There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 7598-35-8 * Storage: {[proInfo.prStorage]}
* 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] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
2
[ 58530-53-3 ]
[ 84249-14-9 ]
[ 7598-35-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
3
[ 7598-35-8 ]
[ 58530-53-3 ]
Reference：
[1] Heterocycles, 2008, vol. 75, # 1, p. 57 - 64
[2] Roczniki Chemii, 1957, vol. 31, p. 569,574[3] Chem.Abstr., 1958, p. 5407
4
[ 7598-35-8 ]
[ 100523-96-4 ]
Reference：
[1] Roczniki Chemii, 1957, vol. 31, p. 569,574[2] Chem.Abstr., 1958, p. 5407
5
[ 52092-43-0 ]
[ 7598-35-8 ]
Reference：
[1] Heterocycles, 2008, vol. 75, # 1, p. 57 - 64
[2] Chemische Berichte, 1992, vol. 125, # 5, p. 1131 - 1140
[3] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 591,598
[4] Roczniki Chemii, 1957, vol. 31, p. 569,574[5] Chem.Abstr., 1958, p. 5407
[6] Journal fuer Praktische Chemie (Leipzig), 1988, vol. 330, # 1, p. 154 - 158
[7] Patent: US6673799, 2004, B1, . Location in patent: Page column 17
Reference：
[1] Chemistry of Heterocyclic Compounds, 2010, vol. 46, # 4, p. 438 - 444[2] Khim. Geterotsikl. Soedin., 2008, # 4, p. 551 - 559,9
8
[ 6945-67-1 ]
[ 7598-35-8 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
9
[ 14305-17-0 ]
[ 7598-35-8 ]
Reference：
[1] Chemische Berichte, 1992, vol. 125, # 5, p. 1131 - 1140
[2] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 591,598
[3] Roczniki Chemii, 1957, vol. 31, p. 569,574[4] Chem.Abstr., 1958, p. 5407
10
[ 58530-53-3 ]
[ 84249-14-9 ]
[ 7598-35-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
11
[ 626-03-9 ]
[ 7598-35-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
12
[ 58530-53-3 ]
[ 84249-14-9 ]
[ 7598-35-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 85,98[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 673,681
13
[ 7598-35-8 ]
[ 151-50-8 ]
[ 10386-27-3 ]
Reference：
[1] Roczniki Chemii, 1957, vol. 31, p. 569,574[2] Chem.Abstr., 1958, p. 5407
14
[ 7598-35-8 ]
[ 22282-72-0 ]
Reference：
[1] Roczniki Chemii, 1957, vol. 31, p. 569,574[2] Chem.Abstr., 1958, p. 5407
15
[ 7598-35-8 ]
[ 89943-12-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium hydroxide In ethanol; water
l) 2-Ethoxy-4-aminopyridine (Den Hertog, Kolder and Combe, 1951) 2-Bromo-4-aminopyridine (4 g). solid sodium hydroxide (4 g) and ethanol (15 ml) were heated in a bomb at 160° C. for 6 hours and allowed to cool. Water was then added and the solvent partially removed under reduced pressure. The mixture was then extracted with ether and the solvent removed, leaving a clear oil of 2-Ethoxy-4-aminopyridine (164 g, 76percent) which slowly crystallized into colourless needles, m.p. 88-89° C.
Reference：
[1] Patent: US5929082, 1999, A,
[2] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 591,598
16
[ 504-24-5 ]
[ 7598-35-8 ]
[ 84539-34-4 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2010, vol. 46, # 4, p. 438 - 444[2] Khim. Geterotsikl. Soedin., 2008, # 4, p. 551 - 559,9
Reference：
[1] Journal of Materials Chemistry C, 2015, vol. 3, # 28, p. 7405 - 7420
19
[ 7598-35-8 ]
[ 98-80-6 ]
[ 21203-86-1 ]
Yield
Reaction Conditions
Operation in experiment
100 %Spectr.
With palladium diacetate In water at 100℃; for 1 h; Inert atmosphere
[0032] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv), (0045) phenylboronic acid (1.341 g, 11 mmol, 1.1 equiv), Pd(OAc)2 ((0.0449 g, 0.2 mmol, 0.02 equiv) or (0.0898 g, 0.4 mmol, 0.04 equiv) as identified in Table 1) and H20 (25 mL, 1384 mmol) in a 3 -neck round-bottom flask was well stirred under reflux at 100 °C in a N2 atmosphere for the time listed in Table 1. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C, and listed in Table 1. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reactions were biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30percent NaOH aqueous solution, and then thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgSC , filtered, and then concentrated in vacuo. The crude product was analyzed by GC and FontWeight="Bold" FontSize="10" Η NMR, as provided in Table 1.
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 38, p. 7598 - 7602
[2] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1489 - 1499
[3] Journal of Organic Chemistry, 2016, vol. 81, # 18, p. 8520 - 8529
[4] Patent: WO2017/112576, 2017, A1, . Location in patent: Paragraph 0032
[5] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
20
[ 7598-35-8 ]
[ 21203-86-1 ]
Yield
Reaction Conditions
Operation in experiment
100 %Chromat.
With palladium diacetate In water at 100℃; for 4 h; Inert atmosphere
[0043] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv), potassium phenyltrifluoroborate (2.760 g, 15 mmol, 1.5 equiv), Pd(OAc)2 (0.0898 g, 0.4 mmol, 0.04 equiv) and 0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was well stirred under reflux at 100 °C in a N2 atmosphere for 4 h. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 °C. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 °C; the time to reach this temperature was approximately 20 - 30 minutes. The reaction was biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30percent NaOH aqueous solution, and then thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgS04, filtered, and then concentrated in vacuo. The crude product was analyzed by GC, as provided in Table 6.
Stage #1: With triethylamine In dichloromethane at 20 - 30℃; Stage #2: With dmap In dichloromethane at 20 - 30℃; for 16 h;
Charge 2-bromopyridin-4-amine (100.0 g), Et3N (64.8 g) and DCM (1.0 L) into the reactionvessel, stir the reaction mixture at 20-30°C for 15-30 mm. Charge DMAP (3.5 g) into the reactionvessel, add (Boc)20 (416.3 g) dropwise into the reaction vessel. Stir the reaction vessel at 20-30°C for 16 h, check the reaction with HPLC. Wash the reaction mixture with water (2 L). Separate the organic phase and concentrate under reduced pressure to give crude product as yellow solid. Slurry the obtained solid with MeOH (300.0 mL) at 20-30°C for 30 mm, then filter to get the title compound(171.2 g) as off-white solid.
l) 2-Ethoxy-4-aminopyridine (Den Hertog, Kolder and Combe, 1951) 2-Bromo-4-aminopyridine (4 g). solid sodium hydroxide (4 g) and ethanol (15 ml) were heated in a bomb at 160 C. for 6 hours and allowed to cool. Water was then added and the solvent partially removed under reduced pressure. The mixture was then extracted with ether and the solvent removed, leaving a clear oil of 2-Ethoxy-4-aminopyridine (164 g, 76%) which slowly crystallized into colourless needles, m.p. 88-89 C.
With ammonium chloride;iron; In ethanol; for 0.5h;Heating / reflux;
Reference Example 17 4-Amino-2-bromopyridine To 450 ml of 67% ethanol aqueous solution were added 8.78 g of 2-bromo-4-nitropyridine N-oxide, 11.2 g of iron powder and 1.2 g of ammonium chloride in that order, and then the mixture was heated under reflux for about 30 minutes.. The insoluble matter was removed by filtration, the thus obtained filtrate was evaporated under reduced pressure, and then the thus formed residue was mixed with an appropriate amount of saturated aqueous sodium bicarbonate and extracted with ethyl acetate.. The organic layer was washed with water, dried and evaporated under reduced pressure, and then the thus formed crude product was purified by a silica gel column chromatography to obtain 4.4 g of the title compound from chloroform-methanol-28% aqueous ammonia (200:9:1, v/v/v) elude as light orange crystals.
With hydrogenchloride; potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene;
b 2-(3,4-Dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1 hydrochloride A solution of 2-bromo-pyridin-4-yl-amine (0.87 g, 5 mmol) and palladium tetrakis(triphenylphosphine) (0.58 g,0.5 mmol) in toluene (25 ml) was stirred at rt for 15 min. Then, 3,4-dihydro-naphthalene-2-boronic acid (0.88 g, 5 mmol) and aqueous 2M K2CO3 solution (5 ml) was added and the resulting mixture refluxed for 30 min. Toluene (50 ml) was added and the organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with (CH2Cl2/CH3OH/NH4OH=300/10/1) to give the free base of the title compound (0.72 g, 65%) as a colorless foam. Treatment with hydrogen chloride gave white crystals, Mp. 231-232 C. (EtOH/Et2O), MS: m/e=222 (M+).
2-(7-chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);
c 2-(7-Chloro-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1 fumarate Following the general method described in example 19b, the title compound was obtained as a white crystalline material by reaction of <strong>[7598-35-8]2-bromo-pyridin-4-ylamine</strong> with palladium tetrakis(triphenylphosphine), 7-chloro-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M K2CO3 solution and crystallization of the free base as the fumarate salt. Mp. 205-207 C. (MeOH), MS: m/e=250 (M+).
2-(5-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);
c 2-(5-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1 fumarate Following the general method described in example 19b, the title compound was obtained as a white crystalline material by reaction of <strong>[7598-35-8]2-bromo-pyridin-4-ylamine</strong> with palladium tetrakis(triphenylphosphine), 5-methoxy-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M K2CO3 solution and crystallization of the free base as the fumarate salt. Mp. 207-208 C. (MeOH), MS: m/e=252 (M-).
2-(7-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);
c 2-(7-Methoxy-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1 fumarate Following the general method described in example 19b, the title compound was obtained as a beige crystalline material by reaction of 2-bromo-pyridin-4-yl-amine with palladium tetrakis(triphenylphosphine), 7-methoxy-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M K2CO3 solution and crystallization of the free base as the fumarate salt. Mp. 193-194 C. (MeOH/Et2O), MS: m/e=252 (M+).
2-(5,7-dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);
c 2-(5,7-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1 fumarate Following, the general method described in example 19b, the title compound was obtained as a white crystalline material by reaction of 2-bromo-pyridin-4-yl-amine with palladium tetrakis(triphenylphosphine), 5,7-dimethyl-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M K2CO3 solution and crystallization of the free base as the fumarate salt. Mp. 231-232 C. (MeOH), MS: m/e:=250 (M+).
2-(5,8-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);
c 2-(5,8-Dimethyl-3,4-dihydro-naphthalen-2-yl)-pyridin-4-yl-amine 1:1 fumarate Following the general method described in example 19b, the title compound was obtained as a white crystalline material by reaction of 2-bromo-pyridin-4-yl-amine with palladium tetrakis(triphenylphosphine), 5,8-dimethyl-3,4-dihydro-naphthalene-2-boronic acid and aqueous 2M K2CO3 solution and crystallization of the free base as the fumarate salt. Mp. 232-233 C. (MeOH), MS: m/e=250 (M+).
With sodium ethanolate; In ethanol; dimethyl sulfoxide; at 155℃; for 0.333333h;Microwave irradiation;
EXAMPLE 184A; A mixture of 4-amino-2-bromo-pyridirie (213 mg), EXAMPLE 6 (100 mg) and 21 wt% sodium ethoxide in etha?ol (03 mL) in dimethylsulfoxide (3 mL) was heated at 1550C under microwave conditions for 20 minutes and concentrated. The concentrate was purified by reverse phase HPLC on a RPl 8 prep cartridge with 0.1% trifluoroacetic <n="88"/>acid/water/acetonitiile. 1H NMR (DMSO-d6) delta 1.43 (s, 9H), 7.33 (dd, .1-5.7, 2 OHz, IH), 7.86 (d, J=I.8Hz, IH), 8.04 (s, IH), 8,20 (d, J=5.8Hz, IH), 10.03 (s, IH).
With triphenylphosphine; In N,N-dimethyl-formamide;
EXAMPLE 16 trans-2-Styryl-pyridin-4-yl-amine Under inert atmosphere (Ar) a mixture of palladium-(II)-acetate (0.117 mg, 0.5 mmol) and triphenylphosphine (0.248 g, 0.9 mmol) in DMF (13 ml) was stirred for 30 min at rt. 2-Bromo-pyridin-4-ylamine (0.90 g, 5.2 mmol) (H. J. den Hertog, C. R. Kolder and W. P. Combe, Rec. Trav. Chim., 1951, 70, 591) was added followed by tributyl-styryl-stannane (3.93 g, 10 mmol). After heating at 130 C. for 15 min the solvent was evaporated and the residue partitioned between AcOEt and 3N HCl. The aqueous phase was neutralized with 6N NaOH and extracted with AcOEt. The organic phase was dried with Na2SO4, concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH=140/10/1) to give the title compound (0.40 g, 39%) as a colorless solid. Mp. 164-165 C. (AcOEt), MS: 196 (M+).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0);
c 2-(6,7-Dihydro-benzo[b]thiophen-5-yl)-pyridin-4-yl-amine 1:1 fumarate Following the general method described in example 19b, the title compound was obtained as a white crystalline material by reaction of 2-bromo-pyridin-4-yl-amine with palladium tetrakis(triphenylphosphine), 6,7-dihydro-benzo[b]thiophene-5-boronic acid and aqueous 2M K2CO3 solution and crystallization of the free base as the fumarate salt. Mp. 199-200 C. (MeOH), MS: m/e=228 (M+).
With triethylamine; In tetrahydrofuran; at 0 - 25℃;
Et3N (0.64 ml_) and di-tert-butyl dicarbonate (4.62 mmol) at 0 C were added to a solution of commercially available 4-amino-2-bromopyirdine (2.31 mmol, 400 mg) in anhydrous THF (5.9 ml_), and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure; then the residue was diluted with EtOAc and sequentially washed with a saturated solution of sodium bicarbonate, water and brine. The organic phase was dried with Na2S04 and concentrated. The crude reaction product was purified by column chromatography over silica gel with a mixture of n- hexane/EtOAc 8:2 as the eluent to afford intermediate O (72% yield). [1H-NMR (CDCIs) d (ppm): 1.52 (s, 9H), 6.68 (bs, 1 H), 7.18 (dd, 1 H, J = 5.6, 2.0 Hz), 7.64 (d, 1 H, J = 1.9 Hz), 8.17 (d, 1 H, J = 5.7 Hz).]
With triethylamine; In dichloromethane;
Step 1 2-Bromo-4-(tert-Butoxycarbonylamino)pyridine Stir a mixture of 4-amino-2-bromopyridine (1.00 g, 5.79 mmol), Et3N (1.75 g, 17.37 mmol) and di-tert-butyl dicarbonate (1.90 g, 8.69 mmol) in CH2Cl2 (20 ml) at RT overnight. Dilute with CH2Cl2(10 ml), wash with saturated aqueous NaHCO3, dry over MgSO4 and concentrate. Purify the residue by column chromatography to give the desired compound.
171.2 g
Charge 2-bromopyridin-4-amine (100.0 g), Et3N (64.8 g) and DCM (1.0 L) into the reactionvessel, stir the reaction mixture at 20-30C for 15-30 mm. Charge DMAP (3.5 g) into the reactionvessel, add (Boc)20 (416.3 g) dropwise into the reaction vessel. Stir the reaction vessel at 20-30C for 16 h, check the reaction with HPLC. Wash the reaction mixture with water (2 L). Separate the organic phase and concentrate under reduced pressure to give crude product as yellow solid. Slurry the obtained solid with MeOH (300.0 mL) at 20-30C for 30 mm, then filter to get the title compound(171.2 g) as off-white solid.
k) 2-Bromo-4-aminopyridine (Den Hertog, Kolder and Combe, 1951) 2-Bromo-4-nitro-pyridine-N-oxide (4 g) was stirred in acetic acid (65 ml) at room temperature and iron powder (4 g) added The mixture was then heated to 100 C. for 1 hour, allowed to cool to room temperature and diluted with water. The mixture was then basified with sodium hydroxide (3M) and continuously extracted with ether, giving a white crystalline solid of 2-Bromo-4-aminopyridine (3.1 g) in quantitative yield, m.p. 97-99 C.
With ammonium chloride; In ethanol;
Reference Example 17 4-Amino-2-bromopyridine To 450 ml of 67% ethanol aqueous solution were added 8.78 g of 2-bromo-4-nitropyridine N-oxide, 11.2 g of iron powder and 1.2 g of ammonium chloride in that order, and then the mixture was heated under reflux for about 30 minutes. The insoluble matter was removed by filtration, the thus obtained filtrate was evaporated under reducedpressure, and then the thus formed residue was mixed with an appropriate amount of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated under reduced pressure, and then the thus formed crude product was purified by a silica gel column chromatography to obtain 4.4 g of the title compound from chloroform-methanol-28% aqueous ammonia (200:9:1, v/v/v) elude as light orange crystals.
Benzenesulfonyl chloride (0.443 mL) was added to a stirred mixture of 2-bromo- 4-aminopyridine (498 mg) and pyridine (10 mL) and the resultant mixture was stirred at room temperature for 1 hour. The pyridine was evaporated and the residue was partitioned between dichloromethane and an aqueous citric acid solution. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The residual solid was purified by column chromatography on silica using a solvent gradient of 2% to 4% methanol in EPO <DP n="147"/>dichloromethane as eluent. There was thus obtained the required starting material as a solid (705 mg); 1H NMR Spectrum: (DMSOd6) 7.12 (m, IH), 7.19 (m, IH), 7.62 - 7.73 (m, 3H), 7.90 (m, 2H), 8.14 (d, IH), 11.45 (s, IH); Mass Spectrum: M+H+ 313.
EXAMPLE 6 Synthesis of N-(2-bromo-4-pyridyl)-N'-phenylurea 2-Bromo-4-aminopyridine (433 mg, 2.5 mmol) was added to 15 ml of dry benzene and the mixture warmed to dissolve the pyridine. 298 mg (2.5 mmol) of phenyl isocyanate was added to the solution and the resulting mixture stirred at room temperature for 20 hrs. The crystals which formed were collected by filtration and subjected to chromatography in a conventional manner using alumina. After developing the column with a benzene-ethyl acetate (2.5:1 volume) solvent mixture, the elude containing the objective compound was collected. After distilling solvent off under reduced pressure, the residue was recrystallized from 70% methanol to give 308 mg of N-(2-bromo-4-pyridyl)-N'-phenylurea: yield 42.1%; m.p. 188-189 C.
Example 5N-(4-[l-(4-fluoropyridin-2-yl)-lH-indol-5-yl]oxy}pyrimidin-2-yl)benzene-l,3-diamine (Compound 76)For the preparation of Compound 77, 2-bromo-4-fluoropyridine was prepared utilizing a modified procedure described in the reference below, and used in the indole arylation reaction. Thibault, C; L'etaeureux, A.; Bhide, R. S.; Ruel, R. Org. Lett. 2003, 5, 5023-5025.Step 1: 2-bromo-4-fluoropyridine.To a stirred suspension of 2-bromopyridin-4-amine (0.50 g, 2.9 mMol) in 50% aqueous HBF4 (6.0 mL) was added a solution of sodium nitrite (0.24 g, 3.5 mMol) in water (3.0 mL) over 5 minutes at 0 0C. The resulting mixture was allowed to warm to ambient, and was stirred for 12 hours. Solid NaHCO3 was added slowly, until CO2 evolution ceased, and the resulting aqueous solution was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with saturated NaHCO3 (1 x 30 mL), and brine (1 x 30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound.
Synthesis of 4-(2-bromo-pyridin-4-ylamino)-3-nitro-benzoic acid methyl ester(3); 2-Bromo-pyridin-4-ylannine 2 (4,3 g; 25 mmol) and NaH 60% (1 ,5 g; 37 mmol) was stirred at O0C for 1 h in dry THF (50 ml) and then a solution of 4-fluoro-3-nitro- benzoic acid methyl ester 1 (5 g; 25 mmol) in dry THF (50 ml) was added dropwise. The resulting cold solution was allowed to reach RT and stirred overnight for completion of the reaction. LCMS showed complete conversion to product and the reaction was quenched by addition of iPrOH and H2O. A precipitate was formed and this was filtered off, dried under educed pressure to obtain 3 as a yellow solid (7,5g). Yield 85%. The product identity and purity was confirmed by NMR and LCMS and taken for the next step.
85%
2-Bromo-pyridin-4-ylannine 2 (4,3 g; 25 mmol) and NaH 60% (1 ,5 g; 37 mmol) was at O0C stirred for 1 h in dry THF (50 ml) and then a solution of 4-Fluoro-3-nit.ro- benzoic acid methyl ester 1 (5 g; 25 mmol) in dry THF (50 ml) was addeddrop. The resulting cold solution was allowed to reach RT and stirred overnight for com- pletion of the reaction. LCMS showed complete conversion to product and the reaction was quenched by addition of iPrOH and H2O. A precipitate was formed and this was filtered off, dried under educed pressure to obtain 3 as a yellow solid (7,5g). Yield 85%. The product identity was confirmed by NMR and LCMS and taken for the next step.
85%
2-Bromo-pyridin-4-ylamine 2 (4.3 g; 25 mmol) and NaH 60% (1.5 g; 37 mmol) was at 0 C. stirred for 1 h in dry THF (50 ml) and then a solution of 4-Fluoro-3-nitro-benzoic acid methyl ester 1 (5 g; 25 mmol) in dry THF (50 ml) was addeddrop. The resulting cold solution was allowed to reach RT and stirred overnight for completion of the reaction. LCMS showed complete conversion to product and the reaction was quenched by addition of iPrOH and H2O. A precipitate was formed and this was filtered off, dried under educed pressure to obtain 3 as a yellow solid (7.5 g). Yield 85%. The product identity was confirmed by NMR and LCMS and taken for the next step.
A solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (0.74 g, 4.3 mmol) in DMF (5 mL) was added to a cooled (0 C.) mixture of NaH (0.31 g, 7.82 mmol, 60% in mineral oil) in DMF (15 mL). The resulting mixture was stirred for 20 minutes at 0 C. and then a solution of 2,6-dichlorobenzoyl chloride (0.82 g, 3.91 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred at 0 C. for 4 hours and then poured onto ice-water (20 mL). The precipitate was collected and filtrate was extracted by EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was combined with the precipitate to afford N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (1.0 g, Yield: 74%). 1HNMR (DMSO-d6, 400 MHz): delta 11.41 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.64-7.54 (m, 4H). LCMS (ESI) m/z: 345.0 [M+H+].
To a round-bottom flask was added sodium hydride (0.31g, 7.82mmol, 60% in mineral oil) and N,N-dimethylformamide (15mL). The resulting suspension was cooled to 0C under nitrogen and then <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (0.74g, 4.3mmol) was added. The mixture was stirred at 0C for 20min and then 2,6-dichlorobenzoyl chloride (0.82g, 3.91mmol) was added dropwise. The reaction was warmed to room temperature, stirred for 12h, and then poured into ice-water (20mL). The mixture was extracted with ethyl acetate (2×50mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford crude desired product (1.0g, 74% yield) that could be used without further purification. 1H NMR (DMSO-d6, 400MHz): delta 11.41 (s, 1H), 8.33 (d, J=5.6Hz, 1H), 7.99 (d, J=1.6Hz, 1H), 7.64-7.54 (m, 4H). LCMS (ESI) m/z=345.0 [M+H]+.
To a cooled (0 C.) solution of 2,6-dichloro-4-iodobenzoyl chloride (70 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol). The mixture was stirred for 10 minutes and then <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (40 mg, 0.23 mmol) was added. The resulting mixture was slowly warmed to 25 C., diluted with ethyl acetate (10 mL), quenched with water (1 mL), washed with saturated Na2CO3 and water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (Pet Ether/EtOAc=20:1 to 3:1) to afford N-(2-bromopyridin-4-yl)-2,6-dichloro-4-iodobenzamide (40 mg, 40% yield). LCMS (ESI) m/z: 470.9 [M+H+].
To a cooled (0 C.) solution of <strong>[7598-35-8]2-bromo-4-aminopyridine</strong> (296 mg, 1.5 mmol) in dry DMF (5 mL) was added NaH (120 mg, 3.0 mmol, 60% dispersion in mineral oil) carefully. The mixture was stirred at room temperature for 30 min and then cooled to 0 C. again. A solution of the acid chloride from the preceeding step in dry DMF (5 mL) was added to the mixture slowly. The resulting mixture was stirred for further an additional hour at room temperature and then quenched with ice-water (20 mL). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EA/PE=1:10) to give N-(2-bromopyridin-4-yl)-2,4,6-trichlorobenzamide (390 mg, yield: 69%). LCMS (ESI) m/z: 378.9 [M+H+].
To a cooled (0 C.) solution of <strong>[7598-35-8]2-bromo-4-aminopyridine</strong> (295 mg, 1.5 mmol) in dry DMF (5 ml) was added NaH (120 mg, 3.0 mmol, 60% dispersion in mineral oil) carefully. The mixture was stirred at room temperature for 30 min and then cooled to 0 C. again. A solution of the acid chloride from the preceeding step in dry DMF (5 ml) was added into the mixture slowly. The resulting mixture was stirred for an additional hour at room temperature and then quenched with ice-water (20 ml). The mixture was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/petroleum ether=1:10) to give N-(2-bromopyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (389 mg, 70% yield). LCMS (ESI) m/z: 369.9 [M+H+].
With dmap; In 1,2-dichloro-ethane; at 20℃; for 1h;
[0100] Preparation 6: 3'-fluoro-6'-methyl-2,2'-bipyridin-4-amine[0101] 2-Bromopyridin-4-amine (9 g, 52.0 mmol) and N,N-dimethylpyridin-4-amine (0.636 g, 5.20 mmol) were dissolved in dichloroethane (100 mL) and a solution of phthaloyl dichloride (10.11 ml, 52.0 mmol) in dichloroethylene (20.0 mL) was added dropwise at room temperature. The reaction was stirred for 1 hour and partitioned between saturated bicarbonate and dichloromethane. The organics were separated and dried over Na2S04, filtered, and evaporated to give a solid. The solid was purified by silica columnchromatography in eluting with a gradient of methanol (0-15%) in dichloromethane/ to afford product solid which was triturated with methanol and heated briefly to afford the title compound (4.8g) as an off white solid. 1H NMR (400 MHz, DMSO-d6) ppm 7.69 (dd, J=5.31, 1.77 Hz, 1 H) 7.86 (d, J=1.77 Hz, 1 H) 7.91 - 7.98 (m, 2 H) 7.99 - 8.08 (m, 2 H) 8.57 (d, J=5.56 Hz, 1 H)
With sodium acetate; Iodine monochloride; In acetic acid; at 75℃; for 3h;
2-Bromo-5-iodopyridin-4-amine (5); [00192] 4-Amino-2-bromopyridine (22.8g, 131 .8mmole) and sodium acetate (20.8g 254mmole) were stirred in acetic acid (82ml_) and a solution of iodine monochloride (1 M in acetic acid, 134ml_, 134 mmole) was added. The mixture was stirred and heated at 75C for 3 hours. Most of the acetic acid was evaporated and the residue was partitioned between water (500ml_) and ethyl acetate (550ml_). The aqueous was again extracted with ethyl acetate (300ml_) The combined extracts were washed twice with 10% sodium carbonate solution (600, 300ml_), with 10% sodium thiosulfate solution (200ml_), with water and with brine, then dried and evaporated. This gave 40.3g of a crude product mix. This was combined with the crude product from a reaction on 7.5g of 4-amino-2- bromopyridine for purification. A large silica column (9cm internal diameter with 28cm bed of silica) was prepared in 5% ethyl acetate in dichloromethane. The crude material was applied in the same solvent. The column was eluted with 5% ethyl acetate in dichloromethane, with 10% ethyl acetate in dichloromethane and with 20% ethyl acetate in dichloromethane to give the desired isomer 5 (20.2g, 38%): 1 H-NMR (CDCI3, 500MHz): delta 4.74 (br s, 2H, NH2), 6.80 (s, 1 H), 8.34 (s, 1 H); and subsequently with 1 :1 ethyl acetate:dichloromethane to give 6 undesired isomer: 2-bromo-3-iodopyridin-4- amine 6 (19.3g, 37%).
37%; 38%
With sodium acetate; Iodine monochloride; acetic acid; at 75℃; for 3h;
2-Bromo-5-iodopyridin-4-amine (5) 4-Amino-2-bromopyridine (22.8 g, 131.8 mmole) and sodium acetate (20.8 g 254 mmole) were stirred in acetic acid (82 mL) and a solution of iodine monochloride (1M in acetic acid, 134 mL, 134 mmole) was added. The mixture was stirred and heated at 75 C. for 3 hours. Most of the acetic acid was evaporated and the residue was partitioned between water (500 mL) and ethyl acetate (550 mL). The aqueous was again extracted with ethyl acetate (300 mL) The combined extracts were washed twice with 10% sodium carbonate solution (600, 300 mL), with 10% sodium thiosulfate solution (200 mL), with water and with brine, then dried and evaporated. This gave 40.3 g of a crude product mix. This was combined with the crude product from a reaction on 7.5 g of <strong>[7598-35-8]4-amino-2-bromopyridine</strong> for purification. A large silica column (9 cm internal diameter with 28 cm bed of silica) was prepared in 5% ethyl acetate in dichloromethane. The crude material was applied in the same solvent. The column was eluted with 5% ethyl acetate in dichloromethane, with 10% ethyl acetate in dichloromethane and with 20% ethyl acetate in dichloromethane to give the desired isomer 5 (20.2 g, 38%): 1H-NMR (CDCl3, 500 MHz): delta 4.74 (br s, 2H, NH2), 6.80 (s, 1H), 8.34 (s, 1H); and subsequently with 1:1 ethyl acetate:dichloromethane to give 6 undesired isomer: 2-bromo-3-iodopyridin-4-amine 6 (19.3 g, 37%).
2.8 g (32.2 mmol, 2 eq) of pyruvic acid (initial product 1 ) were poured into a 50 mL single collar flask, 20 mL of thionyl was added to this and it was heated at reflux for 2 hours. After 2 hours, the reaction mixture was dry concentrated by azeotroping several times with dry toluene. 2.8 g (16.1 mmol, 1 eq) of <strong>[7598-35-8]2-bromo-pyridin-4-ylamine</strong> (initial product 2), diluted in 5 mL of pyridine, was then added, drop-by-drop at 0C, and the mixture agitated at ambient temperature for 16 hours. The reaction mixture was diluted with 50 mL of ethyl acetate, washed with 50 mL of an aqueous solution of saturated sodiumbicarbonate, followed by 3 x 50 mL of water. The organic phase was dry concentrated. The residue was chromatographed on silica with a heptanes / ethyl acetate mixture (2/1 v/v) as eluent. N-(2-bromo-pyridin-4-yl)-2-oxo-propionamide was obtained in the form of a white solid.
The <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (650.0 mg, 3.76 mmol) was taken up in dioxane (25 mL) along with (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (3.97 g, 30.1 mmol) and NaH (451.0 mg, 18.78 mmol). The resulting reaction mixture was stirred at reflux for 48 h, concentrated in vacuo and purified by chromatography to give 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-3-amine as a pale yellow solid (260.0 mg, 40%). MS (ESI) calcd for C11H16N2O3: 224.12; found 224.87 [M+H]
With sodium hydride; In 1,4-dioxane; for 15h;Reflux;
<strong>[7598-35-8]2-bromopyridin-4-amine</strong> (680.0 mg, 3.94 mmol) was taken up in 10 mL of dioxane along with 2,2,2-trifluoroethanol (1.56 g, 15.6 mmol), sodium hydride (373.0 mg, 15.6 mmol). The resulting reaction mixture was stirred refluxed for 15 h, cooled to room temp, concentrated in vacuo and purified by chromatography (EtOAc: Pet ether (1:10)) to afford 2-(2,2,2-trifluoroethoxy)pyridin-4-amine (500.0 mg, 66.2 %). MS (ESI) calcd for C7H7F3N2O 192.05
With sodium acetate; Iodine monochloride; In acetic acid; at 70℃; for 16h;Inert atmosphere;
A 50 mL single necked round bottom flask equipped with reflux condenser, under nitrogen atmosphere, was charged with <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (17) (5.0 g, 28.9 mmol, 1.0 equiv), NaOAc.3H2O (5.90 g, 43.3 mmol, 1.5 equiv), ICl (5.16 g, 31.8 mmol, 1.1 equiv) and glacial acetic acid (19.3 mL) and stirred, at 70 oC, for 16 hours. The reaction mixture was cooled and transferred to a separating funnel and was carefully quenched with portionwise addition of solid powdered NaHCO3 (31.1 g), water (50 mL) and EtOAc (50 mL). The layers were then separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSO4 and the volatiles were evaporated. The residue was purified by portionwise flash column chromatography over silica using n-hexane/ EtOAc (99:1 to 50:50) mixtures as eluent to give 2-bromo-5-iodopyridin-4-amine 18 as a light brown solid (3.70 g, 43%). A sample of which had 1H NMR spectral data and low resolution GC/MS (EI) mass spectral data identical to those in the literature
34%
With sodium acetate; Iodine monochloride; In acetic acid; at 70℃; for 18h;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (15.0 g, 86.7 mmol) and sodium acetate (14.2 g, 173.4 mmol) in glacial acetic acid (150 mL) was added a solution of iodine monochloride (4.9 mL, 95.4 mmol) in glacial acetic acid (70 mL). After heating for 18 h at 70 C, the reaction was cooled to room temperature and poured into water (800 mL). The aqueous solution was partitioned twice with EtOAc. The combined organic layers were washed with saturated aqueous Na2C03, saturated aqueous Na2S203, brine and dried over MgSO i. The organic layer was filtered and concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (gradient 10-60% EtOAc in heptane) to afford the title compound (8.9 g, 34%). LCMS (ESI) [M+H] = 300.0; lH NMR (400 MHz, DMSO-d6) delta 8.16 (s, 1H), 6.77 (s, 1H), 6.50 (s, 2H).
33%
With N-iodo-succinimide; In acetonitrile; at 82℃;
General procedure: NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloropyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL),and the mixture was stirred and held at reflux overnight. Uponcooling to r.t. the solvent was removed in vacuo and the residuepartitioned between EtOAc (250 mL), sat. Na2S2O3 (100 mL), andH2O (250 mL). The organic layer was separated, washed withH2O (2 × 250 mL), separated, and the solvent removed in vacuoto afford an orange oil that was subjected to column chromatographyon silica gel. Elution with 30-50% EtOAc in PE afforded apale orange solid that was rinsed with 25% EtOAc in PE (80 mL).The solids were collected by filtration and sucked dry to afford2-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid.The mother liquors were concentrated to dryness in vacuo andthe residues subjected to column chromatography on silica.Elution with 30-50% EtOAc in PE afforded further pure material(1.90 g)
33.7%
With sodium acetate; Iodine monochloride; acetic acid; at 70℃; for 3h;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (LVIII) (584 g, 3.38 mol, 1 eq) and sodium acetate (554 g, 6.75 mol, 2 eq) in HOAc (2000 mL) was added a solution of iodine monochloride (559 g, 3.44 mol, 176 mL, 1.02 eq) in HOAc (1000 mL) drop-wise at 70 C., the resulting mixture was stirred at 70 C. for 3 h. The mixture was concentrated to remove HOAc and poured into water (20 L). The aqueous solution was extracted with EtOAc (10 L*3). The combined organic layers were washed with saturated aq. Na2CO3 (20 L), saturated aq. Na2S2O3 (10 L), brine (10 L), dried over Na2SO4, filtered and concentrated to give a yellow residue, which was purified by column chromatography (1:1?1:0 petroleum ether:DCM) to obtain 2-bromo-5-iodopyridin-4-amine (II) as a yellow solid (340 g, 1.14 mol, 33.7% yield). H NMR (400 MHz, DMSO-d6) delta ppm 6.56-6.53 (3H, m), 7.73-7.72 (1H, d, J=5.2 Hz); ESIMS found for C5H4BrIN2 m/z 299.9 (M+1).
29%
With sodium acetate; Iodine monochloride; acetic acid; at 50 - 75℃; for 3h;
To a 3-necked round-bottom flask containing <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (100 g, 578 mmol), acetic acid (1 L) and sodium acetate (118 g, 1.44 mol) was added a solution of iodine monochloride (103 g, 635 mmol) in acetic acid (0.5 L) dropwise with stirring at 50 C. The resulting solution was stirred for 3 h at 75 C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting solution was diluted with brine (1 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 0.5 L), saturated aqueous sodium sulfite (0.2 L), and brine (0.3 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash chromatography on silica gel (eluent: 5% EtOAc in dichloromethane) to afford 2-bromo-5-iodopyridin-4-amine (50 g, 29%) as a white solid. LCMS (ESI): RT (min) = 1.114, [M+H]+ = 299, method = L.
With potassium carbonate; In acetone; at 20℃; for 2h;
Step F: Synthesis of N-(2-bromo-4-pyridyl)propanamide Propionyl chloride (460 mg, 5 mmol) was added to a mixture of 4-amino-2 -bromopyridine (519 mg, 3 mmol) and potassium carbonate (1.38g, 10 mmol) in 20 mL of acetone. After the addition, the mixture was stirred at room temperature for 2h. Then the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound (460 mg, 67% yield).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 110℃;Sealed tube;
2-Bromopyridin-4-amine (150 mg, 0.86 mmol), 11 phenylboronic acid (211.4 mg, 1.73 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42.46 mg, 0.054 mmol) were suspended in a mixture of 12 Cs2CO3 2M in 13 water (1.3 mL, 2.60 mmol) and 6.5 mL of 14 1,4-Dioxane. The reaction mixture was degassed and the vial was sealed and heated at 110C overnight. The reaction was quenched with 15 NaOH 1 M and extracted two times with ethyl acetate. The organic layer was washed (NaHCO3 saturated and Brine), dried with sodium sulphate and concentrated under vacuum. The crude was purified by CombiFlash column chromatography (Cyclohexane: Ethyl Acetate) to obtain the 16 amine derivative (91.2 mg, 61.8%). 1H-NMR (400 MHz, DMSO-d6): delta = 8.08 (d, 1 H), 7.90 (d, 2H), 7.44 (t, 2H), 7.37 (t, 1 H), 6.99 (d, 1 H), 6.45 (dd, 1 H), 6.07 (s, 2H). HPLC-MS: Rt 3.014; m/z 170.9 (MH+).
100%Spectr.
With palladium diacetate; In water; at 100℃; for 1.0h;Inert atmosphere;
[0032] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv), (0045) phenylboronic acid (1.341 g, 11 mmol, 1.1 equiv), Pd(OAc)2 ((0.0449 g, 0.2 mmol, 0.02 equiv) or (0.0898 g, 0.4 mmol, 0.04 equiv) as identified in Table 1) and H20 (25 mL, 1384 mmol) in a 3 -neck round-bottom flask was well stirred under reflux at 100 C in a N2 atmosphere for the time listed in Table 1. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 C, and listed in Table 1. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 C; the time to reach this temperature was approximately 20 - 30 minutes. The reactions were biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgSC , filtered, and then concentrated in vacuo. The crude product was analyzed by GC and FontWeight="Bold" FontSize="10" Eta NMR, as provided in Table 1.
To a mixture of the compound 87-lb (100 mg, 0.578 mmol, 1 eq) in DMF (2 mL) was added NaH (92 mg, 2.31 mmol, 4 eq) in one portion at 0C under N2. The mixture was stirred at 0 C for 15 min, then CH3I (0.63 g, 4.44 mmol, 0.27 mL, 7.68 eq) was added at 0C and then the mixture was warmed to 15 C and stirred for 16 h. The reaction was monitored by LCMS. The reaction mixture was diluted with water (15 mL) and extracted with EA (15 mL * 4). The combined organic layers were dried with anhydrous Na2S04, filtered and concentrated in vacuum to give the compound 87-la (130 mg, crude), which was used next step without further purification. XH NMR (400MHz, CDCI3) delta 7.95 (d, J= 6.00 Hz, 1H), 6.65 (d, J= 2.40 Hz, 1H), 6.44 (dd, J= 2.50, 6.10 Hz, 1H), 3.00 (s, 6H).
2-(dithieno[3,2-b:2',3'-d]thiophen-2-yl)pyridine-4-amine (DTT-PA)
A DTT-PAligand was obtained from the reaction of 2-bromopyridine-4-amine (0.79 g, 4.58 mmol) anddithieno[3,2-b:2',3'-d] thiophene-2-boronic acid (1.00 g, 4.16 mmol) by Suzuki coupling.The abstraction and purification processes are the same as described above. Yield: 51.3% (0.62 g); 1H NMR (CDCl3, 500 MHz): δH(ppm) 8.32(s, 1H), 7.25(s, 1H), 7.20(s, 1H),6.96(s, 1H), 6.86(s, 1H), 6.65(s, 1H), 6.27(d, 2H)
With methanol; sodium tetrahydroborate; Pd/AlO(OH); water; at 20℃; for 3h;Sonication; Schlenk technique;
First, Pd/AlO(OH) NP catalyst (40.0 mg, 0.16 mmol %) and 1 mL of H2O/MeOH (v/v = 1/1) were added to a Schlenk tube. Next, the halogenated compound (0.25 mmol) was added. Finally, NaBH4 (0.75 mmol) was added to the reaction mixture and the vessel was closed. The reaction then continued during vigorous stirring under ultrasonic conditions at room temperature and was monitored by GC. Most of the reactions were completed over a time period of 1.5 - 4 h. After completion of the reaction, the catalyst was removed via simple centrifugation at 6000 rpm and then washed three times with methanol and water and allowed to dry for further use. The solvent was evaporated under vacuum. The products were purified by flash column chromatography and the dehalogenated products were then determined by 1H NMR.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 18h;Inert atmosphere;
Under the protection of nitrogen, 0.69g (4.00mmol) 2-bromo-4-aminopyridine, 1.02g (6.40mmol) 2, 6-difluoro-3-boronic acid pyridine, 0.28g (0.24mmol) Pd (PPh 3) 4 soluble in 25mLTHF aqueous solution, add 10 ml of the mass fraction of 5% of K 2 CO 3 aqueous solution, heating to 70 C reflux state, the stirring reaction 18h. After the natural cooling to room temperature, adding proper amount of distilled water, many times proper amount of ethyl acetate extraction. Combined with the phase, anhydrous MgSO 4 drying. Filtration, filtrate under reduced pressure, the crude product obtained after evaporating solvent. Using ethyl acetate: hexane (v/v) =1 [...] 5 as eluant the separation by silica gel column chromatography, to obtain colourless solid product 0.26g, the yield is 63.0%.
1-(((2-(6-(difluoromethyl)pyridin-2-yl)-4-phenoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)methyl)amino)-2-methylpropan-2-ol[ No CAS ]
1-(((4-((2-bromopyridin-4-yl)amino)-2-(6-(difluoromethyl)pyridin-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)amino)-2-methylpropan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃;
Intermediate l0B (crude, 80 mg) was synthesized employing the procedure described for Example 7C (Scheme 7). LCMS: m/z 650.3; rt 1.33 mm; Conditions B.
9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-6-phenoxy-9H-purine[ No CAS ]
N-(2-bromopyridin-4-yl)-9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-purin-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.5%
With sodium hydride; In N,N-dimethyl-formamide; for 3h;
To a solution of Intermediate 9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-6-phenoxy-9H-Purine (330 mg, 0.779 mmol) and <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (539 mg, 3.12mmol) in DMF (4 mL) was added sodium hydride (156 mg, 3.90 mmol) and stirred for 3h. The reaction mixture was quenched carefully with water (25 mL) and allowed to stand for 2 h. The resulting brown precipitate was filtered. The residue was washed with water followed by petroleum ether and dried to get N-(2-bromopyridin-4-yl)-9-(4-methoxybenzyl)-2-(6-methylpyridin-2-yl)-9H-Purin-6-amine (280 mg, 0.557 mmol, 71.5% yield) as a brown solid. LCMS: m/z 504.2 (M+H); rt 2.70 mm; conditions E.
2-(5-fluoro-6-methylpyridin-2-yl)-9-(4-methoxybenzyl)-6-phenoxy-9H-purine[ No CAS ]
N-(2-bromopyridin-4-yl)-2-(5-fluoro-6-methylpyridin-2-yl)-9-(4-methoxybenzyl)-9H-purin-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (0.314 g, 1.812 mmol) in DMF (10 mL) was added NaH (0.065 g, 2.72 mmol) at 0 C. The reaction was stirred at 0 C over 10 mm and was added 2-(5 -fluoro-6-methylpyridin-2-yl)-9-(4-methoxybenzyl)-6-phenoxy- 9H-purine (0.4 g, 0.906 mmol). The reaction mixture was warmed to room temperature over 5 mm and stirred for 3 h. The reaction mixture was quenched with ice cold water(100 mL) and was stirred for 20 mm. The precipitate formed was filtered through a Buchner funnel to get (0.4 g, 85%) as a brown solid. LCMS: m/z 518.0 (M-H); ft 3.10 mm; conditions E.
With palladium diacetate; In water; at 100℃; for 4.0h;Inert atmosphere;
[0043] A mixture of 4-amino-2-bromopyridine (1.730 g, 10 mmol, 1.0 equiv), potassium phenyltrifluoroborate (2.760 g, 15 mmol, 1.5 equiv), Pd(OAc)2 (0.0898 g, 0.4 mmol, 0.04 equiv) and 0 (25 mL, 1384 mmol) in a 3-neck round-bottom flask was well stirred under reflux at 100 C in a N2 atmosphere for 4 h. The initial and final pH values of the aqueous phase were measured before and after the heating was enabled when the temperature was stabilized at 25 - 27 C. The initial reaction time (t = 0) was taken when the reaction mixture reached an internal temperature of 100 C; the time to reach this temperature was approximately 20 - 30 minutes. The reaction was biphasic with an aqueous phase and a solid phase. The cooled reaction mixture was basified to pH > 12 using 30% NaOH aqueous solution, and then thoroughly extracted with ethyl acetate. The combined organic phase was dried over anhydrous MgS04, filtered, and then concentrated in vacuo. The crude product was analyzed by GC, as provided in Table 6.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 60℃; for 18h;Inert atmosphere;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (17.3 g, 100mmol) and Pd(dppf)C12 (4.08 g, 5 mmol) in THF (600 mL), was added via syringecyclobutylzinc(II) bromide (200 mL, 100 mmol). The reaction mixture was stirred at 60 C for 18 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate (300mL), then extracted with EtOAc (2X300mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, Si02, PE/EA) afforded the titleCompound as a brown oil (4.4 g, 30%).
30%
With bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 60℃; for 18h;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (17.3 g, 100mmol) and Pd(dppf)C12 (4.08 g, 5 mmol) in THF (600 mL), was added via syringecyclobutylzinc(II) bromide (200 mL, 100 mmol). The reaction mixture was stirred at 60 C for 18 h. The reaction mixture was treated with saturated aqueous sodium bicarbonate (300mL), then extracted with EtOAc (2X300mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, Si02, PE/EA) afforded the titlecompound as a brown oil (4.4 g, 3 0%).
(E)-methyl 3-(4-aminopyridin-2-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium acetate; In N,N-dimethyl acetamide; at 140℃; for 3h;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (1.04 g, 6.0 mmol) and methyl acrylate (1.55 g, 18 mmol) in DMA (10 mL), were added Pd(dppf)Cl2CH2C12 (490 mg, 0.6 mmol) and NaOAc (1.48 g, 18 mmol). The mixture was stirred at 140 C for 3 h under microwave irradiation. The mixture was cooled, filtered and concentrated. The residue was purified by flash chromatography (DCM/MeOH=10/1). ESI: m/z 179.1 (M+H)+
2,5-dichloropyridine-3-sulfonyl chloride[ No CAS ]
N-(2-bromopyridin-4-yl)-2,5-dichloropyridine-3-sulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
120 g
With pyridine; at 0 - 20℃; for 16h;Inert atmosphere;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (75 g, 433 mmol) in pyridine (750 mL) stirred under nitrogenat 0C was added 2,5-dichloropyridine-3-sulfonyl chloride (128 g, 520 mmol) portionwise. The reactionmixture was stirred at room temperature for 16 h. After this time, pyridine was evaporated under reduced pressure to obtain a crude residue which was poured into ice water. The resulting solid was collected by filtration and dried. The solid was dissolved in EtOAc (2 L) and the organic layer was washed with 10% EDTA solution (2 L). The organic phase was dried over Na2SO4, filtered andconcentrated under reduced pressure to afford the title compound (120 g) as a brown solid. LCMS (Method G) Rt = 2.16 mi [M+H] = 381.9/383.9/385.9.
120 g
With pyridine; at 0 - 20℃; for 16h;Inert atmosphere;
To a solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (75 g, 433 mmcl) in pyridine (750 mL) stirred under nitrogen at 0C was added 2,5-dichloropyridine-3-sulfonyl chloride (128 g, 520 mmcl) portionwise. The reaction mixture was stirred at room temperature for 16 h. After this time, pyridine was evaporated under reduced pressure to obtain a crude residue which was poured into ice water. The resulting solid was collected by filtration and dried. The solid was dissolved in EtOAc (2 L) and the organic layer was washed with 10% EDTA solution (2 L). The organic phase was dried over Na2SO4, filtered andconcentrated under reduced pressure to afford the title compound (120 g) as a brown solid.LCMS (Method D) Rt = 2.16 mm, [M+H] = 381.9/383.9/385.9.
1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropylpiperazine[ No CAS ]
2-(2-fluoro-4-((4-isopropylpiperazin-1-yl)methyl)phenyl)pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 2-methyltetrahydrofuran; water; at 25 - 73℃; for 16h;Inert atmosphere; Large scale;
Method B: 2-Bromopyridin-4-amine (11.5 kg) and a solution of 1-(3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzyl)-4-isopropylpiperazine in 2-methyltetrahydrofuran (145.4 kg of solution,containing 29.8 kg / 82.3 Mol of 1-(3-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzyl)-4-isopropylpiperazine) were dissolved in 2-methyltetrahydrofuran (Ca. 53 kg). Sodium carbonate (35.0 kg) and water (75 kg) were added. Nitrogen was bubbled through the mixture for 3 h at Ca. 25 C. [1,1 ?-Bis(diphenylphosphino)ferrocene]d ichloropalladium(II) (1.36 kg) was added, before nirogen was bubbled through the mixture for 3 h at Ca. 25 C. The mixture was stirred for 16 h at Ca. C. Thetemperature was reduced to Ca. 33 C and water (89 kg) was added. The resulting mixture was stirred for 2 h before the aqueous layer was discarded. The organic layer was filtered through a flash silica gel column (3 kg). Water (60 kg) was added to the organic layer. 20 % citric acid aqueous solution (110 kg) was added until pH=4-6. The organic layer was discarded and n-heptane (60 kg) was added to the aqueous layer. 3O% sodium hydroxide aqueous solution (51 kg) was added at 10 C, adjustingpH=8-9. The temperature was adjusted to Ca. 8 C and the solution was seeded with 2-(2-fluoro-4- ((4-isopropylpiperazin- 1-yl)methyl)phenyl)pyridin-4-amine (0.10 kg). The resulting suspension was stirred for 2 h. 3O% sodium hydroxide aqueous solution (15 kg) was added to adjust pH=10-11. The suspension was further aged for 15 h at Ca. 8 C. The solid product was isolated by filtration, before being dissolved in acetone (262.0 kg) at Ca. 40 C. The resulting solution was concentrated to 30 Lunder reduced pressure, maintaining the temperature below 35 C. Water (65 kg) was added over 3h at Ca. 8 C and the suspension was stirred for 2 h. Water (45 kg) was added over 3.5 h at Ca. 8 Cbefore the suspension was aged for 6 h at 4 C. The solid product was collected by filtration and driedfor 48 h at Ca.28 C under reduced pressure. Finally, 20.1 kg of the title compound was obtained in76 %th yield.
1-(2-bromopyridin-4-yl)-3-(2-chloroethyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
at 50℃; for 5h;
(1) Add 4 mL of 1-chloro-2-isocyanatoethane and 2 g of <strong>[7598-35-8]2-bromo-4-aminopyridine</strong> to a three-necked flask with a condenser tube Pyridine, the system was stirred at 50C for 5 hours,The reaction was monitored by TLC (petroleum ether:ethyl acetate=3:1). The solvent was spin-dried to give a brown oil which was purified on a silica gel column to give 1-(2-bromopyridin-4-yl)-3-(2-chloroethyl)urea, Intermediate A (light yellow solid, 1.6 g, Yield 50%)
50%
at 50℃; for 5h;
(1) Add 4 mL of 1-chloro-2-isocyanatoethyl ester and 2 g of <strong>[7598-35-8]2-bromo-4-aminopyridine</strong> to a three-necked flask with a condenser tube The reaction was stirred at 50 C for 5 h, and the reaction was monitored by TLC. Dry the solvent, A brown oil was obtained and purified on a silica gel column to give 1-(2-bromopyridin-4-yl)-3-(2-chloroethyl)urea. Intermediate A (light yellow solid, 1.6 g, yield 50%).
50%
at 50℃; for 5h;
(1) Add 4 mL to a three-necked bottle with a condenser tubeEthyl 1-chloro-2-isocyanate,2g <strong>[7598-35-8]2-bromo-4-aminopyridine</strong>, the system was stirred at 50 C for 5 h,The TLC monitors the end of the reaction. The solvent was spun dry to give a brown oil.Purified by silica gel column1-(2-bromopyridin-4-yl)-3-(2-chloroethyl)urea(Compound A, white solid, 1.6 g, 50% yield).
ethyl 2-((2-bromopyridin-4-yl)amino)-2-oxoacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 24h;
General procedure: To a stirred solution of 2-fluoro-5-aminopyridine (168 mg, 1.50 mmol) in THF (10 mL) were dropwise added at 0 C ethyl chloroglyoxylate (110 muL, 1.00 mmol) and Et3N (210 muL, 1.50 mmol). The mixture was stirred at room temperature for 24 h. After the precipitate was filtrated off, the filtrate solution was concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with 1.0 M HCl, saturated NaHCO3 and brine, then dried over Na2SO4. Concentration under reduced pressure provided the amidoester (268 mg) as brown oil, which was used without further purification. To a solution of the amidoester (150 mg) in EtOH (5 mL) were added Et3N (246 muL, 1.78 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (190 muL, 1.07 mmol). The reaction mixture was stirred for 2 h at 150 C under microwave irradiation. After being concentrated in vacuo, the residue was extracted with CHCl3, and washed with saturated NaHCO3 and brine, then dried over Na2SO4. Concentration under reduced pressure followed by flash chromatography over silica gel with CHCl3-MeOH (10: 1) provided the title compound 16 (73.3 mg, 41% yield) as white powder.
With N-Bromosuccinimide; In acetic acid; at 20℃; for 16h;
To a stirred solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (2.00 g, 11.6 mmol) in acetic acid (20 mL) was added NBS (2.057 g, 11.56 mmol) and the the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the crude product was purified by Combiilash chromatography (40 g Redisep S1O2 column, eluting with 22% EtOAc in hexanes) to afford the title compound (1.4 g) as an off-white solid. LC/MS: m/z = 251.1 [M+H]+. NMR (400 MHz, CDCh) delta ppm 7.92 (d, J = 3.60 Hz, 1H), 6.56 (d, I = 4.00 Hz, 1H), 4.84 (bs, 2H).
4-(cyclohexylamino)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide[ No CAS ]
3-(4-aminopyridin-2-yl)-4-(cyclohexylamino)-N-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 16h;Inert atmosphere;
To a suspension of the compound 84-1 (40 mg, 0.101 mmol, 1 eq) and the compound 84-la (22 mg, 0.131 mmol, 1.3 eq) in mix solvent of dioxane (1 mL) and H2O (0.15) were added Pd(dppf)Cl2 (7 mg, 10 umol, 0.1 eq) and Na2C03 (32 mg, 0.304 mmol, 3 eq) in one portion under N2. The mixture was stirred at 80 C for 16 h. LCMS showed the starting material was consumed completely and 40% of desired product was formed. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL * 4). The combined organic layers were concentrated under reduced pressure to give a residue. HPLC indicated 60% of desired product was detected. The residue was purified by prep-HPLC. LCMS and XH NMR confirmed the white solid was the Compound 84 (14.25 mg, 39 umol, 39% yield). LCMS (ESI): RT = 0.618 min, mass calcd. For C18H24N4O2S, 360.16 m/z found 361.0[M+H]+. XH NMR (400MHz, CDCI3) delta 9.19 (br s, 1H), 8.19 (d, J = 5.60 Hz, 1H), 8.02 (d, J = 2.40 Hz, 1H), 7.63 (dd, J= 2.00, 8.80 Hz, 1H), 7.03 (d, J= 2.00 Hz, 1H), 6.72 (d, J = 8.80 Hz, 1H), 6.47 (dd, J= 2.00, 5.60 Hz, 1H), 4.69 (q, J = 5.30 Hz, 1H), 4.36 (s, 2H), 3.45 (br s, 1H), 2.60 (d, J = 5.20 Hz, 3H), 2.05 1.98 (m, 2H), 1.80 - 1.71 (m, 2H), 1.64 - 1.58 (m, 1H), 1.44 - 1.25 (m, 4H).
With pyridine; copper diacetate; In 1,4-dioxane; at 15 - 100℃; under 775.743 Torr; for 16h;
Cu(OAc)2 (303 mg, 1.67 mmol, 1 eq) was added to a solution of the compound (1154) 88-lc (116 mg, 0.668 mmol, 0.4 eq) and pyridine (185 mg, 2.34 mmol, 0.19 mL, 1.40 eq) in dioxane (6 mL). The reaction mixture was stirred at 15C for 15 min. The compound 88- lb (100 mg, 1.67 mmol, 1 eq) was added and the reaction was heated to 100C and stirred at 100C under 02 (15 Psi) for 16 h. LCMS showed no desired MS was detected. TLC indicated the compound 88- lc was remained and one new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. XH NMR confirmed that the product was 88-la (35 mg, 0.187 mmol, 11.2% yield). XH NMR (400MHz, CDC13) delta 7.93 (d, J = 5.60 Hz, 1H), 6.62 (d, J=2.00 Hz, 1H), 6.39 (dd, J= 2.20, 5.60 Hz, 1H), 4.32 (br s, 1H), 2.87 (d, J= 5.20 Hz, 3H).
N-(2-bromopyridin-4-yl)-2-chloroacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.5%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h;
To a stirred solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (2 g, 11.5 mmol) in DCM (40mL), DIPEA (4 ml, 23 mmol) and choroacetyl chloride (1.85 mL, 23 mmol) were added at 0C. It was stirred at rt for 3h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography and eluted at 20% EtOAc in pet ether to afford the title compound (2.2 g, 76.5 %) as an off yellow solidLC-MS (method 6): Rt = 1.70 min; m/z = 249.02 (M+H+).
N-(2-bromopyridin-4-yl)-3-phenylpropanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h;
To a stirred solution of <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (500 mg, 2.9 mmol) in THF (20 mL), 3-phenylpropanoyl chloride (585 mg, 3.5 mmol) and DIPEA (1.5 mL, 8.7 mmol) were added and it was stirred at rt for 16 h. The reaction mixture was poured to into ice water (50 ml) and extracted with EtOAc (2 x 100 mL).The organic layer was dried over anhydrous NaiSC , filtered to obtain a crude residue that was triturated in n-pentane and dried to afford the title compound (880, 36 %) as a gummy solid.LC-MS (method 14): R, = 2.27 min; m/z = 305.0 (M+H*).
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 16h;Sealed tube;
In a sealed flask were solved 10 <strong>[7598-35-8]2-bromopyridin-4-amine</strong> (100 mg, 0.58 mmol) and 41 morpholine (0.25 mL, 2.9 mmol) in 0.8 mL of dry 42 DMSO. 43 Potassium carbonate (239.6 mg, 1.73 mmol) was added to the mixture and the reaction was stirred at 190C for 16 hours. The mixture was quenched with 44 NaHCO3 saturated and extracted with ethyl acetate. The organic layer was dried and concentrated. The crude was purified by CombiFlash column chromatography (DCM/MeOH) to afford the desired 45 product (25 mg, 24.1 %). 1H-NMR (400 MHz, DMSO-d6): delta = 7.63 (d, 1 H), 5.98 (dd, 1 H), 5.85 (s, 3H), 3.66 (m, 4H), 3.27 (m, 4H). HPLC-MS: Rt 1.661; m/z 180.0 (MH+).
<strong>[7598-35-8]2-bromopyridin-4-amine</strong> (100 mg, 0.58 mmol) in 1-metilpiperazine (0.64 mL, 5.8 mmol) were heated in a sealed vial at 135C for 16 hours. The reaction was solved in a mixture of diethyl ether and methanol and concentrated. Purification of the solid was carried out by CombiFlash chromatography column (DCM/MeOH) obtained 2-(4-methylpiperazin-1-yl)pyridin-4-amine (84.2 mg, 75.7%). 1H-NMR (400 MHz, DMSO-d6): delta = 7.61 (d, 1 H), 5.95 (dd, 1 H), 5.86 (s, 1 H), 5.82 (s, 2H), 3.33 (m, 4H), 3.04 (m, 4H), 2.23 (s, 3H). HPLC-MS: Rt 1.995; m/z 193.0 (MH+).
With methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II); Cs2CO3; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In 1,4-dioxane; water monomer at 95℃; for 1h; Inert atmosphere;
15.1 Step 1-2-quinazolin-7-ylpyridin-4-amine
To a solution of 2-bromopyridin-4-amine (100 mg, 578 μmol, 1 eq), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (162.8 mg, 635.8 μmol, 1.1 eq) in dioxane (4 mL), H2O (1 mL) was added Cs2CO3 (565 mg, 1.73 mmol, 3.0eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (24.2 mg, 28.9 μmol, 0.05 eq) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl) phenyl] phosphane (27 mg, 57.8 μmol, 0.1 eq) under N2. The reaction mixture was stirred at 95 °C for 1 h. LCMS showed ~10% of the starting material remained. The reaction mixture was poured into saturated EDTA (20 mL) and stirred for 1 h. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was washed with DCM (3 x 5 mL) to afford the title compound 2-quinazolin-7-ylpyridin-4-amine (80 mg, crude) as a light yellow solid. LC-MS(ES+, m/z) 223.2 [(M+H)+]
With methanesulfonato (2-dicyclohexylphosphino-2’,6’- di-isopropoxy-1,1‘-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl)palladium(II); Cs2CO3; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In 1,4-dioxane; water monomer at 95℃; for 1h; Inert atmosphere;
15.1 Step 1-2-quinazolin-7-ylpyridin-4-amine
To a solution of 2-bromopyridin-4-amine (100 mg, 578 μmol, 1 eq), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (162.8 mg, 635.8 μmol, 1.1 eq) in dioxane (4 mL), H2O (1 mL) was added Cs2CO3 (565 mg, 1.73 mmol, 3.0eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (24.2 mg, 28.9 μmol, 0.05 eq) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl) phenyl] phosphane (27 mg, 57.8 μmol, 0.1 eq) under N2. The reaction mixture was stirred at 95 °C for 1 h. LCMS showed ~10% of the starting material remained. The reaction mixture was poured into saturated EDTA (20 mL) and stirred for 1 h. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was washed with DCM (3 x 5 mL) to afford the title compound 2-quinazolin-7-ylpyridin-4-amine (80 mg, crude) as a light yellow solid. LC-MS(ES+, m/z) 223.2 [(M+H)+]
N-(2-bromo-4-pyridyl)-1-methyl-piperidine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With 1-propanephosphonic acid cyclic anhydride; triethylamine In dichloromethane at 20℃; for 18h;
2 Preparation of N-(2-bromo-4-pyridyl)-1-methyl-piperidine-3-carboxamide
To a mixture of 1-methylpiperidine-3-carboxylic acid (222 mg, 1.55 mmol), 2-bromopyridin-4-amine (402 mg, 2.32 mmol) and Et3N (0.78 g, 7.72 mmol) in DMF (4 mL) was addedpropanephosphonic acid anhydride (T3P, 50 wt % in EtOAc, 2.06 mL, 2.32 mmol). The resultingmixture was stirred at r.t. for 18h and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated NaHCO3 and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC using a gradient of water 0.1 % FA/acetonitrile 0.1% FA to afford the title compound (0.182 g, Yield 39%).
39%
With 1-propanephosphonic acid cyclic anhydride; triethylamine In dichloromethane at 20℃; for 18h;
2 Preparation of N-(2-bromo-4-pyridyl)-1-methyl-piperidine-3-carboxamide
To a mixture of 1-methylpiperidine-3-carboxylic acid (222 mg, 1.55 mmol), 2-bromopyridin-4-amine (402 mg, 2.32 mmol) and Et3N (0.78 g, 7.72 mmol) in DMF (4 mL) was addedpropanephosphonic acid anhydride (T3P, 50 wt % in EtOAc, 2.06 mL, 2.32 mmol). The resultingmixture was stirred at r.t. for 18h and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (3X). The combined organic phase was washed with saturated NaHCO3 and brine, dried(MgSO4), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC using a gradient of water 0.1 % FA/acetonitrile 0.1% FA to afford the title compound (0.182 g, Yield 39%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
