* 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, 1951, vol. 73, p. 688
2
[ 74163-81-8 ]
[ 6624-49-3 ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium permanganate In N,N-dimethyl-formamide at 0 - 20℃; for 100.5 h; Inert atmosphere
At 0 °C to a solution of 10.0 g (0.046 mmol) of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 200 ml of N,N-dimethylformamide 5.0 g (0.032 mmol) of KMnO4 was added, which took 30 min. The reaction mixture was stirred at room temperature for 100 h, and TLC (CCl3:CH3OH = 5:1) indicated the complete disappearance of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. The reaction mixture was evaporated under vacuum. The residue was washed with distilled water repeatedly to provide 8.1 g (83percent) of the title compound as a yellow powder. ESI-MS (m/e) 174 [M + H]+; 1H NMR (300 MHz, DMSO) δ/ppm = 10.81 (s, 1 H), 9.52 (s, 1 H), 8.43 (s, 1 H), 7.52 (m, 4 H); 13C NMR (75 MHz, DMSO) δ/ppm = 164.9, 152.3, 143.5, 136.2, 131.3, 129.7, 127.2, 125.8.
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 5, p. 1672 - 1681
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4434 - 4436
[3] Patent: CN106986825, 2017, A,
[4] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
3
[ 27104-73-0 ]
[ 6624-49-3 ]
Yield
Reaction Conditions
Operation in experiment
60.69%
With sodium hydroxide In methanolCooling with ice
Add to 100ml eggplantIsoquinoline-3-carboxylate (3) (858 mg, 4.59 mmol)With a small amount of methanol dissolved, ice salt bath with 2N NaOH to adjust the pH = 12, a white precipitate;After the reaction is over,Ice salt bath with saturated KHSO4 adjusted pH = 7,Remove all solvents.The mixture was dissolved in a mixed solution of dichloromethane and methanol, and the filtrate was collected by filtration.After the filtrate was removed,A white solid (481.7 mg, 60.69percent) was obtained.
Reference：
[1] Patent: CN106986825, 2017, A, . Location in patent: Paragraph 0023; 0033; 0034
[2] Patent: CN107137355, 2017, A, . Location in patent: Paragraph 0088; 0089
[3] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
4
[ 67123-97-1 ]
[ 119-65-3 ]
[ 6624-49-3 ]
Reference：
[1] Journal of the American Chemical Society, 1981, vol. 103, # 15, p. 4642 - 4643
[2] Journal of the American Chemical Society, 1981, vol. 103, # 15, p. 4642 - 4643
5
[ 1125-80-0 ]
[ 6624-49-3 ]
Reference：
[1] Organic Process Research and Development, 2002, vol. 6, # 4, p. 477 - 481
[2] Justus Liebigs Annalen der Chemie, 1958, vol. 613, p. 153,155, 162
6
[ 63-91-2 ]
[ 6624-49-3 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 5, p. 1672 - 1681
[2] Patent: CN106986825, 2017, A,
[3] Patent: CN107137355, 2017, A,
[4] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
7
[ 79815-19-3 ]
[ 6624-49-3 ]
Reference：
[1] Patent: CN106986825, 2017, A,
[2] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 34, p. 8957 - 8965
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 688
[2] Journal of Organic Chemistry, 1958, vol. 23, p. 900
[3] Journal of Organic Chemistry, 1952, vol. 17, p. 471
12
[ 6624-49-3 ]
[ 64-17-5 ]
[ 50458-79-2 ]
Reference：
[1] Journal of Organic Chemistry, 1952, vol. 17, p. 471
[2] Journal of the American Chemical Society, 2008, vol. 130, # 13, p. 4447 - 4458
13
[ 6624-49-3 ]
[ 67123-97-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 3, p. 314 - 319
14
[ 67-56-1 ]
[ 6624-49-3 ]
[ 27104-73-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
Reflux
The compound 3-isoquinolinecarboxylic acid (0801-132) (1.0 g, 5.78 mmol, 1.0 eq.)Dissolved in 30 ml of methanol,Sulfuric acid (0.5 ml) was then added and the reaction was refluxed overnight.After the reaction is finished, add sodium bicarbonate solutionpH to 8, extracted with dichloromethane, liquid-separated, and the organic phase dried over anhydrous sodium sulfate.Spin-drying afforded the compound 3-isoquinolinecarboxylic acid methyl ester (810 mg, 75percent).
Reference：
[1] Patent: CN107383024, 2017, A, . Location in patent: Paragraph 0383
isoquinoline-3-carboxylic acid [5-[5-(1<i>H</i>-benzoimidazol-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1-(3-dimethylamino-propyl)-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
isoquinoline-3-carboxylic acid {1-(3-dimethylamino-propyl)-5-[5-(3<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-yl}-amide[ No CAS ]
isoquinoline-3-carboxylic acid {1-(3-dimethylamino-propyl)-5-[5-(3<i>H</i>-imidazo[4,5-<i>b</i>]pyridin-2-yl)-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-yl}-amide[ No CAS ]
isoquinoline-3-carboxylic acid {1-(3-dimethylamino-propyl)-5-[1-methyl-5-(9<i>H</i>-purin-8-yl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-yl}-amide[ No CAS ]
isoquinoline-3-carboxylic acid (5-{5-[5-(3-dimethylamino-propylcarbamoyl)-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1-methyl-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid (1-methyl-5-{1-methyl-5-[1-methyl-5-(4-methyl-piperazin-1-ylcarbamoyl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid (5-{5-[5-(3-dimethylamino-2,2-dimethyl-propylcarbamoyl)-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1-methyl-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid (1-methyl-5-{1-methyl-5-[1-methyl-5-(2-pyrrolidin-1-yl-ethylcarbamoyl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid (1-methyl-5-{1-methyl-5-[1-methyl-5-(2-thiomorpholin-4-yl-ethylcarbamoyl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid (1-methyl-5-{1-methyl-5-[1-methyl-5-(2-piperidin-1-yl-ethylcarbamoyl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid (1-methyl-5-{1-methyl-5-[1-methyl-5-(2-piperazin-1-yl-ethylcarbamoyl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
isoquinoline-3-carboxylic acid [5-(5-{5-[2-(4-fluoro-piperidin-1-yl)-ethylcarbamoyl]-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
isoquinoline-3-carboxylic acid (1-methyl-5-{1-methyl-5-[1-methyl-5-(3-piperidin-1-yl-propylcarbamoyl)-1<i>H</i>-pyrrol-3-ylcarbamoyl]-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1<i>H</i>-pyrrol-3-yl)-amide[ No CAS ]
4-hydroxy-1-{2-[1-methyl-4-(1-methyl-4-(1-methyl-4-(isoquinoline-3-carboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido]ethyl}piperidine[ No CAS ]
N-[1-methyl-5-([1-methyl-5-([1-methyl-5-([3-(4-morpholinyl)propyl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-3-isoquinolinecarboxamide[ No CAS ]
isoquinoline-3-carboxylic acid [5-(5-{5-[2-(4,4-difluoro-piperidin-1-yl)-ethylcarbamoyl]-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl}-1-methyl-1<i>H</i>-pyrrol-3-ylcarbamoyl)-1-methyl-1<i>H</i>-pyrrol-3-yl]-amide[ No CAS ]
8-chloromethyl-6-{5-[(isoquinoline-3-carbonyl)-amino]-1<i>H</i>-indole-2-carbonyl}-4-(4-nitro-phenoxycarbonyloxy)-2-trifluoromethyl-3,6,7,8-tetrahydro-3,6-diaza-<i>as</i>-indacene-1-carboxylic acid methyl ester[ No CAS ]
methyl (1S)-1-chloromethyl-3-[5-[(isoquinolin-3-ylcarbonyl)amino]-1H-indol-2-ylcarbonyl]-5-(4-methylpiperazin-1-ylcarbonyl)oxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate[ No CAS ]
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide);
[3-BIPHENYL-4-YL-(2S)-[(ISOQUINOLINE-3-CARBONYL)-AMINO]-PROPIONIC ACID] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (100 mg, 0.1 [MMOL)] was reacted with <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (78 mg, 0.5 [MMOL)] as described in general procedure A. The resulting compound was hydrolyzed according to general procedure C to afford the title product (132 mg, 81 percent) as a white solid.
3-[[4-[4-[(4-bromophenyl)(ethoxyimino)methyl]-1-piperidinyl]-4-methyl-1-piperidinyl]carbonyl]isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;
To a solution OF OXIME-AMINE, 4- [ (4-BROMOPHENYL) (ethoxyimino) methyl]-1-(4-methyl-4- piperidinyl) piperidine (50 mg, 0.12 MMOL), <strong>[6624-49-3]3-isoquinolinecarboxylic acid</strong> (25 mg, 0.14 MMOL), and Et3N (44 mg, 0.43 MMOL) in DMF (3mL, anhydrous) was added HATU (60mg, 0. 16MMOL) at room temperature. Atter 16 h the reaction mixture was poured into ice water. The solid was collected by filtration, and RE-DISSOLVED in CH2CI2. The organic phase was dried over NA2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (CH2CI2-MeOH, 9: 1) to afford the title compound as a light yellow powder. MS: 564 (M++1).
With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In dichloromethane; for 18h;Product distribution / selectivity;
Step 1: Isoquinoline-3-carboxylic acid methoxy-methyl-amide 2.46 g (12.9 mmol) of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> hydrate was dissolved in 100 mL dichloromethane under room temperature. 1.38 g (14.1 mmol) of methoxymethyl amine was added followed by addition of 4.55 g (15.5 mmol) of 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and 1.44 g (14.1 mmol) of triethylamine. The reaction was stirred for 18 hour and 250 ml of water was added. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuum. Purification using flash chromatography, elution with 100percent ethyl acetate yielded to 2.70 g of product as colorless solid. LC-MSD, m/z for C14H25NO3 [M+H]+: 217.3, [M+2H]+: 218.3. LC retention time on HPLC, C18 column gradient 20-95percent acetonitrile with 0.1percent TFA in 4 min: 0.492 min.
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 20℃; for 3h;
Example 1 Production of N-benzyl-2-[3-benzyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine a) Production of N-methoxy-N-methylisoquinoline-3-carboxyamide [Show Image]; 200 mg of <strong>[6624-49-3]3-isoquinolinecarboxylic acid</strong>, 169 mg of N,O-dimethylhydroxylamine monohydrochloride, 332 mg of WSC, and 582 mg of triethylamine were dissolved in 2 mL of dichloromethane, followed by stirring at room temperature for 3 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform alone) to obtain 169 mg (yield 67percent) of a title compound as a pale yellow solidified product. 1H-NMR (CDCl3) delta: 3.47 (3H, s), 3.80 (3H, s), 7.69 (1H, ddd, J = 1.2, 8.0, 8.0 Hz), 7.76 (1H, ddd, J =1.2, 8.0, 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 8.02 (1H, d, J = 8.0 Hz), 8.14 (1H, s), 9.25 (1H, s).
With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In acetonitrile; for 48h;Product distribution / selectivity;
Step 1: Isoquinoline-3-carboxylic acid methoxy-methyl-amide In 50 mL of acetonitrile was dissolved 0.49 g (2.60 mmol) of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> monohydrate. To this 0.28 g (2.87 mmol) of O,N-dimethyl-hydroxylamine hydrochloride, 0.4 mL (2.87 mmol) triethylamine and 0.921 g (3.13 mmol) of 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride hydrate were added and stirred for 2 days and then evaporated. A mixture of dichloromethane and water was added to it and the organic layer was evaporated and purified using flash chromatography (0-20percent methanol in dichloromethane). Fractions containing pure product were evaporated to yield 210 mg of the free base as a white solid. LC-MSD, m/z for C12H12N2O2 [M+H]+: 217.4, [M+Na]+: 239.4
With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide;
Example 18 Preparation of N-(trans-4-methylcyclohexyl)isoquinoline-3-carboxamide (406) A solution of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (346 mg, 2 mmol), and 1,1'-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3*15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 377 mg (70percent) of 406: rt=9.65 min.; m/z (rel. int.) 268 (M+, 9), 240 (6), 223 (16), 211 (17), 197 (13), 173 (22), 156 (55), 128 (100), 112 (38), 101 (15), 77 (10).
N-[3-(8-(2,6-difluorophenyl)-2-[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)-4-methylphenyl]-3-isoquinolinecarboxamide trifluoacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;
37b) iV-r3-(8-(2.6-difluorophenylV2-([2-hydroxy-l-(hvdroxynietlivpietliyllanimol- 7-QXQ-7, 8-dihvdropyrido [2,3 -^pyrimidin-4- yl)-4-methylphenyl] -3 - isoquinolinecarboxamide trifluoroacetateTo <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (11.5 mg, 0.066 mmol, 1 eq) was added HATU (38.02 mg, 0.1 mmol, 1.5 eq) in DMF (250 uL). DIPEA (34.84 uL, 0.2 mmol, 3 eq) was then added. The resulting mixture was then allowed to stand for about 5 minutes before 4-(5-amino-2-methyl-phenyl)-8-(2,6-difluoro-phenyl)-2-(2- hydroxy- 1 -hydroxymethyl-ethylamino)-8H-pyrido[2,3 -d]pyrimidin-7-one (30.23 mg, 0.066 mmol, 1 eq) was added. The resulting mixture was shaken to ensure efficient mixing of the reagents then was left to stand overnight. The solvent was then removed in vacuo. The residue was dissolved in methanol and was then placed down an aminopropyl SPE flushing the column with methanol. The elute from the SPE was then treated with NaOH (2 M, 200 uL) and the mixture was allowed to stand for about 1 hr. This was followed by HCl (2M, 200 uL) then the solvent was removed in vacuo. The residue was purified by MDAP. LC-MS m/z 609 (M+H)+, 3.31 min (ret time). EPO <DP n="158"/>
With thionyl chloride; In toluene; at 0 - 50℃; for 0.833333h;
To a solution of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (0.200, g, 1.155 mmol) in anhydrous toluene (3 mL) cooled to 0 C., is added 253 mL of thionyl chloride, and the mixture is stirred for 20 minutes. The temperature is increased to 50 C. and the mixture is stirred for additional 30 minutes until the formation of white solid in the mixture. It is then cooled and the solvents are removed in vacuo, followed by the addition of toluene (2*3 mL) and their removal in vacuo. Fresh toluene (3 mL) is then added to the mixture and it is cooled to 0 C. To the mixture is added Huenig's base (502 muL, 2.89 mmol) followed by the addition of amine (0.343 g, 1.39 mmol) and stirred for half an hour. The reaction mixture is allowed to warm to room temperature and is stirred for another 2 hours. To the reaction is added 10 mL of water followed by the addition of HCl (4 mL, 1 N). The layers are separated and the aqueous layer is washed with toluene and the combined organic fractions are washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. Toluene is decanted and filtered through silica gel using toluene (40 mL). The resulting solution is evaporated and dissolved in (dichloromethane, 8 mL), washed with saturated sodium carbonate (15 mL), dried by passing through silica plug, and eluding with dichloromethane. The solvents are removed in vacuo, to provide desired product (0.290 g, 62.5%). LCMS: 403.00 (M+H+).
With thionyl chloride; for 1h;Heating / reflux;
5.109 ISOQUINOLINE-3-CARBOXYLIC ACID [2-(2,6-DIOXOPIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]AMIDE A mixture of isoquinoline 3-carboxylic acid (0.39 g, 2.0 mmol) and thionyl chloride (10 mL) was heated to reflux for 1 hour. Excess thionyl chloride was removed under vacuum. To the acid chloride, was then added 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), THF (30 mL) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was stirred at reflux for 90 minutes. The solvent was evaporated and the crude residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.67 g of the product with 96:4 methylene chloride-methanol, in 76% yield: mp 198-200 C.; 1H NMR (DMSO-d6) delta 2.07-2.11 (m, 1H), 2.53-2.66 (m, 2H), 2.85-2.97 (m, 1H), 5.02 (d, J=6.3 Hz, 2H), 5.19 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.71-7.92 (m, 5H), 8.21 (d, J=7.8 Hz, 1H), 8.28 (d, J=7.8 Hz, 1H) 8.59 (s, 1H), 9.43 (s, 1H), 9.65 (t, J=6.3 Hz, 1H), 11.17 (s, 1H); 13C NMR (DMSO-d6) delta 22.0, 31.0, 38.5, 48.9, 120.0, 121.9, 127.2, 127.8, 128.0, 129.2, 129.3, 131.4, 131.6, 133.0, 134.8, 135.4, 139.2, 143.4, 151.7, 164.7, 167.0, 167.6, 169.9, 172.8; Anal. calcd for C24H18N4O5.0.5H2O: C, 63.85; H, 4.24; N, 12.41. Found: C, 63.85; H, 3.93; N, 12.31.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 2h;
Oxalyl chloride (91 muL, 1.04 mmol, 1.8 eq) was added dropwise to a mixture of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (100 mg, 0.58 mmol, 1.0 eq) and DMF (5 muL, 0.06 mmol, 0.1 eq) in DCM (1.7 mL). The reaction was stirred for 2 hrs. The reaction was concentrated under reduced pressure to give a yellow residue of isoquinoline-3-carbonyl chloride, which was used in the next step without purification.
With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In acetonitrile;
Following the general procedure of acid-amine coupling as shown in Example 23, Compound 8 (25 mg, 0.033 mmol) was treated with <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> hydrate (8.6 mg, 0.045 mmol), DIEA (0.0163 mL, 0.094 mmol) and the coupling reagent PyAOP (29.3 mg, 0.056 mmol) in acetonitrile (3 mL). After purification by Prep.HPLC column, a white solid as TFA salt was obtained as final 1:1 diastereomers (Compound 28) (19.9 mg, 66percent yield). (Compound 28, 48110-188A): 1H NMR(CD3OD, 500 MHz) delta:9.37 (s, 1H), 8.65 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.95 (t, J=7.6 Hz, 1H), 7.87t, J=7.6 Hz, 1H), 5.75 (m, 1H), 5.32 (m, 1H), 5.14 (m, 1H), 4.84 (m, 1H), 4.63 (m, 1H), 4.50 (m, 1H), 4.08-4.18 (m, 2H), 2.95 (m, 1H), 2.43 (m, 1H), 2.1-2.36 (m, 4H), 1.90 (dd, J=7.9 Hz, 5.8 Hz, 0.5H), 1.82 (dd, J=7.9 Hz, 5.2 Hz, 0.5H), 1.43 (m, 1 H), 1.01-1.32 (m, 13H), 0.97 (m, 1H), 0.49 (m, 2H), 0.17 (m, 2H). LC-MS (retention time: 1.573 minutes.), MS m/z 693(MH+).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Step H; Isoquinoline-3-carboxylic acid 2-(3-isobutyrylamino-5-methoxycarbonyl-phenyl)-2-oxo-ethyl ester To a solution of N-[3-(2-bromo-acetyl)-5-propionyl-phenyl]-isobutyramide (Fw 395, 4 g, 10 mmol) in dry DMF (25 mL) was added of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> monohydrate (2.5 g, 13 mmol) and DIEA (5 mL) subsequently. The reaction mixture was stirred at rt for 1 h and then diluted with 150 mL of EtOAc, the organic phase was washed with 5percent NaHCO3 aq., dried over Na2SO4 and concentrated to afford the keto-ester was used directly in the next step.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
