determined under the same conditions. In some experiments His-HspB powder was used, obtained by using vacuum freeze-drying methods.
(S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one succinate salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione of Formula (I), 1000 ml methanol and 119 g methyl amine were added to RBF at 25 C. to 35 C. The reaction was heated to 60 C. to 65 C. for 1-2 hours. To the reaction mass succinic acid (15 g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50 C. and maintained for 30 minutes. The reaction mass was cooled to 25 to 35 C. and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml*2) afforded succinate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one of Formula (JS).
9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine monosuccinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.05 g
In isopropyl alcohol; acetonitrile;Reflux;
To a solution of 9-[(R)-2-[[(S)-[[(S)-l-(isopropoxycarbonyl) ethyl] amino] phenoxy phosphinyl] methoxy] propyl] adenine (lgm, 0.0021 mol) in mixture of acetonitrile (20 gms)/ Isopropanol (6gms), succinic acid (0.22 gms, 0.0019 mol) was added and the reaction mixture was heated to reflux to dissolve the solids. The reaction mass was filtered in hot condition, filtrate cooled to 5°C and maintained for 16 hours. The product was isolated by filtration, rinsed with acetonitrile (6 gms), and dried to obtain 1.05 gms of succinate salt as a white crystalline powder. HPLC purity: 99.49percent The XRPD is set forth in Figure 05.
543 mg
In ethyl acetate;Reflux;
The TAF (476mg, 1.0mmol) and succinic acid (118mg, 1.0mmol) was suspended in ethyl acetate (10.0 ml of) the solution was heated at reflux until the solids dissolve,Hot filtration undissolved particles, then add the appropriate amount of n-hexane and then heated until turbidity appears still to clarify and slowly cooled to room temperature and overnight at this temperature, the product was isolated by filtration, washed with cold ethyl acetate and n-hexane (V / V = 1: 1) washed with a mixed solution, and dried in vacuo to give 534mg of a white solid powder.
In acetonitrile; at 20℃;
10 mg (0.027 mmol) of (S)-isopropyl-2-(((S)-((((R)- 1 -(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate was dissolved in 0.42 8 mL of acetonitrile. 3.3 mg (0.027 mmol) of succinic acid was dissolved in 0.8 mL of acetonitrile. Both the solutions were mixed together and the obtained solution was left at the room temperature. During slow evaporation of the solvent a white crystalline substance was separated. The crystalline product was dried in a vacuum drier (200 mBar) at the roomtemperature for 2h. Melting point: 108°C (DSC). XRPD: see Figure 19. JR spectrum: see Figure 21.
N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine[ No CAS ]
[ 159766-56-0 ]
succinic acid-[Pen]-QTWQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Peptide monomers of the present invention were synthesized using the Merrifield solid phase synthesis techniques on Protein Technology's Symphony multiple channel synthesizer. The peptides were assembled using HBTU (0-Benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluoro-phosphate), Diisopropylethylamine(DIEA) coupling conditions. For some amino acid couplings PyAOP(7-Azabenzotriazol- 1 -yloxy)tripyrrolidinophosponium hexafluorophosphate) and DIEA conditions were used. Rink Amide MB HA resin (100-200 mesh, 0.57 mmol/g) was used for peptide with C-terminal amides and pre-loaded Wang Resin with N-a-Fmoc protected amino acid was used for peptide with C-terminal acids. The coupling reagents (HBTU and DIEA premixed) were prepared at lOOmmol concentration. Similarly amino acids solutions were prepared at 100 mmol concentration. Peptide inhibitors of the present invention were identified based on medical chemistry optimization and/or phage display and screened to identify those having superior binding and/or inhibitory properties.[00611] The peptides were assembled using standard Symphony protocols. The peptide sequences were assembled as follows: Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4ml of DMF followed by treatment with 2.5ml of 20% 4-methyl piped dine (Fmoc de- protection) for lOmin. The resin was then filtered and washed two times with DMF (4ml) and re -treated with N-methyl piperifine for additional 30 minute. The resin was again washed three times with DMF (4 ml) followed by addition 2.5ml of amino acid and 2.5ml of HBTU-DIEA mixture. After 45min of frequent agitations, the resin was filtered and washed three timed with DMF (4 ml each). For a typical peptide of the present invention, double couplings were performed. After completing the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling.
(R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide monosuccinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
In 2-methyltetrahydrofuran; at 20 - 25℃; for 1h;
Example 12: Preparation of Mirabegron Monosuccinate SaltTo Mirabegron free base (3.0 g, 0.01 moles) was added 2- methyltetrahydrofuran (30 mL) and succinic acid (0.90 g, 0.01 moles). The mixture was stirred at 20-25 C for 1 hour and the obtained suspension wasfiltered, washed with 2-methyltetrahydrofuran (1 x 6 mL) and dried to afford Mirabegron monosuccinate salt (3.1 g, 79% yield). A PXRD diffractogram of this sample is shown in Figure 8. 1H NMR (300 MHz, DMSO-d6) 6 10.0 (s, 1H), 7.6-7.4 (m, 1H), 7.4-7.2 (m, 5H), 7.2-7.1 (m, 2H), 6.9 (s, 2H), 6.3 (s, 1H), 4.8-4.6 (m, 1H), 3.4 (s, 2H), 3.0-2.7 (m, 6H), 2.3 (s, 4H).
1-(2,3-difluoro-6-nitrophenyl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.7%
With toluene-4-sulfonic acid; In 5,5-dimethyl-1,3-cyclohexadiene; for 7h;Dean-Stark; Reflux;
2,3-difluoro-6-nitro-aniline 76.63g (440mmol), 57.12g succinic acid (484mmol), and p- toluene sulfonic acid 8.37g a (44mmol) was dissolved in xylene 880ml, a Dean-Stark tube use was refluxed dehydrated with 7 hours. After cooling, the solvent was evaporated. The resulting crude crystals were washed with ethyl acetate / hexane = 1/1, and dried under reduced pressure. 1- (2,3-difluoro-6-nitrophenyl) pyrrolidine-2,5-dione 107.82g (420.9mmol, 95.7% yield)
The TAF (476mg, 1.0mmol) and succinic acid (59.0mg, 0.5mmol) was suspended in acetonitrile (5.0ml) solution was heated to reflux, hot filtered undissolved particles, an appropriate amount of chloroform was added and then heated until cloudiness appears stationary and slowly cooled to clarify -5 ~ 0 , overnight at this temperature, the product is isolated by filtration, washed with cold chloroform, and dried in vacuo to give 135mg of a white solid powder.
The TAF (476mg, 1.0mmol) and succinic acid (82.6mg, 0.7mmol) was suspended in ethyl acetate (5.0ml) solution was heated to reflux, hot filtered undissolved particles, an appropriate amount of petroleum ether was added until cloudiness appears after heating to clarify and still slowly cooled to -5 ~ 0 , and overnight at this temperature, the product was isolated by filtration, washed with cold ethyl acetate and petroleum ether (V / V = 1: 1) was washed with a mixed solution and dried in vacuo to give 193mg of a white solid powder.
The TAF (476mg, 1.0mmol) and succinic acid (53.1mg, 0.45mmol) was suspended in isopropanol (5.0ml) solution was heated to reflux, hot filtered undissolved particles, an appropriate amount of diethyl ether was added until cloudy after and still further heated slowly cooled to clarify -5 ~ 0 , overnight at this temperature, the product is isolated by filtration, washed with cold diethyl ether solution was dried in vacuo to give 98.0mg of a white solid powder.
1-(3-hydroxypropyl)-5-(2R)-2-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}aminopropyl-2,3-dihydro-1H-indole-7-carbonitrile succinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: 3- {5- (2R) -2-aminopropyl} -7-cyano-2,3-dihydro-1H-indol-1-yl}Propyl benzoate(2R, 3R) -mono-tartaric acid salt(Mono-tartaric acid salt of the compound of formula (II)),Potassium carbonate (80 g),And a mixed solvent of acetonitrile and dimethylacetamide (ACN / DMAC = 500 mL / 500 mL) was heated to 80 DEG C,Stir for 30 min. To the reaction mixture were added 70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula 3) and 9.70 g of KI,The reaction was carried out at the same temperature for 10 hours.The reaction mixture was cooled to room temperature,And extracted with 1 L of ethyl acetate and 1.5 L of water.The organic layer obtained by layer separation was washed with 1 L of brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing again with 200 mL of ethyl acetate, the solvent was removed by distillation. 400 mL of methanol, 100 mL of water and 20 g of KOH were added to the obtained residue. After the mixture was stirred at room temperature for 10 hours,1 L of ethyl acetate and 1 L of water were added and extracted for 10 minutes.The organic layer obtained by layer separation was washed sequentially with 1 L of saturated aqueous solution and 1 L of saturated brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing with 200 mL of ethyl acetate,18 g of oxalic acid was added.The reaction mixture was stirred at 50 for 30 minutes, It cooled to room temperature.600 mL of isopropyl ether was added to the reaction mixture,Stirred for 2 hours, and then filtered.The obtained crystals were washed with 200 mL of isopropyl ether,At 40 for 10 hours to give the titled compound as a dried in vacuo to 88 g.The reaction was carried out in the same manner as in Example 1, except that 23 g of succinic acid was used instead of oxalic acid to obtain 92 g of tabular compound.Yield: 82%Purity: 99.5%Impurities (dimer): Not more than 0.1%
General procedure: Stage I (0144) Table 11 illustrates the selected counter ions for the salt screening of beta-GPA. Salt screening experiments were designed in 1:1.1 equivalence (eq) for beta-GPA to counter ion. [table-us-00011-en] TABLE 11 List of selected counterions beta- Counterion Counterion GPA sequence molecular Sample ID (mg) Counterion wt 2162-42-1 to 4 30 Hydrochloric 1 36.46 acid (36-38%)* 2162-42-5 to 8 30 Hydrobromic 2 80.91 acid (48%)* 2162-42-9 to 12 30 Sulfuric acid 3 98.08 (95-98%)* 2162-42-13 to 16 30 Phosphoric acid 4 98.00 (85%)* 2162-42-17 to 20 30 Methane sulfonic 5 96.11 acid (98%)* 2162-42-21 to 24 30 Maleic acid 6 116.07 2162-42-25 to 28 30 Fumaric acid 7 116.07 2162-42-29 to 32 30 Tartaric acid 8 150.09 2162-42-33 to 36 30 Ethanesulfonic 9 110.13 acid 2162-42-37 to 40 30 Ethanedisulfonic 10 190.20 acid 2162-42-41 to 44 30 Citric acid 11 192.12 2162-42-45 to 48 30 Malic acid 12 134.09 2162-42-49 to 52 30 Lactic acid 13 90.08 2162-42-53 to 56 30 Aspartic acid 14 133.1 2162-42-57 to 60 30 Succinic acid 15 118.09 2162-42-61 to 64 30 Sodium 16 40.00 hydroxide 2162-42-65 to 68 30 Potassium 17 56.11 hydroxide 2162-42-69 to 72 30 Oxalic acid 18 90.03 2162-45-1 to 4 30 Magnesium 19 58.32 hydroxide 76 salt screening experiments of beta-GPA with 19 different counter ions were set up with 30 mg of beta-GPA. Sets of four vials for each counterion were set up with four different solvents (0.3 mL): ethanol:water (9:1), isopropanol, acetone:water (9:1) and acetonitrile. (0146) Appropriate amounts of beta-GPA and the counterion were dissolved in the respective solvents and heated to 70-75 C. until dissolved. An additional 0.1 mL of water was added to the samples containing isopropanol, acetone:water (9:1) and acetonitrile. To samples containing L-aspartic acid, around 1.5 mL of water was required to dissolve the solids. After a clear solution was obtained, the samples were left for stirring at room temperature. Solids were observed in the following samples: 2163-42-4, 25, 26, 27, 28, 45 and 53 through 75. The solids were filtered and analyzed by XRPD immediately as wet sample. The samples that did not yield solids were placed in the oven at 50 C. for drying. The following samples resulted in solids after overnight drying: 2162-42-2, 1, 2, 3 and 21 through 24. The experiments with L-aspartic acid, sodium hydroxide, potassium hydroxide, and magnesium hydroxide resulted in the precipitation of either beta-GPA or the counterion. All the experimental observations were recorded after every step and are listed in Table 12. [table-us-00012-en] TABLE 12 Results of Salt screening Sample ID Counterion Solvent After 24 hours After Drying XRPD 2162-42-1 Hydrochloric EtOH:H2O (9:1) Clear Solution White Solid Pattern 1A 2162-42-2 Acid IPA Clear Solution White Solid 2162-42-3 Acetone:H2O (9:1) Clear Solution White Solid 2162-42-4 MeCN White Solid N/A 2162-42-5 Hydrobromic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-6 Acid IPA Clear Solution Gel N/A 2162-42-7 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-8 MeCN Clear Solution Gel N/A 2162-42-9 Sulfuric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-10 IPA Clear Solution Gel N/A 2162-42-11 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-12 MeCN Clear Solution Gel N/A 2162-42-13 Phosphoric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-14 IPA Clear Solution Gel N/A 2162-42-15 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-16 MeCN Clear Solution Gel N/A 2162-42-17 Methanesulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-18 Acid IPA Clear Solution Gel N/A 2162-42-19 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-20 MeCN Clear Solution Gel N/A 2162-42-21 Maleic Acid EtOH:H2O (9:1) Clear Solution White Solid Pattern 6A 2162-42-22 IPA Clear Solution White Solid 2162-42-23 Acetone:H2O (9:1) Clear Solution White Solid 2162-42-24 MeCN Clear Solution White Solid 2162-42-25 Fumaric Acid EtOH:H2O (9:1) White Solid N/A Pattern 7A 2162-42-26 IPA White Solid N/A 2162-42-27 Acetone:H2O (9:1) White Solid N/A 2162-42-28 MeCN White Solid N/A 2162-42-29 L-Tartaric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-30 IPA Clear Solution Gel N/A 2162-42-31 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-32 MeCN Clear Solution Gel N/A 2162-42-33 Ethanesulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-34 Acid IPA Clear Solution Gel N/A 2162-42-35 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-36 MeCN Clear Solution Gel N/A 2162-42-37 Ethanedisulfonic EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-38 Acid IPA Clear Solution Gel N/A 2162-42-39 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-40 MeCN Clear Solution Gel N/A 2162-42-41 Citric Acid EtOH:H2O (9:1) Clear Solution Gel N/A 2162-42-42 IPA Clear Solution Gel N/A 2162-42-43 Acetone:H2O (9:1) Clear Solution Gel N/A 2162-42-44 MeCN Clear Solution Gel N/A 2162-42-45 L-Malic Acid EtOH:H2O (9:1) White Solid N/A Pattern 12A 2162-42-46 IPA Clear Solution Gel N/A 2162-42-47 Acetone:H2O (9:1) Clear Solution Gel N/...
Succinate Salt (0213) Around 72 g (0.55 moles) of beta-GPA was added to 400 mL of ethanol:water (9:1) in 500 mL jacketed vessel at 75 C. and a slurry was made. To this, a slurry of succinic acid, prepared by adding 71.2 g (0.6 moles) in 200 mL ethanol:water (9:1) at 65 C., was added. The temperature of the reactor was brought down to 18 C. and the reaction mixture was left for overnight stirring. Sample ID: 2162-62-1. (0214) The following day, the slurry was filtered and the solid was washed twice with 20 mL of isopropanol. The cake was placed in a vacuum oven at 45 C. for drying. Yield=101.3 g (97%). The solid was analyzed by XRPD and the formation of beta-GPA succinate (Pattern 15 A) was confirmed.
4-[3-chloro-4-(N'-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.68 g
In ethanol; at 25 - 70℃; for 16h;
Succinic acid (0.15 g) was added to a mixture of <strong>[417716-92-8]lenvatinib</strong> free base (0.5 g) and ethanol (10 mL) at 70C and stirred for 1 hour at 65-70C. The reaction mixture was cooled to 25 C to 30C and then stirred for 15 hours at 25 C to 30C. The solid obtained was filtered and then washed with ethanol (5mL). The solid was dried under reduced pressure at 50C to 55C for 18 hours to obtain the title compound. Yield: 0.68 g
At room temperature, AZD9291 (5.0 g, 10 mmol) was added to the reaction flask. Add 50 ml of acetone and stir to dissolve An aqueous solution (20 mL) of succinic acid (1.18 g, 12 mmol) was added dropwise with stirring. Yellow solids precipitated, Stir for about half an hour, Suction filtration The filter cake is rinsed with a small amount of acetone. drying, Obtained as a yellow particulate solid 4.68 g (7.6 mmol), Yield: 76%, Purity: 99.4%, Light yellow solid.
In Isopropyl acetate; at 20 - 50℃;Sealed tube; Sonication;
A mixture of 99 5 mg of Compound (I), 27 1 mg (1 eq) of succime acid, and 0 75 mL of isopropyl acetate was sonicated for about 30 minutes in a sealed 4 mL amber glass vial. The sample was agitated by a magnetic stir bar at about 50 C for about 1 hour, and then cooled to room temperature where the sample remained stirring for about 1 week. The solids were isolated by centrifuge and were dried under vacuum overnight at about 50 C. ?H NMR showed about 1 equivalent succinic acid.
With trimethylsilyl trifluoromethanesulfonate; In 1,4-dioxane; at 25℃;
Add 1,4-dioxane 20 mL to a 100 mL single-mouth bottle.<strong>[171228-49-2]Posaconazole</strong> 2.5g (3.56mmol),Succinic acid 0.42 g (3.56 mmol),Trimethylsilyl triflate 0.79 g (3.56 mmol),The reaction was stirred at 25 ± 5 C overnight.TLC monitors the reaction completely,The reaction was dropwise added with 3.5 mL of a 1M aqueous solution of sodium hydrogen carbonate.Concentrated to dryness, dissolved in 30 mL of dichloromethane.Filtered, the filtrate was washed with water 3×30 mL, and the dichloromethane phase was collected.Dry over anhydrous sodium sulfate,Filtration and concentration of white solid 2.7 g yield 94.7%,The purity is 96.8%.
Took 45 mg of LY2157299 monohydrate and mixed with 8.3 mg succinic acid, added 0.3 mL of methanol, ground at 10 C. to dryness, and obtained 46 mg succinate cocrystal form, yield 89%.