* 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] Journal of the American Chemical Society, 1944, vol. 66, p. 1479,1482
[2] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[3] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
2
[ 98-92-0 ]
[ 121-69-7 ]
[ 13438-65-8 ]
Reference:
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1479,1482
3
[ 98-92-0 ]
[ 100-55-0 ]
Reference:
[1] ACS Catalysis, 2016, vol. 6, # 1, p. 47 - 54
[2] Chemical Science, 2017, vol. 8, # 5, p. 3576 - 3585
4
[ 98-92-0 ]
[ 100-55-0 ]
[ 3731-52-0 ]
Reference:
[1] Chemical Science, 2016, vol. 7, # 5, p. 3432 - 3442
5
[ 98-92-0 ]
[ 100-55-0 ]
[ 3731-52-0 ]
Reference:
[1] Chemical Science, 2016, vol. 7, # 5, p. 3432 - 3442
Reference:
[1] European Journal of Organic Chemistry, 2002, # 23, p. 4054 - 4062
[2] Heterocycles, 1993, vol. 36, # 11, p. 2513 - 2522
[3] Organic Letters, 2008, vol. 10, # 22, p. 5115 - 5118
[4] Chemistry - A European Journal, 2012, vol. 18, # 18, p. 5506 - 5509
[5] New Journal of Chemistry, 2013, vol. 37, # 8, p. 2257 - 2260
[6] Archiv der Pharmazie, 2015, vol. 348, # 1, p. 34 - 45
[7] Chemical Biology and Drug Design, 2014, vol. 84, # 6, p. 721 - 731
[8] Patent: CN103804409, 2016, B,
[9] Patent: CN104327042, 2016, B,
10
[ 67-56-1 ]
[ 98-92-0 ]
[ 6960-22-1 ]
[ 7250-52-4 ]
[ 7145-28-0 ]
[ 7150-23-4 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 8, p. 2837 - 2846
[2] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 8, p. 2837 - 2846
[3] Chemistry Letters, 1986, p. 209 - 212
[4] Chemistry Letters, 1986, p. 209 - 212
[5] Chemistry Letters, 1986, p. 209 - 212
11
[ 67-56-1 ]
[ 98-92-0 ]
[ 6960-22-1 ]
[ 7250-52-4 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 9, p. 3055 - 3056
12
[ 98-92-0 ]
[ 4138-26-5 ]
Yield
Reaction Conditions
Operation in experiment
98.4%
With hydrogen In isopropyl alcohol at 75℃; for 4 h;
122.12 g (1.00 mol) of nicotinamide was dissolved in 500 mL of 2-propanol. To the resulting solution was charged 14.4 g of palladium-carbon (10percent), and the solution was stirred for 4 hours at 75° C. under hydrogen pressure of 0.5 MPa. After the reaction was completed, the palladium-carbon was filtered and separated. The filtered palladium-carbon was washed with 100 mL of 2-propanol. The filtrate and the washing liquid were combined and condensed, and 126.08 g of white crystals of nipecotamide in a racemic form was obtained. The yield was 98.4percent. The resultant was confirmed to be the target object by NMR.
Reference:
[1] Patent: US2012/123128, 2012, A1, . Location in patent: Page/Page column 3
[2] Synlett, 2006, # 9, p. 1440 - 1442
[3] Chemistry - A European Journal, 2009, vol. 15, # 28, p. 6953 - 6963
[4] Synlett, 2008, # 8, p. 1125 - 1128
[5] Journal of the American Chemical Society, 1949, vol. 71, p. 1680
[6] Journal of Organic Chemistry, 1952, vol. 17, p. 547,553
13
[ 98-92-0 ]
[ 24517-64-4 ]
Reference:
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
14
[ 98-92-0 ]
[ 62476-56-6 ]
Reference:
[1] Patent: CN108484492, 2018, A,
15
[ 98-92-0 ]
[ 462-08-8 ]
[ 39856-57-0 ]
Reference:
[1] Archiv der Pharmazie (Weinheim, Germany), 1902, vol. 240, p. 358
16
[ 98-92-0 ]
[ 6515-09-9 ]
Reference:
[1] Patent: CN108484492, 2018, A,
17
[ 98-92-0 ]
[ 10366-35-5 ]
Reference:
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
18
[ 98-92-0 ]
[ 5345-47-1 ]
Reference:
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
19
[ 98-92-0 ]
[ 553-53-7 ]
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[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1681 - 1692
[2] Journal of Biological Chemistry, 1943, vol. 147, p. 651
[3] Farmaco, Edizione Scientifica, 1953, vol. 8, p. 204,208
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5368 - 5373
[5] Patent: WO2016/162785, 2016, A1, . Location in patent: Page/Page column 22
20
[ 67-56-1 ]
[ 98-92-0 ]
[ 5657-51-2 ]
[ 5657-52-3 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1982, vol. 55, # 9, p. 3055 - 3056
21
[ 64648-13-1 ]
[ 98-92-0 ]
[ 40055-37-6 ]
Reference:
[1] Organic Preparations and Procedures International, 1995, vol. 27, # 1, p. 103 - 106
22
[ 50-00-0 ]
[ 98-92-0 ]
[ 3569-99-1 ]
Reference:
[1] Roczniki Chemii, 1953, vol. 27, p. 396,401[2] Chem.Abstr., 1955, p. 1033
[3] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2> 138, p. 289,291
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 1, p. 158 - 162
[5] Journal of Chemical Sciences, 2014, vol. 126, # 5, p. 1285 - 1290
Nicotinamide suspended in 35% neutralized formaldehyde solution was refluxed for an hour at 100C,cooled and recrystallized from acetone to yield Nhydroxymethylnicotinamide. This solid was heated at 200C to yield 1a. The product was recrystallized fromhot water. Diffractable quality crystals were obtainedfrom DMF.
With hydrogen;palladium 10% on activated carbon; In isopropyl alcohol; at 75℃; under 3750.38 Torr; for 4h;
122.12 g (1.00 mol) of nicotinamide was dissolved in 500 mL of 2-propanol. To the resulting solution was charged 14.4 g of palladium-carbon (10percent), and the solution was stirred for 4 hours at 75° C. under hydrogen pressure of 0.5 MPa. After the reaction was completed, the palladium-carbon was filtered and separated. The filtered palladium-carbon was washed with 100 mL of 2-propanol. The filtrate and the washing liquid were combined and condensed, and 126.08 g of white crystals of nipecotamide in a racemic form was obtained. The yield was 98.4percent. The resultant was confirmed to be the target object by NMR.
D-α-phenylglycine chloride hydrochloride[ No CAS ]
+5°C,trimethylchlorosilane[ No CAS ]
[ 98-92-0 ]
[ 551-16-6 ]
[ 109-89-7 ]
6-(D-α-aminophenyl-acetamido)-2,2-dimethyl-penam-3-carboxylic acid[ No CAS ]
[ 69-53-4 ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane; water;
Example 1 6-(D-alpha-aminophenyl-acetamido)-2,2-dimethyl-penam-3-carboxylic acid. To a suspension of (<strong>[551-16-6]6-APA</strong>) <strong>[551-16-6]6-aminopenicillanic acid</strong> (54g; 0.25 mole) in methylene chloride (450 ml), diethylamine (36.5; 0.5 mole) is added. To the so obtained solution, at a temperature from 0 to +5°C,trimethylchlorosilane (54.5g;0.5 mole) is added. After 90 minutes at 25°-30°C, the silylating reaction is completed. The reaction mixture is cooled to -30°C and nicotinamide (36.6 g; 0.3 mole) and D-alpha-phenylglycine chloride hydrochloride (51.5 g; 0.25 mole) are added. The suspension is kept two hours at -5°C and, thereafter, 30 minutes at + 10°C. It is treated with water (300 ml) and the phases are separated. The aqueous phase is treated with concentrated NH4H to the isoelectric point (PH=4.5). After 1 hour at 0°/+5°c, the antibiotic is filtered off and then it is washed with H2 until disappearance of Clmin It is dried under vacuum, to obtain 85g of ampicillin. 3H2. Yield: 84.3 percent.
[0103] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide co-crystal, as shown in FIG. 11. [0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4).
[0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4).
In ethanol;
[0103] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide co-crystal, as shown in FIG. 11. [0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4).
In methanol;
[0103] 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were dissolved in 4 mL of DMSO, methanol or ethanol. Slow evaporation of the solvent yielded colorless needles of a 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide co-crystal, as shown in FIG. 11. [0104] Using a separate method, 25 mg (0.1058 mmol) <strong>[298-46-4]carbamazepin</strong>e and 12 mg (0.0982 mmol) nicotinamide were ground together with mortar and pestle. The solid was determined to be 1:1 <strong>[298-46-4]carbamazepin</strong>e/nicotinamide microcrystals (XPD). [0105] Crystal data: (Bruker SMART-APEX CCD Diffractometer), C21H18N4O2, M=358.39, monoclinic P2I/n; a=5.0961(8), b=17.595(3), c=19.647(3) , beta=90.917(3), U=1761.5(5) 3, T=200(2) K, Z=4, mu(Mo-Kalpha)=0.090 mm-1, Dc=1.351 Mg/m3, lambda=0.71073 3, F(000)=752, 2thetamax=56.600, 10919 reflections measured, 4041 unique (Rint=0.0514). Final residuals for 248 parameters were R1=0.0732, wR2=0.1268 for I>2?(I), and R1=0.1161, wR2=0.1430 for all 4041 data. [0106] Crystal packing: The co-crystals contain hydrogen bonded carboxamide homodimers. The 1 amines are bifurcated to the carbonyl of the nicotinamide on each side of the dimer. The 1 amines of each nicotinamide are hydrogen bonded to the carbonyl of the adjoining dimer. The dimers form chains with ?-? interactions from the phenyl groups of the CBZ. [0107] Infrared Spectroscopy: (Nicolet Avatar 320 FTIR), unsymmetrical and symmetrical stretching shifts down to 3443 cm-1 and 3388 cm-1 accounting for 10 amines; 1 amide CO stretching at 1690 cm-1; N-H in-plane bending at 1614 cm-1; C-C stretching shifted down to 1579 cm-1; aromatic H's from 800 cm-1 to 500 cm-1 are present. [0108] Differential Scanning Calorimetry: (TA Instruments 2920 DSC), 74.49 C. (endotherm) and 59.05 C. (endotherm), m.p.=153-158 C. (MEL-TEMP), (<strong>[298-46-4]carbamazepin</strong>e m.p.=190.2 C., nicotinamide m.p.=150-160 C.). [0109] Thermogravimetric Analysis: (TA Instruments 2950 Hi-Resolution TGA), 57.94% weight loss starting at 205.43 C. followed by complete decomposition. [0110] X-ray powder diffraction: (Rigaku Miniflex Diffractometer using Cu Kalpha (lambda=1.540562), 30 kV, 15 mA). The powder data were collected over an angular range of 3 to 40 2theta in continuous scan mode using a step size of 0.02 2theta and a scan speed of 2.0/minute. XRPD: Showed analogous peaks to the simulated XRPD derived from the single crystal data. XRPD analysis experimental (calculated): 6.5 (6.7); 8.8 (9.0); 10.1 (10.3); 13.2 (13.5); 15.6 (15.8); 17.8 (18.1); 18.3 (18.6); 19.8 (20.1); 20.4 (20.7); 21.6 (22.); 22.6 (22.8); 22.9 (23.2); 26.7 (27.0); 28.0 (28.4).
11.1 g
In methanol; cyclohexane; at 17 - 22℃; under 724.572 - 782.178 Torr; for 3h;
An anti-solvent (33.4g/97.5 wt % of anhydrous cyclohexane) and a solvent (0.75g/2.5 wt % of anhydrous methanol) were poured into the flow mixer to form a liquid medium for cocrystallisation of the precursor components of the active cocrystalline material. The motion generator was operated to provide an oscillatory motion to the liquid medium (stroke amplitude = 10mm; frequency 1.5Hz) and an active precursor component and a cocrystal coformer precursor component (8.3 lg <strong>[298-46-4]carbamazepin</strong>e and 4.3g nicotinamide (stoichiometric ratio 1:1), respectively) were then introduced into the flow mixer. The reaction took place at ambient temperature and pressure as described in Example 1. After 3 hours, the motion generator was stopped and the slurry of the liquid medium, active cocrystalline material and residual precursor components were removed from the flow mixer and were subjected to a filtration process. Any remaining solvent was allowed to evaporate from the residue. The residue (11. lg) was analysed using powder x-ray diffraction spectroscopy and confirmed to contain 1:1 <strong>[298-46-4]carbamazepin</strong>e:niotinamide cocrystal.
at 175℃;
Example 3 of the present invention consists in a mixture of <strong>[298-46-4]carbamazepin</strong>e (CARB anhydrous from TCI Development Co., Ltd.) and nicotinamide (NIC, from Sigma-Aldrich Company,Ltd), in a molar proportion 1:1 (total mass of -30 grams). Further processing of the physical mixture was identical to the procedure applied in EXAMPLE 1 and 2. Total melting of the physical mixture was observed at 175C. Spray congealing was conducted in the same equipment and in the same conditions as in EXAMPLE 1 and 2 (i.e. open-cycle mode, extended set-up, jacketed two fluid nozzle with 1.20 mm tip). The atomization flow rate was set to 11.8 L/min, while the congealing gas flow rate was maintained to 0.35 m3/min. The inlet and outlet temperatures (i.e. T_in and T_out, respectively) of the congealing gas after stabilization were 50C and 36C. At the end of the process, the resultant powders were characterized by the same analytical techniques and respective experimental methods as in EXAMPLE 1 and 2 (i.e. mDSC, XRPD and SEM) for characterization. The pure API, coformer and respective physical mixture were also analyzed through mDSC and XRPD for comparison.FIG.7 shows the mDSC heat flow curves correspondent to the thermal analysis of pure CARB, pure NIC, 1:1 CARB:NIC AC physical mixture and 1:1 CARB:NIC powder obtained using spray congealing.Similarly to the DSC profile of pure CAF, pure CARB first underwent a polymorphic transformation at 150C and second the melting of the new phase formed at 186C (J. Pharm. Sd. 2003, 92(11), 2260-71). The thermogram of pure NIC presented a single endothermic peak at 126C attributed to the thermodynamic melting of the material. The thermogram of the 1:1 CARB:NIC physical mixture showed two sharp endothermic peaks at 122C and 157C, which corresponded to the eutectic and cocrystal melting, respectively. Another endothermic peak was observed at a temperature of 103C with a much smaller associated enthalpy as compared with aforementioned endothermic peaks, which may correspond to a phase transformation. The thermogram observed for the powder produced using spray congealing was in agreement with the thermogram of the respective physical mixture and was indicative that cocrystals were formed. Similarly to EXAMPLE 2, the endotherm correspondent to the eutectic disappeared while the peak correspondent to the melting of the cocrystal was still observed at 154C. These results were in agreement with the literature, where 1:1 CARB:NIC cocrystals were produced using different manufacturing approaches (Cryst. Growth Des. 2009, 9(5). 2377-86; Pharm, Res, 2012, 29, 806-17).
In water; at 80℃; for 5h;Heating; Green chemistry;
For the slurry conversion synthesis, 2 mmol of <strong>[298-46-4]carbamazepin</strong>e (472.5 mg) was weighed in a beaker. In a different recipient, 2 mmol of nicotinamide (244.3mg) and 1.5 mL of ultrapure water were placed. This solution was added to the <strong>[298-46-4]carbamazepin</strong>e powder and the reaction was monitored by Raman spectroscopy. The reaction was heated using an IKA heating plate, model C-MAG HS 7, equipped with electronic thermometer and magnetic stirrer.
With silver hexafluoroantimonate; In acetonitrile; at 0 - 20℃; for 4h;
[0128] Synthesis of beta-3,5-p-chlorobenzoyl-1-nicotinamide-2-deoxyriboside. 100 mg (0.3 mmol) of 4 was added to a flame-dried flask containing 90 mg (0.8 mmol) nicotinamide. To a second flask, 20 mg (0.2 mmol) nicotinamide and 100 mg AgSbF6 (0.3 mmol) was added, with 5 mL acetonitrile to dissolve the salt. The silver solution was cooled to 0 C. with ice and then added rapidly by syringe to the flask containing the base and sugar. The solution was stirred chilled in an ice bath and a grayish precipitate formed. The reaction was stirred for 2 hours chilled and then warmed to room temperature and stirred an additional 2 hours. The reaction mixture was evaporated, the residue redissolved in MeOH and filtered through Celite. The filtrate was evaporated. The material was determined by NMR to contain the desired product in a mixture of stereoisomers (9:1 beta:alpha) in a yield of 85%. 1H NMR, d3-MeOD delta: (9.54 s, 1H), (9.25, s, 1H), (8.93, d, 1H), (8.2, m, 1H), (8.0-7.8, m, 4H), (7.6-7.3, m, 4H), (6.79, t, 1H), (5.77, m, 1H), (5.01, m, 1H), (4.99-4.4, m, 3H), (3.44, m, 1H), (2.9, m, 1H).
In ethyl acetate; at 20 - 70℃; for 25.25h;Product distribution / selectivity;
Example 2; A 100 mL round bottom flask was charged with 5.01 g adefovir dipivoxil (0.0100 moles), followed by 1.23 g nicotinamide (1.01 equivalents) and 50 mL ethyl acetate. The mixture was stirred and heated to 65-70 C. A clear solution was achieved after 15 minutes at which time the heating was stopped. The solution was allowed to passively cool to room temperature. During the cooling phase, about 1 hour, the precipitation of a white solid was observed. The resulting slurry was stirred at room temperature for 24 hours. The crystalline solid was collected by suction filtration and dried in vacuo (40-45 C.) affording 5.00 g (80%) of ADE:NIC cocrystals. PXRD as shown in FIG. 1.
Example 9 Composition of unsaponificable fraction of tall oil pitch. A composition containing unsaponificable tall oil pitch extract (5% by weight); sulphur containing amino acids (0.8%); zinc (1.6% by weight); vitamin B (0.3%); lycopene (2%) and water q.s.p. 100% by weight was prepared.
2.2 Synthesis of the complexes 2.2.1 [Cu(3-Me-2-tpc)2(nia)2] (1) The blue crysatals were obtained by dissolving of copper(II) nitrate (2.5 mmol) and equimolar quantities of <strong>[23806-24-8]3-methyl-2-thiophene-carboxylic acid</strong> and nicotinamide (5 mmol) in 50 cm3 of acetonitrile. The resulting solution was refluxed for 3 h and then left to slowly evaporate at ambient temperature. Well-shaped crystals, suitable for X-ray structure analysis, were collected after a few days by filtration, washed with acetonitrile and finally dried at ambient temperature (yield 74%).
2.2 Synthesis of the complexes 2.2.1 [Cu(3-Me-2-tpc)2(nia)2] (1) The blue crysatals were obtained by dissolving of copper(II) nitrate (2.5 mmol) and equimolar quantities of <strong>[23806-24-8]3-methyl-2-thiophene-carboxylic acid</strong> and nicotinamide (5 mmol) in 50 cm3 of acetonitrile. The resulting solution was refluxed for 3 h and then left to slowly evaporate at ambient temperature. Well-shaped crystals, suitable for X-ray structure analysis, were collected after a few days by filtration, washed with acetonitrile and finally dried at ambient temperature (yield 74%).
General procedure: The precursor complex [<strong>[14126-40-0]Co(PPh3)2Cl2</strong>] was prepared as reported earlier [15]. Methanolic solutions of the ligand (2mmol) and the precursor complex (2mmol) were mixed and heated at 50C for 3h with constant stirring. Then the mixture was evaporated to a volume of half of its original volume in vacuum and left to cool to room temperature. The precipitated complex was filtered in vacuum and washed with diethyl ether. The products were recrystallized from methanol.
[Zn(μ3-3,3'-thiodipropionate)(nicotinamide)2]n[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
General procedure: A mixture of Co(OAc)2·4H2O (1mmol, 0.249g) and 3,3?-thiodipropionic acid (tdpH2) (1mmol, 0.178g) in water (20mL) was stirred at 80C for 1h and then isonicotinamide (2mmol, 0.244g) in ethanol (10mL) was added to the mixture. The obtained solution was stirred at 80C for 2h. The resulting solution was filtered and evaporated at room temperature. The pink crystals obtained were washed with water (20mL) and dried in air. Yield: 0.153g, 32% (based on Co(OAc)2·4H2O).
6.1.3 Preparation of Azacytidine/Nicotinamide Cocrystal (Method B) [00299] A mixture of 85.7 mg (0.351 mmol) of azacytidine, 42.4 mg (0.347 mmol) of nicotinamide, 40 of a 1 :2 (v:v) mixture of methanol and water, and one stainless steel grinding ball was placed in a polyether ether ketone (PEEK) grinding cup. The cup was closed and agitated on a Retsch mill at 100% power for about 20 minutes. The grinding ball was removed and the contents of the cup were recovered to give 126.3 mg (99% yield) of pure azacytidine/nicotinamide cocrystal. XRPD analysis of a pure sample of the azacytidine/nicotinamide cocrystal is provided (FIG. 14A). DSC analysis shows endothermic event, likely melting, at about 166 C, other endothermic events at about 157 C and 208 C were also observed. The events at 157 C and 166 C may indicate a melt followed by a crystallization of another solid phase. TG analysis shows negligible weight loss up to 130 C and a 37.1 % weight loss from 140-220 C, indicating that the corystal is essentially anhydrous (FIG 14C). DVS analysis shows that the cocrystal is not very hygroscopic (FIG. 14D); furthermore, the crystalline form of the cocrystal did not change on exposure to elevated relative humidity, as evidenced by essentially identical XRPD patterns before and after DVS analysis (FIG 14A-B). A 1H-NMR spectrum shown peaks from both azacitidine and nicotinamide; integrationsindicate the cocrystal contains a 1 : 1 molar ratio of those components.
Example 6 Preparation of Zoledronic, Nicotinamide, and Water Complex by Solvent-Drop Grinding 99 mg of zoledronic acid is ground with 44 mg of nicotinamide and 40 mul of water is added to the solid mixture. The solids gathered after grinding are stored.
In water;
99 mg of zoledronic acid was ground with 44 mg of nicotinamide and 40 mu of water was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis. The material was characterized by PXRD and FTIR corresponding to FIG. 1 1 and FIG. 12, respectively.
Cu(3-methylsalicylate)<SUB>2</SUB>(nicotinamide)<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Copper acetate (0.5 mmol) was dissolved in ethanol and was left under vigorous stirring with nicotinamide (5 mmol) and then <strong>[83-40-9]3-methylsalicylic acid</strong> (1 mmol) was washed down to the reaction mixture with some amount of solvent. The green-blue product precipitated within few minutes, it was filtered off, and the motherliquid was left to crystallize at ambient temperature. Blue crystals formed, were separated and dried at room temperature. The obtained crystals were suitable for X-ray analysis.
Cu(5-methylsalicylate)<SUB>2</SUB>(nicotinamide)<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
Copper acetate (0.5 mmol) was dissolved in ethanol under stirring. The nicotinamide (1 mmol) was added under stirring to thereaction mixture and than it was followed by washing down the <strong>[83-40-9]3-methylsalicylic acid</strong> (1 mmol) with some amount of ethanol. The dark green product was filtered off, and the mother liquid was left to crystallize at ambient temperature. Blue crystals formed were separated and dried at room temperature. The obtained crystals were suitable for X-ray structure determination. [Cu(5-Mesal)2(nia)2] Anal Calc: C, 55.13; H, 4.29; N, 9.18. Found: C, 54.88; H, 4.21; N,9.13.
1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; water;
6.3.10 Cocrystal Solid Form 6 Form 6 was prepared in grinding experiments when nicotinamide was used as coformer and the mixture of THF and water (50/50) was used as solvent. Form 6 is a THF/water solvated cocrystal form of Compound 1 and nicotinamide.
General procedure: A mixture of Cu(OAc)2·2H2O (1.0mmol, 0.20g) and 2,2?-iminodiacetic acid (1.0mmol, 0.131g) were stirred in water at 70C for 30min and then nicotinamide (2.0mmol, 0.24g) in methanol (5.0mL) was added to the mixture. The obtained solution was stirred at 70C for 2h. After 2h, the resulting blue solution was filtered and evaporated at room temperature. Blue crystals of 1 were obtained one week later. Yield: 0.28g, 83% (based on Cu(OAc)2·2H2O).
10 g of niacinamide and 7.7 g of chloroacetic acid were dissolved in 300 mL of tetrahydrofuran, followed by stirring at 35C for 2 hours.After the stirring was completed, the concentrate obtained by distillation under reduced pressure was recrystallized from 15 mL of dichloromethane, filtered, and washed with 20 mL of dichloromethaneWashed to give 14.8 g of nitutyric acid (Compound A) as a white solid (Fig. 1).
1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3‘,4‘:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)butan-1-one nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; at 20℃; for 2h;
TGA-DSC analysis of the other slurry experiments using nicotinamide does not show any melting events, meaning the experiments conducted in acetonitrile or ethyl acetate do not form a co-crystal. This experiment is repeated at a gram scale. First, ITI-007 free base and nicotinamide are each dissolved in methanol. Subsequently, the obtained solutions were added in a 1:1 ratio to a vial. The mixture is stirred at room temperature for 2 hours, but no precipitation is observed. The solution is evaporated under vacuum to give a brown sticky solid. XRPD analysis of this brown sticky solid shows this to be nicotinamide itself.
[Co(nicotinamide)2(theophylline)2(SCN)2]*6H2O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium hydroxide; In ethanol; at 80 - 85℃; for 2h;pH Ca.7;
General procedure: TP of 0.97g (5mmol) was dissolved in water. An aqueous solution of the metal salt was added and placed in a magnetically-stirred 25ml round bottom flask. This was followed by the addition of an ethanolic solution (0.61g, 5mmol) of NA and an aqueous solution (0.48g, 5 mmnol) of KSCN at the molar ratio of 1:2:2:2 (M:NA:TP:KSCN). The pH of the solution was adjusted to ?7 by adding 0.1M NaOH in water and the system was refluxed for two hours at 80-85C. The solid material obtained were washed in water, recrystallized with ethanol:water mixture and dried. The yields were obtained between 70 and 85%. All complexes were air stable and soluble only in organic solvents. [Co(NA)2 (TP)2(SCN)2]·6H2O (1): Yield (%): 85. Color: Orange. M.P. (C): 162. Elemental Analysis (%): Calcd.: C 37.86, H 4.51, N 22.08, O 21.63, S 7.21, Co 6.71; Found: C 37.80, H 4.41, N 22.01, O 21.53, S 7.17, Co 6.68, FT-IR (cm-1): 3302.95 nu(NH), 2117.83 nu(SCN), 1666.84 nu(C=O), 1626.78 nu(C=N),1610.00 nu(C=C), 1251.62 nu(C-N), 714.06 nu(CS), 555.84 nu(M-N), 466.82, nu(MSCN). UV-Vis. 647, 388, 239. Magnetic Moment (BM): 4.55. Conductivity (Omega-1cm2mol-1): 20.81. MS (m/z, EI): 888.0; Found: 887.54.
Preparation of <strong>[3681-99-0]puerarin</strong> nicotinamide total amorphous material 2.00g <strong>[3681-99-0]puerarin</strong> and0.58g of niacinamide was added to 50mL of methanol,Ultrasonic solution at room temperature to obtain a clear solution,The clear solution was rotary-evaporated at 35 ° C under reduced pressure and dried under vacuum at 25 ° C for 12 h to afford white powder 2.
With tris(3-hydroxypropyl)phosphine; nicotinamide phosphoribosyltransferase; tris hydrochloride; ATP; magnesium chloride; In water; at 37℃;pH 7.5;Enzymatic reaction;Kinetics;
For the NTPase assays, NAMPT or NAMPT-H247A was incubated at 37 C with an NTP in TMT buffer (50 mM Tris-HCl, 10 mM MgC12, 1 mM THP, pH 7.5). The routinely-used NTP concentration was 2 mM. However, for the kinetic analysis ATP and GTP hydrolysis, the NTP concentration ranged from 0.25 mM to 4 mM. Other agents (FK-866, CHS-828, GNI-50, PNP, NMN) were included where indicated. At the indicated times, an aliquot of the sample was quenched by the addition of an equal volume of 1 M perchloric acid (PCA). Samples were stored at -80 C until processed for LC/MS/MS. The values for Vmax and Km (ATP and GTP hydrolysis) were deduced using the on-line Michaelis-Menten kinetics tool at (0160) http://www.graphpad.com/quickcalcs/ttestl/?Format=SEM For the NMN production assay, NAMPT (20 nM) was incubated in the presence of NAM (10 muMu), PRPP (50 muMu) in TMT buffer. Where indicated, NTPs (2 mM) were also included. NMN was assayed using a chemical method which converts NMN into a fluorescent derivative. Briefly, an aliquot (37.5 mu) of the NMN- containing sample was sequentially mixed with 15 mu of 20% acetophenone (in DMSO) and 15 mu of 2M KOH. The mixture was placed on ice for approximately 10 min. Next, 67.5 mu of 100% formic acid was added to each sample, vortexed, and then incubated at 37 C for 20 min. Samples (100 mu) were transferred to a 96-well opaque bottom plate and fluorescence (Ex/Em = 382/445 nm) was measured using a SpectraMax M5 plate reader (Molecular Devices, Sunnyvale, CA).
General procedure: Three cocrystals of DA were prepared with ISO, NIC and THE by means of liquid assisted grinding method using a catalytic quantity of solvent. DA-ISO, DA-NIC, and DA-THE were prepared by triturating a 1:1 stoichiometric ratio of DA (368.29mg) with ISO (122.13mg), NIC (122.13mg) and THE (180.16mg) along with 4 drops (0.4mL) of ethanol in a glass mortar and pestle for around 120min. All the cocrystals were prepared using the solvent drop grinding method. The time and dimension of mortar and pestle were optimized in different experiments for the uniformity of cocrystals in all the batches. Grinding was done for 30, 60 and 120min and found that effective grinding was achieved after 120min. Moreover, the melting point of each batch was determined and after that, they all were mixed together. The dried final products were scratched out and stored in desiccators at temperature 25±2C/40% RH for further analysis.
Ethanol (1 5mL) and nicotinamide (0.2g) were charged in a RBF at 25±5C and the contents were heated to 60-65C and stirred for 30 min at 60-65C. Methyl ethyl ketone (15mL) and Vadadustat (0.5g) were charged into the reaction mass at 60-65C. The reaction mass was stirred for 30 minutes at 60- 65C. The mass was then slowly cooled to 25±5C and maintained under stirring at 25±5C for 16 hours. The reaction mass was cooled to 0-5C and stirred for 2-3 hours. The product obtained was filtered, washed with methyl ethyl ketone (2 mL) and dried under vacuum for 3 hours at 40C. The solid obtained was identified as 1 :1 co-crystal of Vadadustat Nicotinamide. Yield: 0.45 g.