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CAS No. : | 2516-97-4 | MDL No. : | MFCD00051843 |
Formula : | C3H6O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NYEHUAQIJXERLP-UHFFFAOYSA-N |
M.W : | 138.14 | Pubchem ID : | 3732841 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 27.27 |
TPSA : | 79.82 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.71 cm/s |
Log Po/w (iLOGP) : | -0.12 |
Log Po/w (XLOGP3) : | -0.8 |
Log Po/w (WLOGP) : | 0.2 |
Log Po/w (MLOGP) : | -1.09 |
Log Po/w (SILICOS-IT) : | -0.79 |
Consensus Log Po/w : | -0.52 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.06 |
Solubility : | 120.0 mg/ml ; 0.87 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.4 |
Solubility : | 55.3 mg/ml ; 0.401 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.06 |
Solubility : | 158.0 mg/ml ; 1.14 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.66 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogenchloride In 1,4-dioxane for 16 h; Heating / reflux | [0348] Method 14-1: Schemes 14a describes the synthesis of compound 72 of Formula IScheme 14aO O OMethanesulfonyl-acetic acid (69) (5 3 g, 38 4 mmol) was suspended in ethyl alcohol (5O mL) A 4M solution of HCl in dioxane (8 mL) was added The mixture stirred at reflux for 0 5 h, everything had dissolved at this point The mixture continued to stir at reflux for a total of 16 h Upon cooling, the solution was concentrated in vacuo to approximately 20 mL The oil was diluted with ethyl acetate (300 mL), washed with water (100 mL), brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to a golden oil Purification by flash column chromatography (30percent ethyl acetate in hexanes, Merck silica gel 60, 40-63 μm) afforded the desired product, methanesulfonyl-acetic acid ethyl ester (70) (5 67 g, 34 12 mmol, 89 percent yield), as a <n="161"/>clear oil upon concentrating. 1HNMR (400 MHz, DMSO-d6) δ: 1.22 (3H, t, J= 7.0 Hz), 3.13 (3H, s), 4.17 (2H, quartet, J= 7.0 Hz), 4.38 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide; In acetic acid; | A. (Methylsulfonyl)acetic acid To a solution of (methylthio)acetic acid (3.20 g, 30.0 mmol) in 15 ml acetic acid were added with cooling hydrogen peroxide (5.83 g, 60.0 mmol) and the mixture was stirred for five days at room temperature. The volatiles were distilled off in vacuo and the residue dried for 8 hours in vacuo. The resulting oil crystallized on seeding overnight. The crystals were triturated with ether, filtered off with suction, washed with ether and dried to give 2.51 g of the title A compound, m.p. 112-113 C. | |
91%Spectr. | With sodium tungstate (VI) dihydrate; sodium thiosulfate; dihydrogen peroxide; In water; at 60 - 70℃;Green chemistry; | General procedure: As shown in Figure 1,A 500 ml first Erlenmeyer flask was charged with 100 g of 3-methylthioacetic acid (thioether)3.1g sodium tungstate dihydrate,500ml water. The first conical flask is placed on the first balance corresponding to the first pump 11,The first pump 11 is set by the automatic feeding software to set the feeding speed of 21 g / min.To a 500 ml second Erlenmeyer flask was added 225 g of hydrogen peroxide (3.5% strength). The second conical flask is placed on the second balance corresponding to the second pump 12,The second pump 12 is set by the automatic feeding software to set a feed rate of 7.8 g / min.In a 1000 ml third Erlenmeyer flask was added 58.0 g of sodium thiosulfate,745ml aqueous solution as a quenching reagent.Erlenmeyer flask placed on the third balance of the third pump 13,The third pump 13 is set by the automatic feeding software to set the feeding speed of 27.8 g / min.A 1000 ml fourth Erlenmeyer flask was charged with 450 g of ethyl acetate as an extraction solvent.The conical flask is placed on the fourth balance corresponding to the fourth pump 14,The fourth pump 14 is set by the automatic feeding software to set a feed rate of 15.6 g / min.200ml continuous (tube) reactor temperature 60 ~ 70 ,Continuous quenching reactor temperature 0 ~ 10 ,Continuous extraction column maintained at room temperature.The first pump 11 and the second pump 12 are simultaneously operated by the automatic feeding system, and the first conical flask,The material in the second conical flask is pumped into the continuous reactor 20,After 5 minutes, the third pump 13 is operated,The quench reagent in the third conical flask was pumped into the continuous quench reactor 30,The fourth pump 14 is operated,Ethyl acetate in a fourth Erlenmeyer flask was pumped into a continuous extraction column 40 with mechanical agitation.The system exiting the continuous quench reactor 30 enters a continuous extraction column 40 for continuous extraction and separation to obtain a light component organic phase and a heavy component aqueous phase.Organic phase collection,Concentration to remove solvent gave 98% HPLC purity oil.The data for the resulting product is as follows:The above data shows that the product is 3- (methylsulfonyl) acetic acid,Quantitative detection with NMR internal standard,The yield of 3- (methylsulfonyl) acetic acid was 82%Its structural formula is |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound N-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]methylsulfonylacetamide (199 mg) was prepared from 5(S)-aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one (150 mg) and methylsulfonylacetic acid (105 mg) in the same manner as described for EXAMPLE 62. [0544] MS (EI+) m/z: 377 (M+). [0545] HRMS (EI+) for C17H19N3O5S (M+): calcd, 377.1045; found, 377.1035. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 10 mmol of starting compound [A1,] 12 mmol of methanesulfonyl-acetic acid and 10 mmol of triethylamine in 50 [ML] of [DICHLOROMETHANE] is stirred for 60 min after which 20 mmol of (3-dime- thylamino-propyl)-ethyl-carbodiimide hydrochloride is added. The resulting mixture is stirred for 18 h at RT and then successively washed with diluted hydrochloric acid and aqueous sodium carbonate. After drying over magnesium sulfate, the solvent is evaporated and the residue crystallised from methanol. M. p. [169-170C] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-pyrrolidin-2-one; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 24h; | Example 21 24 A mixture of amine 13 (0.065 g, 0.15 mmol), METHANESULFONYL acetic acid (0.061 g, 0.45 mmol), EDC. HC1 (0.086 g, 0.45 mmol), HOBt (0.061 g, 0.45 mmol), NMP (0.165 mL, 1.5 mmol), DCM (1.5 ML) and DMF (1.5 mL) was stirred at r. t. for 24 h. The mixture was poured into saturated NAHCO3 and extracted with EtOAc. The organic layer was separated, washed with brine, dried with anhydrous NA2S04, concentrated by rotary evaporation and purified by flash chromatography on silica gel with a gradient elution of 15-20% MeOH/DCM mixed with 1-2% NH40H to yield 24 as a white solid (0.052 G).'H NMR 5 (DMSO, 500 MHz): 11.19 (s, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 4.13 (s, 2H), 3.63 (m, 2H), 3.54 (m, 2H), 3.32 (m, 2H), 3.11 (s, 3H), 2.92 (m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.40 (m, 3H), 2.08 (m, 2H), 1.92 (m, 2H), 1.83 (m, 1H), 1.69 (m, 1H), 1.54 (m, 2H), 1.40 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H), 1.19 (m, 1H). MS (ES): 556 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); for 1.5h; | A mixture of 3- [ (l-amino-5-ethyl-lH-pyrrol-2-yl) carbonyl] benzonitrile (300 mg),methanesulfonylacetic acid (208 mg),1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (361 mg), and 1-hydroxybenzotriazole (254 mg) in N, N-dimethylformamide (1mL) was stirred for 1.5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water two times, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give a pale brown solid. Flash silica gel column chromatography eluting with ethyl acetate-hexane= 1/2 to 1/0 affordedN- [2- (3-cyanobenzoyl)-5-ethyl-lH-pyrrol-1-yl]-2- (methylsulfonyl) acetamide as a pale brown foam, which was solidified upon standing (505 mg). N- [2- (3-Cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2- (methylsulfonyl) acetamide NMR (CDCl3, delta) : 1.29 (3H, t, J=7Hz), 2.62 (2H, q, J=7 Hz, ), 3.28 (3H, s), 4.15 (2H, s), 6.12 (1H, d, J=5Hz), 6.75 (1H, d, J=5Hz), 7.58 (1H, t, J=9Hz), 7.82 (1H, d, J=9Hz), 8. 01 (1H, d, J=9Hz), 8.06 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | Example 34 5-Fluoro-N-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110 mg, 0.276 mmol), 1-hydroxybenzotriazole (46 mg, 0.304 mmol) and N-methylmorpholine (67 mul, 0.611 mmol) were added to a solution of 2-methanesulfonyl-acetic acid (57 mg, 0.42 mmol) in dichloromethane (2.5 ml) under nitrogen at room temperature and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89 mg, 0.468 mmol) was added. The reaction was stirred at room temperature for 18 h and quenched with sat. ammonium chloride (0.5 ml) and diluted with water (3 ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluding with a solvent gradient of dichloromethane:methanol:concentrated aqueous ammonia (99.5:0.5:0.05 changing to 95:5:0.5, by volume) to give 5-fluoro-N-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (85 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): delta=8.10-8.11 (1H, d), 7.97-8.00 (1H, m), 7.28-7.33 (1H, t), 7.08-7.13 (1H, d), 7.04 (1H, s), 6.95-6.99 (1H, d), 4.36-4.41 (1H, d), 4.12-4.20 (1H, m), 3.97-4.03 (1H, d), 3.10-3.20 (1H, m, partially masked by solvent), 3.09 (3H, s), 2.98-3.04 (1H, m), 2.44 (3H, s), 1.98-2.08 (2H, t), 1.60-1.72 (1H, m), 1.44-1.58 (1H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 505, [M-H]+ 481. Anal. Found C, 52.15; H, 5.08; N, 8.56. C21H24FN3O5S2 requires C, 52.38; H, 5.02; N, 8.73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | A mixture of 5- [ (3-AMINOPHENYL) ETHYNYL]-N- {3-CHLORO-4- [ (3- FLUOROBENZYL) oxy] phenyl} pyrimidin-4-amine (50 mg, 0.11 mmol) (example 63), (methylsulfonyl) acetic acid (17 mg, 0.12 MMOL), 1- (3-DIMETHYLAMINOPROPYL)-3- ethylcarbodiimide hydrochloride (25 mg, 0.13 MMOL) and 1-hydroxybenzotriazole hydrate (14 mg, 0.11 MMOL) in DIMETHYLFORMAMIDE (1 mL) was stirred at rt under nitrogen for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water, with brine, dried and concentrated. Chromatography on silica gel eluting with ethyl acetate gave the title compound as a white solid (40 mg, 64%). 1H NMR (400 MHz, DMSO-d6) A 3.16 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 7.13-7. 55 (m, 9H), 7.74 (d, J=3 Hz, 1H), 7.95 (s, 1H), 8.52 (s, 2H), 9.06 (s, 1H), 10.55 (s, 1H) ; ESIMS : 565 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; | A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18.2 mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at once, and the resultant solution was stirred at ambient temperature. The solution was poured into water, and the product crystallized. The product, 5.4 g (99%), was collected by filtration and was used without any further purification in the subsequent reaction. MS m/z 320 (MH+). 1H NMR(DMSO-d6) delta 3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32-7.55 (m, 7H) and 10.32 (s, 1H). |
99% | A. N- (4-Benzyloxy-phenyl)-2-methanesulfonyl-acetamide A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18. 2 mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at once, and the resultant solution was stirred at ambient temperature. The solution was poured into water, and the product crystallized. The product, 5.4 g (99%), was collected by filtration and was used without any further purification in the subsequent reaction. MS m/z 320 (MH+). 1H NMR (DMSO-d6) 8 3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32- 7.55 (m, 7H) and 10.32 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3 - 36h; | (4-(3-Fluorobenzyloxy)-3-chlorophenyl)-(6-(2-(2-(methylsulfonyl)acetamidoethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine (4-(3-Fluorobenzyloxy)-3-chlorophenyl)-(6-(2-(2-aminoethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine (0.229 mmol) was reacted with methanesulfonyl acetic acid (0.252 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.252 mmol) in DMF as outlined in procedure (I) to provide the title compound after purification by chromatography. 1H NMR (CDCl3) delta 8.82 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 8.14 (d, 1H), 8.02 (m, 1H), 7.92 (d, 1H), 7.81 (s, 1H), 7.62 (m, 1H), 7.55 (s, 1H), 7.36 (m, 1H), 7.21 (m, 2H), 7.02 (m, 2H), 5.18 (s, 2H), 3.95 (s, 2H), 3.91 (m, 2H), 3.36 (m, 2H), 2.88 (s, 3H). Electrospray MS m/z 625.87 (MH+). I) Reaction of a Carboxylic Acid and an Amine Through a Coupling ProcedureAn acid, such as that afforded from General Procedure (H) was dissolved in a suitable solvent such as DMF and a coupling reagent was added, for example 1,1'-carbonyidiimidazole. The amine was added and the reaction was stirred at room temperature for 3-36 h. Upon completion as judged by TLC, an extractive work-up was done. Desired amide was either precipitated from an organic solvent in acceptable purity or the material was purified using column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h; | Example 47: Preparation of iV-{4-[3-chloro-4-(3-fluoro-benzyloxy)- phenyIaminoJ-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-3- phenyl-propionamide0.08 g of methanesulfonylacetic acid, 0.21 g of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.08 g of 1- hydroxylbenzotriazole dissolved in 10 ml of methylene chloride were reacted with 0.15 g of the compound obtained in (46-1) of Example 46 at room temperature for 24 hours. The reacted solution was extracted with methylene chloride 2 times after adding saturated sodium bicarbonate solution, washed with saturated saline solution, dried over magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain the title compound (0.1 g, 55%).1H-NMR (DMSO-d6, 300MHz): delta 10.29(s, IH), 9.76 (s, IH), 8.94 (d, IH), 8.59 (s, IH), 8.47 (s, IH), 7.94 (d, IH), 7.71 (m, 3H), 7.30 (m, 8H), 5.36 (m, IH), 5.23 (s, 2H), 4.10 (m, 2H), 3.36 (m, 2H), 3.04 (s, 3H); MS(ESI): [M+H+] 662.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 12h; | (74-2) Preparation of 3-(2-methanesulfonyl-acetylamino)-N-[4-(l-phenyl- ethylamino)-quinazolin-6-yl]-propionamide40 mg of 1 -hydroxy lbenzotriazole and 114 mg of l-(3- dimethylaminoprorhoyl)-3-ethylcarbodiimide hydrochloride were added to 41 mg of methanesulfonylacetic acid dissolved in 2 ml of THF, and reacted with 50 mg of the compound obtained in (74-1) at room temperature for 12 hours. The reacted solution was extracted with 6 ml of ethylacetate 3 times after adding 4 ml of water, dried over anhydrous magnesium sulfate, and filtered and distilled EPO <DP n="80"/>under a reduced pressure. 5 ml of diethylether was added to the resulting residue dissolved in 0.5 ml of methanol to obtain solid, and the solid was filtered under a reduced pressure and dried to obtain the title compound (3 mg,-%).1H-NMR(CD3OD, 300MHz): delta 8.59 (s, IH), 8.39 (s, IH), 7.79-7.68 (m, 211), 7.22-7.46 (m, 5H), 4.04 (s, 2H), 3.65 (m, 3H), 2.73 (t, J=6 Hz, 2H)5 1.70 (d, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃; for 2.5h; | (78-2) Preparation of N-[4-(l-benzyl-lH-indazol-5-ylamino)-quinazolin-6-yl]- 3-(2-methanesulfonyl-acetylamino)-propionamide EPO <DP n="83"/>50 mul of pyridine and 87 mg of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride were added to 63 mg of methanesulfonylacetic acid dissolved in 3 ml of THF at 00C , reacted with 50 mg of the compound obtained in (78-1) at for 30 mins while heating to room temperature and the resulting solution was stirred at room temperature for 2 hours. The reacted solution was extracted with 6 ml of ethylacetate 3 times after adding 4 ml of water, dried over anhydrous magnesium sulfate, and filtered and distilled under a reduced pressure. 5 ml of diethylether was added to the resulting residue dissolved in 0.5 ml of methanol to obtain solid, and the solid was filtered under a reduced pressure and dried to obtain the title compound (11 mg, 17%).1H-NMR (CD3OD, 300MHz): delta 8.76 (s, IH), 8.46 (s, IH), 8.09-8.12 (m, 3H), 7.76-7.79 (m, 2H), 7.59-7.65 (m, 2H), 7.25-7.32 (m, 5H), 5.69 (s, 2H), 4.05 (s, 2H), 3.58 (m, 2H), 3.24 (s, 3H), 2.90 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 2h; | (81-2) Preparation of 4-{6-[3-(2-methanesulfonyl-acetylamino)- propionylamino]-quinazolin-4-ylamino}-N-phenyl-benzamide32 mg of hydroxyl-benzotriazole and 90 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 32 mg of methanesulfonylacetic acid dissolved in 2 ml of THF, and reacted with 50 mg of the compound obtained in (81-1) at room temperature for 2 hours. The reacted solution was extracted with 6 ml of ethylacetate 3 times after adding 4 ml of water, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain the title compound (10 mg, 16%).1H-NMR (CD3OD, 300MHz): delta 8.77 (s, IH), 8.62 (s, IH), 8.00-8.07 (m, 4H), 7.82 (s, 2H), 7.73 (d, J=9 Hz5 2H), 7.41 (t, J=7.5 Hz, 2H), 7.17 (t, J=7.5 Hz, IH), 4.08 (s, 2H), 3.67 (t, J=7 Hz, 2H), 3.14 (s, 3H) 2.77 (t, JM Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 12h; | (83-2) Preparation of N-[4-(biphenyl-4-ylamino)-quinazolin-6-yl]-3-(2- methanesulfonyl-acetylamino)-propionamide56 mg of hydroxyl-benzotriazole and 160 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 58 mg of methanesulfonylacetic acid dissolved in 5 ml of THF, and reacted with 80 mg of the compound obtained in (83-1) at room temperature for 12 hours. The reacted solution was extracted with 10 ml of ethylacetate 3 times after adding 5 ml of water, dried over anhydrous magnesium sulfate, and filtered and distilled under a reduced pressure. 5 ml of diethylether was added to the resulting residue dissolved in 0.5 ml of methanol to obtain solid, and the solid was filtered under a reduced pressure and dried to obtain the title compound (30 mg, o/ O. ). EPO <DP n="87"/>1H-NMR (CD3OD5 300MHz): delta 8.76 (s, IH). 8.56 (s, IH), 7.84-7.89 (m, 3H), 7.63-7.73 (m, 5H), 7.42 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.5 Hz, IH), 4.1 (s, 2H), 3.68 (t, J=7 Hz, 2H), 3.16(s, 3H), 2.77 (t, J=7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 12h; | Example 130: Preparation of iV-{4-[3-chloro-4-(pyridin-2-ylmethoxy)- phenylamino]-quinazoIin-6-yl}-3-(2~methanesulfonyl-acetylamino)- propionamide56 mg of 1-hydroxylbenzotriazole and 85 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 31 mg of methanesulfonylacetic acid dissolved in 2 ml of THF, and the solution was reacted at room temperature for 12 hours after adding 50 mg of the compound obtained in (129-1) of Example 129. The reacted solution was extracted with 10 ml of ethylacetate 3 times after adding 5 ml of water, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain the title compound (5.2 mg, 8%).1H-NMR (CD3OD, 300MHz): delta 8.66 (s, IH), 8.54 (bs, IH), 8.47 (s, IH), 7.93 (m, 2H), 7.70 - 7.75 (m, 3H), 7.58 (m, IH), 7.39 (t, J = 5 Hz, IH), 7.17 (d, J = 9 Hz, IH), 5.29 (s, 2H), 4.03 (s, 2H), 3.64 (t, J = 6 Hz, 2H), 3.29 (s, 3H), 2.72 (t, J= 6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 12h; | Example 133: Preparation of 7V-{4-[3-chIoro-4-(pyridin-3-yImethoxy)- phenylamino]-quinazolin-6-yI}-3-(2-methanesulfonyl-acetylamino)- propionamide56 mg of 1-hydroxylbenzotriazole and 85 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 31 mg of methansulfonylacetic acid dissolved in 2 ml of THF, and reacted at room temperature for 12 hours after adding 50 mg of the compound obtained in (132- 1) of Example 132. The reacted solution was extracted with 10 ml of ethylacetate 3 times after adding 5 ml of water, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain the title compound (16 mg, 25%).1H-NMR (DMSO-d6, 300MHz): delta 8.74 (s, IH), 8.70 (s, IH), 8.66 (d,J=2 Hz5 IH), 8.50 (s, IH), 8.21 (d, J=8 Hz, IH), 8.11 (d, J=2.5 Hz, IH), 7.93- 7.98 (m, 2H), 7.85 (dd, J=9, 2.5 Hz, IH), 7.69 (bs, IH), 7.43 (d, J=9 Hz, IH)5 EPO <DP n="112"/>5.29 (s, 2H), 4.11 (s, 2H)5 3.71 (t, J=6 Hz, 2H), 3.16 (s, 3H), 2.79 (t, J=6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 2h; | Example 3: Preparation of iV-({4-[3-chloro-4-(3-fluoro~benzyloxy)- phenylamino]-quinazolin-6-ylcarbamoyl}-methyI)-2-methanesulfonyl- acetamide16 mg of 1-hydroxylbenzotriazole and 53 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 18 mg of methanesulfonylacetic acid dissolved in 3 ml of THF, and the solution was reacted at room temperature for 2 hours after adding 50 mg of the compound obtained in (2-1) of Example 2. The reacted solution was extracted with distilled water, and the resulting residue was filtered under a reduced pressure to obtain the title compound (44 mg, 70%).1H-NMR (CDCl3, 300MHz): delta 8.60 (s, IH), 8.52 (s, IH), 7.82 (d, IH),7.69 (m, 2H), 7.54 (dd, IH), 7.31 (m, 2H), 7.21 (t, 2H), 6.97 (m, 2H), 5.12 (s, 2H), 4.12 (s, 2H), 4.03 (s, 2H), 3.14 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6h; | Example 8: Preparation of (25)-Lambdar-{4-[3-chloro-4-(3-fluoro-benzyloxy)- phenylamino]-qumazolm-6-yl}-2-(2-methanesulfonyl-acetamino)-4- methanesulfanyl-butyramide43 mg of 1-hydroxylbenzotriazole, 103 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 150 mg of the compound obtained in (7-1) of Example 7 were added to 47.2 mg of methanesulfonylacetic acid dissolved in 6 ml of methylene chloride, and the solution was reacted at room temperature for 6 hours. The reacted solution was washed with distilled water, dried over magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain the title compound (40 mg, 22%).1H-NMR (CDCl3, 300MHz): delta 9.31 (s, IH), 8.51 (s, IH), 8.39 (d, IH), 8.24 (s, IH), 7.72 (d, IH), 7.52 (m, 3H), 7.33 (m, IH), 7.18 (t, 2H), 7.00 (t, IH), 6.83 (d, IH), 5.03 (s, 2H), 4.85 (m, IH), 4.18 (m, 2H), 3.15 (s, 3H), 2.61 (t, 2H), 2.18 (m, 2H), 2.03 (s, 3H); MS(ESI): [M+H+] 647. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 9h; | Example 17: Preparation of l-(2-methanesulfonyl-acetyI)-pyrrolidine-2- carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]- quinazolin-6-yI}-amide21 mg of 1-hydroxylbenzotriazole and 67 mg of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 30 mg of methanesulfonylacetic acid dissolved in 5 ml of THF, and reacted at room temperature for 9 hours after adding 70 mg of the compound obtained in (16-1) of Example 16. The reacted solution was washed with distilled water, dried over magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent- chloroform : methanol = 15 : 1) to obtain the title compound (66 mg, 76%).1H-NMR (CDCl3, 300MHz): delta 8.59 (s, IH), 8.57 (s, IH), 7.82 (d, IH), 7.75 (d, IH), 7.54 (m, 2H), 7.29 (m, IH), 7.19 (m, 2H), 6.91 (m, 2H), 5.09 (s, 2H), 4.79 (m, IH), 4.10 (dd, 2H), 3.92 (m, IH), 3.69 (m, IH), 3.13 (s, 3H)5 2.41 (m, IH), 2.12 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | Example 21: Preparation of LambdaL{4-[3-chloro-4-(3-fluoro-benzyloxy)- phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)- propionamide0.12 g of methanesulfonylacetic acid, 0.34 g of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.12 g of methylene chloride dissolved in 2 ml of methylene chloride was stirred at room temperature for 2 hours after adding 0.2 g of the compound obtained in (20-1) of Example 20. The reacted solution was filtered under a reduced pressure EPO <DP n="52"/>after adding saturated sodium bicarbonate to obtain the title compound as solid (0.2 g, 80%).1H-NMR (DMSO-d6, 300MHz): delta 10.35 (s, IH), 9.83 (s, IH), 8.66 (s, IH), 8.50 (m, 2H), 7.95 (s, IH), 7.86 (d, IH), 7.65 (m, 2H), 7.48 (m, IH), 7.32 (m, 2H)5 7.18 (m, 2H), 5.23 (s, 2H), 4.08 (s, 2H), 3.44 (m, 2H), 3.11 (s, 3H), 2.58 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 46h; | Example 43: Preparation of 7V-{4-[3-chloro-4-(3-fluoro-benzyloxy)- phenylamino]-quinazolin-6-yl}-3-(2-methanesulfonyl-acetylamino)-2- methyl-propionamide0.03 g of methanesulfonylacetic acid, 0.08 g of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.03 g of 1- hydroxylbenzotriazole dissolved in 3 ml of methylene chloride were reacted with 0.05 g of the compound obtained in (42-1) of Example 42 at room temperature for 46 hours. The reacted solution was filtered under a reduced pressure after adding saturated sodium bicarbonate solution to obtain the title compound as solid (0.4 g5 64%). EPO <DP n="63"/>1H-NMR (DMSO-d6, 300MHz): delta 10.29 (s, IH)5 9.79 (s, IH), 8.71 (d, IH)5 8.49 (m, 2H), 7.98 (d, IH)5 7.85 (d, IH)5 7.73 (m, 2H)5 7.46 (m, IH), 7.25 (m,4H), 5.25 (s, IH), 4.10 (s, 2H), 3.11 (s, 3H)5 2.75 (m, 2H), 2.20 (m, IH)5 1.18 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | Example 39 (3R,4S)-1-[(methylsulfonyl)acetyl]-3-phenyl-N-{2-(trifluoromethoxy)-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}piperidine-4-amine The reaction and purification in the same manner as in Example 5 using the compound (0.34 g) obtained in Example 34 and methanesulfonylacetic acid (0.12 g) gave the title compound as a white amorphous solid (0.043 g, 12%). MS(ESI+): 607(M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In tetrahydrofuran; ISOPROPYLAMIDE; at 20℃; for 6h; | A mixture of the compound produced in Reference Example 42 (0.108g), 1-hydroxy-1H-benzotriazole monohydrate (0.0412g), 1-ethyl-3-(3-dimethylaminopropyl)-carboximide (0.108g), methanesulfonylacetic acid (0.0619g), N,N-dimethylacetamide (20ml) and tetrahydrofuran (2ml) was stirred at room temperature for 6 hours. A saturated aqueous sodium hydrogencarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with column chromatography (basic silica gel, developing solvent : n-hexane/ethyl acetate=1/1 ?ethyl acetate), and further purified with HPLC, and the obtained solid was recrystallized from ethyl acetate to obtain the title compound (0.0281g). 1H-NMR (DMSO-d6) delta:3.14 (3H,s), 4.17 (2H,s), 4.48 (2H,d, J=5.4Hz), 6.63 (1H,d,J=3.6Hz), 7.18 (1H,m), 7.23 (1H,d,J=8.7Hz), 7. 28-7.34 (3H,m), 7.46 (1H,m), 7.76 (1H,dd,J=8.7,2.1Hz), 8.07 (1H,d,J=2.1Hz), 7.46 (1H,m), 7.76 (1H,dd,J=8.7,2.1Hz), 8.07 (1H,d, J=2.1Hz), 8.50(1H,s), 9.02 (1H,brt,J=5.4Hz), 10.11 (1H,brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | A mixture of 6 (150 mg, 0.288 mmol), <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (79.6 mg, 0.576 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (166 mg, 0.870 mmol), 1-hydroxybenzotriazole monohydrate (HOBt) (133 mg, 0.870 mmol) and triethylamine (0.40 mL) in N,N-dimethylformamide (DMF) (5.0 mL) was stirred at room temperature for 20 h. Water (50 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (100 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/AcOEt eluent, 0:1 to 1:4) to give 129 mg (79%) of 1a as colorless crystals. mp 177-178 C. 1H NMR (CDCl3) delta: 3.12 (3H, s), 3.64-3.75 (2H, m), 3.98 (2H, s), 4.43-4.53 (2H, m), 6.62 (1H, d, J = 3.0 Hz), 7.07 (1H, d, J = 9.0 Hz), 7.09-7.15 (1H, m), 7.18-7.33 (4H, m), 7.40-7.45 (1H, m), 7.77 (1H, dd, J = 9.0, 2.7 Hz), 7.96 (1H, d, J = 2.7 Hz), 8.19 (1H, s), 8.51 (1H, s). Anal. Calcd for C24H21ClF3N5O4: C, 50.75; H, 3.73; N, 12.33. Found: C, 50.85; H, 3.71; N, 12.38. |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | Example 160 Production of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (79.6 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate ? ethyl acetate:methanol=4:1). Crystallization from ethyl acetate-diisopropyl ether gave the title compound (128 mg) as colorless powder crystals. 1H-NMR (CDC13) delta: 3.12 (3H, s), 3.64-3.75 (2H, m), 3.98 (2H, s), 4.43-4.53 (2H, m), 6.62 (1H, d, J= 3.0 Hz), 7.07 (1H, d, J= 9.0 Hz), 7.09-7.15 (1H, m), 7.18-7.33 (4H, m), 7.40-7.45 (1H, m), 7.77 (1H, dd, J= 9.0, 2.7 Hz), 7.96 (1H, d, J= 2.7 Hz), 8.19 (1H, s), 8.51 (1H, s). melting point: 177-178C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | (iii) Production of N-{2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl)acetamide A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (160 mg), <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (82.3 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg), 1-hydroxybenzotriazole monohydrate (137 mg), triethylamine (0.42 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate ? ethyl acetate: methanol=4:1) and crystallization from ethanol-ethyl acetate-diisopropyl ether to give the title compound (112 mg) as pale-yellow crystals. 1H-NMR (CDCl3) delta: 3.12 (3H, s), 3.64-3.76 (2H, m), 3.99 (2H, s), 4.34-4.52 (2H, m), 6.62 (1H, d, J= 3.0 Hz), 6.81-6.84 (1H, m), 6.86-6.95 (2H, m), 7.08 (1H, d, J= 8.7 Hz), 7.17-7.24 (2H, m), 7.29-7.34 (1H, m), 7.76 (1H, dd, J= 8.7, 2.7 Hz), 7.95 (1H, d, J= 2.7 Hz), 8.18 (1H, s), 8.51 (1H, s). melting point: 133-135C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | (iii) Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}acetamide A solution of 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (174 mg), <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (54 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (79 mg) and triethylamine (0.273 mL) in N,N-dimethylformamide (7.69 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (60 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 ? 92:8), and crystallized from diisopropyl ether to give the title compound (92 mg) as colorless crystals. 1H-NMR (DMSO-d6) delta 2.14 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.56 (2H, t, J= 6 Hz), 6.48 (1H, d, J= 3 Hz), 6.89 (2H, m), 7.06 (2H, m), 7.48 (1H, t, J= 8 Hz), 7.59 (3H, m), 8.30 (1H, s), 8.55 (1H, br s), 8.67 (1H, t, J= 6 Hz). melting point: 106-108C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | General procedure: A mixture of 6 (150 mg, 0.288 mmol), <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (79.6 mg, 0.576 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (166 mg, 0.870 mmol), 1-hydroxybenzotriazole monohydrate (HOBt) (133 mg, 0.870 mmol) and triethylamine (0.40 mL) in N,N-dimethylformamide (DMF) (5.0 mL) was stirred at room temperature for 20 h. Water (50 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (100 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/AcOEt eluent, 0:1 to 1:4) to give 129 mg (79%) of 1a as colorless crystals.The following compound 2a was prepared from 7 by a method similar to that described for 1a. |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | (iii) Production of N-[2-(4-[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (113 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-dimethylformamide (5.0 mL) were added a solution of triethylamine (419 mg) in N,N-dimethylformamide (1.25 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (173 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 16 hrs, water was added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/methanol=100/0 ? 80/20), and recrystallized from ethanol-ethyl acetate-diisopropyl ether to give the title compound (151 mg) as crystals. 1H-NMR (CDCl3) delta: 3.13 (3H, s), 3.6-3.8 (2H, m), 3.99 (2H, s), 4.4-4.6 (2H, m), 6.62 (1H, d, J= 3.4 Hz), 6.85-6.95 (2H, m), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m), 7.7-7.8 (1H, m), 7.95-8.0 (1H, m), 8.19 (1H, s), 8.52 (1H, s). melting point: 206-207C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h; | Production of N- ( 2- { 4- [ ( 3-chloro-4- { 3- [ 4- ( trifluoromethyl ) -1, 3-thiazol-2- yl]phenoxy} phenyl) amino] -5H-pyrrolo [3, 2-d]pyrimidin-5- yl } ethyl ) -2- (methylsulfonyl ) acetamideTo a solution of 5- ( 2-aminoethyl ) -N- ( 3-chloro-4- { 3- [ 4- (trifluoromethyl ) -1, 3-thiazol-2-yl]phenoxy}phenyl) - 5H-pyrrolo [ 3 , 2-d] pyrimidin-4-amine dihydrochloride (200 mg) , methylsulfonylacetic acid(69 mg) and 1- hydroxybenzotriazole (75 mg) in N, N-dimethylformamide (5.0 mL) were added triethylamine (0.23 mL) and 1-ethyl- 3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (105 mg) under ice-cooling, and the mixture was stirred at room temperature for 6 hr. Water was added to the <n="323"/>reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate :methanol=100 : 0?95 : 5) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (179 mg) as colorless crystals. 1H-NMR (CDCl3) 6: 3.12 (3H, s), 3.65-3.75 (2H, m) , 3.98 (2H, s), 4.45-4.55 (2H, m) , 6.60-6.,65 (IH, m) , 7.08 (2H, d, J = 9.0 Hz), 7.21 (IH, d, J = 3.0 Hz), 7.25-7.30 (2H, m) , 7.42 (IH, t, J = 8.0 Hz), 7.65-7.75 (2H, m) , 7.75(IH, s), 7.95 IH, 20 (IH, s) 51 (IH, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Production of N- ( tert-butyl) -3- ( 2-chloro-4- { [ 5- ( 2- { [ (methylsulfonyl) acetyl] amino } ethyl ) -5H-pyrrolo[3,2- d] pyrimidin-4-yl] amino } phenoxy) benzamide hydrochloride A mixture of 3- ( 4- { [ 5- (2-aminoethyl ) -5H- pyrrolo [3, 2-d] pyrimidin-4-yl] amino } -2-chlorophenoxy) -N- (tert-butyl ) benzamide dihydrochloride (166 mg) , methylsulfonylacetic acid (62 mg) , l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg) , triethylamine (0.100 mL) and N, N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-»15 : 85 ). The objective fractions were concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol and IN hydrogen chloride/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol- ethyl acetate to give the title compound (121 mg) as white crystals.1H-NMR (DMSO-d6) delta: 1.36 (9H, s), 3.06 (3H, s), 3.50-3.61 (2H, m) , 4.07 (2H, s), 4.67-4.77 (2H, m) , 6.67 (IH, d, J= 3.1 Hz), 7.13-7.20 (IH, m) , 7.25 (IH, d, J= 8.9 Hz), 7.37 (IH, m) , 7.47 (IH, t, J= 8.0 Hz), 7.60-7.69 (2H, <n="342"/>m) , 7.85 (IH, s) , 7.93 (IH, d, J= 2.5 Hz) , 7.96 (IH, d, J= 3.1 Hz) , 8.74 (IH, s) , 8.78-8.87 (IH, m) , 9.99 (IH, br s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Production of N- <tert-butyl ) -3- (2-chloro-4- { [ 5- ( 2- { [ (methylsulfonyl) acetyl] amino } ethyl) -5H-pyrrolo[3,2- d]pyrimidin-4-yl] amino }phenoxy) -5- ( trifluoromethyl ) benzamide ,A mixture of 3- ( 4- { [ 5- (2-aminoethyl ) -5H- pyrrolo [3, 2-d] pyrimidin-4-yl ] amino }-2-chlorophenoxy) -N- (tert-butyl) -5- (trifluoromethyl ) benzamide dihydrochloride (186 mg) , methylsulfonylacetic acid (62 mg), l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N, N-dimethylformamide (3 itiL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-»15 : 85) and basic silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-»10 : 90 ) . The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (146 mg) as white crystals. 1H-NMR (CDCl3) delta: 1.48 (9H, s), 3.14 (3H, s), 3.60-3.74 (2H, m) , 4.00 (2H, s), 4.40-4.54 (2H, m) , 6.06 (IH, br s), 6.58 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.8 Hz), <n="351"/>7.21 (IH, d, J= 3.0 Hz), 7.35 (IH, m) , 7.46 (IH, m) ,7.58 (IH, m) , 7.78 (IH, dd, J= 2.3 Hz, 8.8 Hz), 7.87-7.96 (IH, m) , 7.97 (IH, d, J= 2.3 Hz), 8.29 (IH, br s), 9.46 (IH, s) |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Production of N- { 2- [ 4- ( { 3-chloro-4- [ 3- ( 1 , 1-difluoro-2 , 2- dimethylpropyl )phenoxy] phenyl} amino) -5H-pyrrolo [3, 2- d] pyrimidin-5-yl ]ethyl}-2- (methylsulfonyl ) acetamideA mixture of 5- ( 2-aminoethyl ) -N- { 3-chloro-4- [ 3- (1, l-difluoro-2, 2-dimethylpropyl ) phenoxy] phenyl } -5H- pyrrolo [ 3 , 2-d] pyrimidin-4-amine dihydrochloride (168 mg) , methylsulfonylacetic acid (62 mg), l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole monohydrate (69 mg), triethylamine (0.100 mL) and N, N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-»20 : 80) . The objective fractions were <n="530"/>concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (153 mg) as a white powder. 1H-NMR (CDCl3) delta: 1.04 (9H, s), 3.14 (3H, s), 3.65-3.75 ; (2H, m) , 3.98 (2H, s), 4.44-4.53 (2H, m) , 6.59 (IH, d, J -= 3.0 Hz), 6.98-7.04 (2H, m) , 7.07 (IH, m) , 7.15 (IH, d, J = 7.7 Hz), 7.21 (IH, d, J = 3.0 Hz), 7.34 (IH, d, J = 8.0 Hz), 7.62 (IH, t, J = 5.5 Hz), 7.72 (IH, dd, J = 2.5Hz, 8.9 Hz) , 7.94 IH, d, J = 2.5 Hz), 8.18 (IH, br s) 8.50 (IH, s) |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Production of N- [2- ( 4- [ 1- ( 3-fluorobenzyl) -IH- indazol-5-yl ] amino }-5H-pyrrolo[3,2-d] pyrimidin-5- yl) ethyl] -2- (methylsulfonyl ) acetamideA mixture of 5- ( 2-aminoethyl ) -N- [ 1- ( 3- fluorobenzyl) -lH-indazol-5-yl ] -5H-pyrrolo[3,2- d] pyrimidin-4-amine trihydrochloride (183 mg) , methylsulfonylacetic acid (74.2 mg), l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg) , ' triethylamine (0.15 mL) and N, N-dimethylformamide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate : methanol=90 : 10 ) and crystallized from isopropyl ether to give the title compound (134 mg) as crystals. 1H-NMR (DMSO-d6) delta: 3.07 (3H, s), 3.48 (2H, q, J= 6 Hz), <n="570"/>4.04 (2H, s) , 4.56 (2H, t, J= 6 Hz) , 5.69 (2H, s) , 6.45 (IH, d, J= 3 Hz) , 7.00-7.20 (3H, m) , 7.30-7.40 (IH, m) ,7.57 (2H, m) , 7.68 (IH, d, J= 9 Hz) , 7.95 (IH, m) , 8.10(IH, s) , 8.21 (IH, s) , 8.58 (IH, br s) , 8.65 (IH, t, J= 6 Hz) . |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Production of N- [2- ( 4- { [3-chloro-4- (3- methylphenoxy) phenyl ] amino }-5H-pyrrolo[3,2-d]pyrimidin- 5-yl) ethyl] -2- (methylsulfonyl ) acetamideA mixture of 5- ( 2-aminoethyl ) -N- [ 3-chloro-4- ( 3- methylphenoxy) phenyl] -5H-pyrrolo [3, 2-d] pyrimidin-4-amine dihydrochloride (140 mg), methylsulfonylacetic acid (62 mg) , l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N, N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol : ethyl acetate=0 : 100-»15 : 85 ) . The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to <n="280"/>give the title compound (147 mg) as a white powder. 1H-NMR (CDCl3) delta: 2.33 (3H, s), 3.13 (3H, ,s), 3.63-3.76(2H, m) , 3.70 (2H, s), 4.41-4.53 (2H, m) , 6.58 (IH, d, J= 3.3 Hz), 6.75-6.84 (2H, m) , 6.90 (IH, d, J= 7.4 Hz), ; 7.01 (IH, d, J= 8.7 Hz), 7.16-7.24 (2H, m) , 7.55-7.64(IH, m) , 7.69 (IH, dd, J= 8.7, 2.7 Hz), 7.89 (IH, d, J= 2.7 Hz), 8.14 (IH, br s), 8.48 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Production of N- { 2- [ 4- ( { 3-chloro-4- [ 3- (cyclopropylmethoxy) phenoxy] phenyl} amino) -5H- pyrrolo[3,2-d] pyrimidin-5-yl] ethyl}-2- (methylsulfonyl) acetamide hydrochloride <n="445"/>5 - ( 2 -Aminoethyl ) -N- { 3 - chloro- 4 - [ 3 -(cyclopropylmethoxy) phenoxy] phenyl } -5H-pyrrolo [3,2- d]pyrimidin-4-amine dihydrochloride (187 mg) , methylsulfonylacetic acid (74.2 mg) , N,N- dimethylformamide (6.9 mL) , 1-hydroxybenzotriazole (72.5 mg) , triethylamine (0.15 mL) and l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg) were stirred at room temperature for 16 hr. The mixture was partitioned between ethyl acetate (80 mL) /water (50 mL) . The organic layer was dried over anhydrous magnesium sulfate and concentrated < under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate :methanol=100 : 0->85 : 15 ) and basic silica gel column chromatography (ethyl acetate :methanol=100 : 0-»85 : 15 ). The obtained compound was dissolved in ethyl acetate (4 mL) , treated with 4N hydrogen chloride/ethyl acetate solution (0.18 mL) , and crystallized from diisopropyl ether/ethyl acetate to give the title compound (167 mg) as white crystals.1H-NMR (DMSO-de) delta: 0.20-0.40 (2H, m) , 0.50-0.60 (2H, m) , 1.10-1.40 (IH, m) , 3.05 (3H, s), 3.50-3.60 (2H, m) , 3.80 (2H, d, J= 7.0 Hz), 4.07 (2H, s), 4.73 (IH, t, J= 7.0 Hz), 6.40-6.55 (2H, m) , 6.60-6.75 (2H, m) , 7.20-7.30 (2H, m) , 7.63 (IH, dd, J= 2.0 Hz, 9.0 Hz), 7.90 (IH, d, J= 2.0 Hz), 7.96 (IH, d, J= 3.0 Hz), 8.72 (IH, s), 8.87 (IH, m) , 10.05 (IH, br s) . |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 24h; | Product ion o f N- ( 2 - { 4 - [ ( 3 -methyl - 4 - { 3 - [ ( IE ) - 3 - <n="554"/>methylbut-1-en-l-yl] phenoxy } phenyl ) amino] -5H- pyrrolo[3,2-d] pyrimidin-5-yl } ethyl) -2- (methylsulfonyl) acetamide hydrochlorideA mixture of 5- (2-aminoethyl ) -N- ( 3-methyl-4- { 3- [ (IE) -3-methylbut-1-en-l-yl] phenoxy} phenyl) -5H- pyrrolo [ 3 , 2-d] pyrimidin-4-amine dihydrochloride (74.8 mg) and methylsulfonylacetic acid (31.1 mg) was dissolved in tetfahydrofuran (0.4 mL)/N,N- dimethylformamide (0.4 mL) , 1-hydroxybenzotriazole (32.5 mg) , triethylamine (0.2 mL) and l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (45.0 mg) were added successively thereto, and the mixture was stirred at room temperature for 24 hr . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane : ethyl acetate=20 : 80-»0': 100-»ethyl acetate:methanol=90 : 10) to give N- (2- { 4- [ (3-methyl-4- { 3- [ (IE) -3-methylbut-1-en-l-yl] phenoxy} phenyl) amino] -5H- pyrrolo [3, 2-d]pyrimidin-5-yl}ethyl) -2-(methylsulfonyl ) acetamide . The compound was dissolved in ethyl acetate and treated with 4N hydrogen chloride/ethyl acetate solution, and the precipitate was collected by filtration to give the title compound (32.5 mg) as a yellow powder.1H-NMR (DMSO-d6) delta: 1.05 (6H, d, J= 6.8 Hz), 2.22 (3H, s), 2.36-2.55 (IH, m) , 3.06 (3H, s), 3.47-3.62 (2H, m) , 4.06 (2H, s), 4.69 (2H, t, J= 6.4 Hz), 6.20-6.42 (2H, m) , 6.64 (IH, d, J= 3.0 Hz), 6.69-6.78 (IH, m) , 6.93- 7.03 (2H, m) , 7.16 (IH, d, J= 8.0 Hz), 7.31 (IH, t, J= 8.0 Hz), 7.44 (IH, dd, J= 2.5 Hz, 8.6 Hz), 7.53 (IH, d, J= 2.5 Hz), 7.90 (IH, d, J= 3.0 Hz), 8.67 (IH, s), 8.79 (IH, t, J= 5.6 Hz), 9.85 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Production of N- [2- ( 4- { [3-chloro-4- ( 3- fluorophenoxy) phenyl] amino} -5H-pyrrolo [3, 2-d] pyrimidin- 5-yl) ethyl] -2- (methylsulfonyl ) acetamideA mixture of 5- (2-aminoethyl ) -N- [ 3-chloro-4- ( 3- fluorophenoxy) phenyl] -5H-pyrrolo [3, 2-d] pyrimidin-4-amine dihydrochloride (141 mg) , methylsulfonylacetic acid (62 mg) , l-ethyl-3- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (86 mg) , 1-hydroxybenzotriazole (69 mg) , triethylamine (0.100 mL) and N, N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol : ethyl <n="283"/>acetate=0 : 100-»15 : 85) . The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (146 mg) as a white powder. 1H-NMR (CDCl3) delta: 3.14 (3H, s), 3.64-3.76 (2H, m) , 3.98 j(2H, s), 4.43-4.54 (2H, m) , 6.59 (IH, d, J= 3.3 Hz), 6.63-6.70 (IH, m) , 6.73-6.82 (2H, m) , 7.08 (IH, d, J= 8.9 Hz), 7.18-7.31 (2H, m) , 7.57-7.65 (IH, m) , 7.75 (IH, dd, J= 2.5 Hz, 8.9 Hz), 7.93 (IH, d, J= 2.5 Hz), 8.19 (IH, br s) , 8.49 (IH, s) |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Production of N- [2- ( 4- { [ 4- ( 3-chlorophenoxy) -3- methylphenyl] amino} -5H-pyrrolo[3,2-d] pyrimidin-5- yl) ethyl] -2- (methylsulfonyl ) acetamideA mixture of 5- (2-aminoethyl ) -N- [ 4- ( 3- chlorophenoxy) -3-methylphenyl ] -5H-pyrrolo [3,2- d] pyrimidin-4-amine dihydrochloride (167 mg), methylsulfonylacetic acid (74 mg) , l-ethyl-3- ( 3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg) , triethylamine (0.15 itiL) and N, N-dimethylformamide (6.9 inL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively <n="286"/>with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate :methanol=85 : 15 ) to give the title compound (177 mg) as colorless crystals.1H-NMR (DMSO-d6) delta: 2.13 (3H, s), 3.09 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.05' (2H, s), 4.55 (2H, t, J= 6 Hz), 6.46 (IH, d, J= 3 Hz), 6.80-6.95 (2H, m) , 7.00 (IH, d, J= 9 Hz), 7.11 (IH, m) , 7.37 (IH, t, J= 8 Hz), 7.56 (3H, m) , 8.28 (IH, s), 8.52 (IH, br s), 8.66 (IH, m) . |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h; | Production of N- { 2- [ 4- ( { 5-chloro-6- [ 3- <n="297"/>(trifluoromethyl) phenoxy]pyridin-3-yl } amino) -5H- pyrrolo[3,2-d] pyrimidin-5-yl] ethyl}-2- (methylsulfonyl ) acetamideA mixture of 5- ( 2-aminoethyl ) -N- { 5-chloro-6- [ 3- (trifluoromethyl )phenoxy]pyridin-3-yl}-5H-pyrrolo[3,2- d] pyrimidin-4-amine trihydrochloride (95 mg), methylsulfonylacetic acid (47 mg) , l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide hydrochloride (98 mg) , 1-hydroxybenzotriazole (78 mg) and triethylamine (0.12 mL) in N, N-dimethylformamide (5.0 mL) was stirred at room temperature for 14 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate : methanol=85 : 15 ) to give the title compound (86 mg) as colorless crystals. 1H-NMR (CDCl3) 6: 3.10 (3H, s), 3.62-3.78 (2H, m) , 3.98 (2H, s), 4.41-4.53 (2H, m) , 6.63 (IH, d, J= 3.0 Hz), 7.21 (IH, d, J= 3.0 Hz), 7.29-7.55 (5H, m) , 8.41-8.50 (4H, m) . |
Yield | Reaction Conditions | Operation in experiment |
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2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 fromExample 3 (4.17 g) was converted via General Procedure B-3 to yield 5.67 g of tert-butyl 4- ((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-l-carboxylate. Tert- butyl 4-((2-chloro-4-morpholinothieno [3 ,2-d]pyrimidin-6-yl)methyl)piperazine- 1 -carboxylate (Ig) was reacted with 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 1.02 g of tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-4- mophiholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-l-carboxylate. This intermediate was then converted to the HCl salt of 5-(4-morpholino-6-((piperazin-l-yl)methyl)thieno[3,2- d]pyrimidin-2-yl)pyrimidin-2 -amine via General Procedure D. [00277] The HCl salt of 5-(4-morpholino-6-((piperazin- 1 -yl)methyl)thieno[3,2- d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was then reacted with methanesulfonylacetic acid via General Procedure B to generate 56 mg of 101. MS (Ql) 533.2 (M)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | A solution of methanesulfonyl acetic acid (0.43 mmol) in 1.5 mL of anh. DMF was treated with 2.0 eq. of CDI for ~1 hr. Next, 1.0 eq. of 2-(2-aminopyrimidineO-5-yl)- N- hydroxy-4-morpholinothieno[3,2-J]pyrimidine-6-carboxamidine was added portion- wise as a solid. This reaction was stirred at room temperature for >1 hr. then flash heated on an EmrysOptimizer microwave at 150 C for 10 minutes. The crude material was purified by RP-HPLC to give 333 in 17% yield. MS (Ql) 475.2 (M) + |
Yield | Reaction Conditions | Operation in experiment |
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89% | With hydrogenchloride; In 1,4-dioxane; for 16h;Heating / reflux; | [0348] Method 14-1: Schemes 14a describes the synthesis of compound 72 of Formula IScheme 14aO O OMethanesulfonyl-acetic acid (69) (5 3 g, 38 4 mmol) was suspended in ethyl alcohol (5O mL) A 4M solution of HCl in dioxane (8 mL) was added The mixture stirred at reflux for 0 5 h, everything had dissolved at this point The mixture continued to stir at reflux for a total of 16 h Upon cooling, the solution was concentrated in vacuo to approximately 20 mL The oil was diluted with ethyl acetate (300 mL), washed with water (100 mL), brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to a golden oil Purification by flash column chromatography (30% ethyl acetate in hexanes, Merck silica gel 60, 40-63 mum) afforded the desired product, methanesulfonyl-acetic acid ethyl ester (70) (5 67 g, 34 12 mmol, 89 % yield), as a <n="161"/>clear oil upon concentrating. 1HNMR (400 MHz, DMSO-d6) delta: 1.22 (3H, t, J= 7.0 Hz), 3.13 (3H, s), 4.17 (2H, quartet, J= 7.0 Hz), 4.38 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
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With diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 40h; | 6-Methoxy-l'- (2-phenoxyethyl)-2, 3,4, 9-tetrahydrospiro[beta-carboline-1, 3'-pyrrolidine] (EXAMPLE 10,60 mg, 0.16 mmol),N, N-diisopropylcarbodiimide (32pu, 0.21 mmol), (methylsulfonyl) acetic acid (29 mg, 0.21 mmol) (29 mg, 0.21 mmol) and DCM(1 mL) <Desc/Clms Page number 74>were shaken at ambivalent temperature for 16h. MoreN, N-diisopropylcarbodiimide (32L, 0.21 mmol) and (methylsulfonyl) acetic acid (29 mg, 0.21 mmol) were added to the reaction, which was shaken an additional 24h and than the solvent was removed. The product was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% triflouroacetic acid. Yield: 15.9 mg (20%). HPLC 96%,RT : 1.901 (10-97% MeCN over 3 min). 1H NMR (270 MHz, Methanol-d3) No. ppm 2.77-2. 91 (m, 4 H) 3.11 (s, 3 H) 3.64-3. 97 (m, 4 H) 3.81 (s, 3 H) 4.17-4. 25 (m, 2H) 4.36-4. 45 (m, 4 H) 4.63 (d, J=3. 46 Hz, 2 H) 6.83 (dd, J=8. 91,2. 47 Hz, 1 H) 6.92-7. 16 (m, 4 H) 7.19-7. 40 (m, 3 H). MS(ESI+) m/z 498 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; HATU; In dichloromethane; at 20℃; for 16h; | Example 15Methyl 2-(4-((N-(3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl)-2-(methylsulfonyl)acetamido)methyl)phenyl)acetate; To a solution of the product from example 1 (221mg) in DCM (10 mL) was added 2- <strong>[2516-97-4](methylsulfonyl)acetic acid</strong> (66.4 mg) followed by TEA (0.201 mL) and HATU (201mg).The reaction mixture was stirred at rt for 16h then the solvents were evaporated. <n="67"/>The crude product was purified by RPHPLC to afford the title compound (120 mg) as a white solid.1R NMR DMSO-d6: delta 8.07 - 7.93 (m, IH), 7.66 - 7.56 (m, IH), 7.47 - 7.37 (m, IH), 7.29 - 7.04 (m, 5H), 6.43 (s, 2H), 4.71 (s, IH), 4.59 - 4.37 (m, 5H), 3.67 - 3.55 (m, 5H), 3.15 (s, 3H), 2.93 - 2.80 (m, 2H), 2.72 (s, IH), 2.10 - 1.93 (m, 2H), 1.84 - 1.68 (m, 2H), 1.49 - 1.32 (m, 2H), 1.30 - 1.19 (m, IH), 0.95 (t, 3H) MS: 580 ES+ |
Yield | Reaction Conditions | Operation in experiment |
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The product of the previous step (0.360 g, 0.760 mmol) was dissolved in DCM (10 mL). Trifluoroacetic acid (10 mL) was added and the reaction mixture was stirred for 2 h, concentrated, and dissolved in water (5 mL) and acetonitrile (5 g). The resulting solution was frozen and lyophilized to give the title compound (220 mg) which was used without further purification. (m/z): [M+H]+ calcd for C22H35N3O2, 374.27; found 373.8. Example 33-endo-(8-2-[(2-Ethylbutyl)-(2-methanesulfonylacetyl)amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxybenzamideTo a solution of 3-endo-(8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl-2-hydroxybenzamide TFA (20 mg, 0.033 mmol) (Preparation 8), 1 methanesulfonyl-acetic acid (5.05 mg, 0.0366 mmol) and DIPEA (17 muL, 0.10 mmol) in DMF (10.3 mL) was added N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (15 mg, 0.040 mmol). The reaction mixture was stirred for 2 h, concentrated, and purified by preparative HPLC to give the title compound as its TFA salt (8.8 mg). (m/z): [M+H]+ calcd for C25H39N3O5S 494.26; found: 494.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; | To a solution of 3-endo-(8-2-[(4,4-difluoro-cyclohexylmethyl)-amino]-ethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-hydroxy-benzamide (310 mg, 0.74 mmol) in DMF (2.1 mL) was added DIPEA (154 muL, 0.88 mmol) followed by methanesulfonyl-acetic acid (112 mg, 0.81 mmol) and then N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (336 mg, 0.88 mmol). The reaction mixture was stirred overnight, concentrated, and purified by preparative HPLC to give the title compound as it TFA salt (199 mg). 1H NMR (CD3OD, 400 mHz) delta (ppm) 7.69 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.70-7.64 (m, 2H), 7.44-7.34 (m, 3H), 7.32 (dd, J=7.5 Hz, 1.8 Hz, 1H), 6.84 (t, J=7.8 Hz, 1H), 6.6-6.1 (m, 1H), 4.12 (dd, J=17.8 Hz, 8.4 Hz, 2H), 3.80-3.68 (m, 2H), 3.18-3.06 (m, 1H), 2.46-2.30 (m, 2H), 2.29-2.14 (m, 2H), 2.03-1.93 (m, 1H). (m/z): [M+H]+ calcd for C26H37F2N3O5S 542.24; found 542.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 3-endo-{8-[2-(2-ethylbutylamino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide (40.0 mg, 0.11 mmol) in N,N-dimethylformamide (200 muL) was added methanesulfonyl-acetic acid (18.6 mg, 0.13 mmol) and N,N,N'N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (51.1 mg, 0.13 mmol) and the reaction was stirred for 1 h at room temperature. The reaction mixture was concentrated and purified by preparative HPLC to give the TFA salt of the title compound (32.0 mg). (m/z): [M+H]+ calcd for C25H49N3O4S, 478.27; found 478.4. 1H NMR (DMSO 400 MHz) delta (ppm) 9.0 (2, 1H), 7.9-8.1 (m, 2H), 7.6-7.8 (m. 2H), 7.3-7.4 (m, 2H), 4.1 (br. 2H), 3.6-3.8 (m, 2H), 2.9-3.4 (m, 8H), 2.4-2.6 (m, 2H), 1.9-2.1 (br. 2H), 1.5-1.6 (m, 3H), 1.2-1.3 (m, 4H), 0.8-1.0 (m, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 3-endo-{8-[3-(2-ethylbutyllamino)propyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-benzamide (30.0 mg, 0.08 mmol) in N,N-dimethylformamide (200 muL) was added methanesulfonyl-acetic acid (13.4 mg, 0.10 mmol) and N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (36.8 mg, 0.10 mmol). The reaction was stirred for 1 h at room temperature. The reaction mixture was concentrated and purified by preparative HPLC to give the TFA salt of the title compound (28.3 mg). (m/z): [M+H]+ calcd for C26H41N3O4S, 492.28; found 492.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In tetrahydrofuran; N,N-dimethyl acetamide; N,N-dimethyl-formamide; | Example 285 Production of 1,3-dimethyl-N-{2-methyl-5-[(2-[(methylsulfonyl)acetyl]amino}imidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide In the same manner as in Example 279 and using <strong>[2516-97-4](methylsulfonyl)acetic acid</strong> (100 mg, 0.73 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (63 muL, 0.73 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (91 mg, 38%) was obtained as a pale-yellow solid. 1H-NMR (DMSO-d6, 300 MHz) delta 2.20 (3H, s), 2.25 (3H, s), 3.17 (3H, s), 3.99 (3H, s), 4.37 (2H, s), 6.81 (1H, s), 7.07-7.14 (2H, m), 7.29 (1H, d, J=2.7 Hz), 7.35 (1H, d, J=8.7 Hz), 8.01 (1H, s), 8.08 (1H, d, J=9.5 Hz), 9.79 (1H, s), 11.26 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 5h; | A mixture of 4-(4-[5-(2-aminoethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]amino}-2-chlorophenoxy)-1,3-dihydro-2H-indol-2-one dihydrochloride (149 mg) and methylsulfonylacetic acid (74 mg) was dissolved in a mixed solvent of tetrahydrofuran (0.8 mL)/N,N-dimethylformamide (0.8 mL), triethylamine (0.4 mL), 1-hydroxybenzotriazole (89.7 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg) were added, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=20:80?0:100?ethyl acetate:methanol=85:15) to give the title compound (136 mg) as a pale-orange powder. 1H-NMR (DMSO-d6) delta: 3.09 (3H, s), 3.38 (2H, s), 3.41-3.53 (2H, m), 4.04 (2H, s), 4.56 (2H, t, J = 6.6 Hz), 6.33 (1H, d, J = 8.3 Hz), 6.49 (1H, d, J = 3.0 Hz), 6.60 (1H, d, J = 7.6 Hz), 7.10-7.22 (2H, m), 7.62 (1H, d, J = 3.0 Hz), 7.69 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.94 (1H, d, J = 2.2 Hz), 8.33 (1H, s), 8.58-8.74 (2H, m), 10.51 (1H, br s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (100 mg), 3-chloro-4-(1H-indol-4-yloxy)aniline (87 mg) and isopropyl alcohol (5 mL) was stirred at 80C for 12 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction system under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=60:40?100:0) to give a crude product (150 mg). The obtained crude product (140 mg) was dissolved in tetrahydrofuran (4 mL), 4N hydrochloric acid/ethyl acetate (4 mL) was added, and the mixture was stirred at 70C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. Diisopropyl ether was added, and the precipitated powder was collected by filtration. A mixture of the obtained powder, methylsulfonylacetic acid (70 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg), 1-hydroxybenzotriazole (70 mg), triethylamine (0.35 mL) and N,N-dimethylformamide (7.0 mL) was stirred at room temperature for 16 hr. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate?ethyl acetate:methanol=90:10), and crystallized from diisopropyl ether to give the title compound (76 mg) as colorless crystals. 1H-NMR (DMSO-d6) delta: 3.09 (3H, s), 3.46 (2H, q, J = 5.9 Hz), 4.04 (2H, s), 4.56 (2H, t, J = 5.9 Hz), 6.32 (1H, br s), 6.41 (1H, d, J = 8.0 Hz), 6.48 (1H, d, J = 2.7 Hz), 6.95-7.06 (2H, m), 7.19 (1H, d, J = 8.0 Hz), 7.31 (1H, d, J = 2.7 Hz), 7.60 (2H, br s), 7.93 (1H, s), 8.31 (1H, s), 8.52-8.75 (2H, m), 11.28 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (100 mg), 3-chloro-4-[(1-methyl-1H-indol-4-yl)oxy]aniline (90 mg) and isopropyl alcohol (5 mL) was stirred at 80C for 12 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction system under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=60:40?100:0) to give a crude product (160 mg). The obtained crude product (120 mg) was dissolved in tetrahydrofuran (4 mL), 4N hydrochloric acid/ethyl acetate (4 mL) was added, and the mixture was stirred at 70C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. Diisopropyl ether was added, and the precipitated powder was collected by filtration. A mixture of the obtained powder, methylsulfonylacetic acid (60 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), 1-hydroxybenzotriazole (70 mg), triethylamine (0.30 mL) and N,N-dimethylformamide (7.0 mL) was stirred at room temperature for 16 hr. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate?ethyl acetate:methanol=90:10), and crystallized from diisopropyl ether to give the title compound (62 mg) as colorless crystals. 1H-NMR (DMSO-d6) delta: 3.09 (3H, s), 3.46 (2H, d, J = 5.8 Hz), 3.81 (3H, s), 4.04 (2H, s), 4.56 (2H, t, J = 5.8 Hz), 6.32 (1H, d, J = 2.8 Hz), 6.40-6.52 (2H, m), 6.98-7.14 (2H, m), 7.19-7.27 (1H, m), 7.31 (1H, d, J = 3.2 Hz), 7.53-7.66 (2H, m), 7.94 (1H, d, J = 2.3 Hz), 8.32 (1H, s), 8.57-8.74 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | Example 18: Lambda/-(4-(4-(3-(3-terf-Butyl-1 -p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-yl)-2-(2-(methylsulfonyl)acetamido)acetamide Intermediate G1 DIPEA To a solution of <strong>[2516-97-4]2-<strong>[2516-97-4](methylsulfonyl)acetic acid</strong></strong> (33.1 mg, 240 mumol) in dry DCM (3.0 mL) under nitrogen was added 1-chloro-Lambda/,Lambda/,2-trimethylprop-1-en-1 -amine (31.7 muL, 240 mumol) and the reaction mixture maintained at RT for 1.5 hr. The resulting mixture was added to a solution of Intermediate G1 (45 mg, 80 mumol) and DIPEA (55.6 muL, 319 mumol) in dry DCM (2.0 mL) at 00C under nitrogen and the combined reaction mixture was kept at 00C for 30 min and then at RT for 2 hr. The reaction was quenched by addition of a 1 % solution of NH3 in MeOH (3.0 mL) and the resulting mixture was maintained at RT for 1 hr and was then evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 35- 85%, gradient elution) followed by trituration with ethyl acetate to afford the title compound, Example 18, as a pale brown solid (7 mg, 12%); R' 2.21 min (Method 2); m/z 684 (M+H)+ (ES+); 1H NMR (400MHz, DMSO-d6) delta: 1.29 (9H, s), 2.40 (3H, s), 3.08 (3H, s), 3.98 (2H, d), 4.14 (2H, s), 6.41 (1 H, s), 6.75 (1 H, dd), 7.34 (1 H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (2H, m), 7.64 (1 H, m), 7.83 (1 H, dd), 7.96 (1 H, d), 8.09 (1 H, d), 8.21 (1 H, d), 8.55 (1 H, t), 8.79 (1 H, br s), 9.12 (1 H, br s), 10.65 (1 H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 15h; | Process 7; Production of N-[4-[5-[3-bromo-5-(trifluoromethyl) phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-chlorophenyl] methyl-2-(methylsulfonyl) acetamide To a solution of 0.15 g of 3-(4-aminomethyl-3-chlorophenyl)-5-[3-bromo-5-(trifluoromethyl) phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole and 0.083 g of (methylsulfonyl) acetic acid in 3 mL of dichloromethane, 0.11 g of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride was added and the resultant mixture was stirred at room temperature for 15 hours. After the completion of the reaction, the reaction mixture was diluted with 3 mL of chloroform, and then 3 mL of a saturated sodium hydrogen carbonate aqueous solution was added to the diluted reaction mixture, followed by separating off the organic phase. The separated organic phase was dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order. From the resultant organic phase, the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluding with ethyl acetate to obtain 0.14 g of the objective substance as a white crystal. Melting point: 125.0 to 128.0C 1H NMR (CDCl3, Me4Si, 300 MHz) delta 7.95 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.54 (dd, J=7.8, 1.8 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 6.93 (t, J=6.2 Hz, 1H), 4.59 (d, J=6.2 Hz, 2H), 4.10 (d, J=17.4 Hz, 1H), 3.92 (s, 2H), 3.69 (d, J=17.4 Hz, 1H), 3.05 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | A flask was charged with methanesulfonyl-acetic acid (14 mg, 0.10 mmol), EDCI (30 mg, 0.15 mmol), HOBt (14 mg, 0.10 mmol), DIEA (36 muL, 0.20 mmol) and 0.5 mL DCM and stirred at 25 0C. After 10 min, a solution containing 4-cyano- IH- imidazole-2-carboxylic acid (2-cyclohex-l-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (40 mg, 0.08 mmol) (as prepared in Example 20, step (b)) and NEt3 (14 muL, 0.09 mmol) in 0.5 mL DCM was added and the reaction allowed to proceed for 10 h at 25 C. The reaction mixture was loaded on a 5-g SPE cartridge (silica) and the title compound was eluted with 10 % EtOEta/EtOAc to give 10 mg (25 %) of a white solid. 1H-NMR (400 MHz, CDCl3): delta 11.60 (br s, IH), 9.52 (s, IH), 8.30 (d, IH), 7.74 (s, IH), 7.60 (dd, IH), 7.03 (d, IH), 5.86 (m, IH), 4.84 (m,lH), 4.18 (s, 2H), 4.12 (m, IH), 3.32 (m, IH), 3.20 (s, 3H), 2.82 (m, 2H), 2.30 (m, 4H), 1.98 (m, 2H), 1.84 (m, 5H), 1.72 (m, IH). Mass spectrum (EST, m/z): Calcd. for C25H29N5O4S, 496.2 (M+H), found 496.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Production of N- { 2- [ 4- ( { 3 , 5-dichloro-4- [ 3- ( dimethylamino) phenoxy] phenyl} amino) -5H-pyrrolo [3, 2- d]pyrimidin-5-yl]ethyl}-2- (methylsulfonyl ) acetamide A mixture of tert-butyl [2- ( 4-chloro-5H- pyrrolo [ 3 , 2-d] pyrimidin-5-yl ) ethyl ] carbamate (150 mg) , 3, 5-dichloro-4- [3- (dimethylamino) phenoxy] aniline (150 mg) and isopropyl alcohol (8.0 mL) was stirred at 800C for 12 hr. Under ice-cooling, to the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate : hexane=60 : 40->100 : 0 ), the obtained crude product (150 mg) was dissolved in tetrahydrofuran (10 mL), 4N hydrogen chloride/ethyl acetate solution (5.0 mL) was added, and the mixture was stirred at 700C for 20 hr. The solvent was evaporated under reduced pressure, <n="385"/>ethanol and diisopropyl ether were added to the residue, and precipitated powder was collected by filtration and dissolved in N, N-dimethylformamide (7.0 mL) . Methylsulfonylacetic acid (70 mg) , l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (160 mg) , JL-hydroxybenzotriazole (70 mg) and triethylamine (0.15 mL) were added to the mixture, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate : methanol=90 : 10 ), and crystallized from diisopropyl ether to give the title compound (74 mg) .1H-NMR (DMSO-de) delta: 2.89 (6H, s), 3.11 (3H, s), 3.44-3.49(2H, m) , 4.06 (2H, s), 4.55-4.59 (2H, m) , 5.89-7.11 (5H, m) , 7.66-8.69 (5H, m) , 8.77 (IH, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Production of N- (2- ( 4- ( ( 3-chloro-4- ( 4-fluoro-3- methylphenoxy) phenyl) amino) -5H-pyrrolo[3,2-d] pyrimidin- <n="292"/>5-yl) ethyl) -2- (methylsulfonyl) acetamideA mixture of tert-butyl [2- ( 4-chloro-5H- pyrrolo [3, 2-d] pyrimidin-5-yl) ethyl] carbamate (1.00 g), 3-chloro-4- ( 4-fluoro-3-methylphenoxy) aniline (1.51 g) and isopropyl alcohol (10 mL) was stirred at 800C for 12 hr. Aqueous sodium bicarbonate was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was separated and purified by silica gel column chromatography (eluent, ethyl / acetate : hexane=60 : 40-»100 : 0 ) to give a crude product (1.52 g) . The obtained crude product (150 mg) was dissolved in tetrahydrofuran (22.2 mL) . 4N Hydrogen chloride/ethyl acetate solution (11.5 mL) was added, and the mixture was stirred at 700C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. Diisopropyl ether was added, and the precipitated powder was collected by filtration. A mixture of the obtained powder, methylsulfonylacetic acid (74 mg), l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide hydrochloride (103 mg) , 1-hydroxybenzotriazole (72 mg) , triethylamine (0.15 mL) and N, N-dimethylformamide (7.0 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate->ethyl acetate :methanol=90 : 10 ) and crystallized from diisopropyl ether to give the title compound (116 mg) as colorless crystals. 1H-NMR (DMSO-de) delta: 2.22 (3H, s), 3.10 (3H, s), 3.46 (2H, <n="293"/>q, J = 6.0 Hz) , 4.04 (2H, s) , 4.55 (2H, t, J = 6.0 Hz) , 6.49-7.17 (5H, m) , 7.61-7.93 (3H, m) , 8.33 (IH, s) , 8.65-8.66 (2H, m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | General procedure: A solution of intermediate 2 (TFA salt) (20 mg, 0.026 mmol) in acetonitrile (1 ml) was treated with carboxylic acid (0.031 mmol), HBTU (0.031 mmol), and DIPEA (0.078 mmol). The reaction mixture was maintained at room temperature for 1-4 h, concentrated, and purified by prep-HPLC (MeCN/ 0.1% TFA in water) to afford 3c-e and 3g-j as off-white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 1.0 equivalent of the appropriate carboxylic acid in dimethylformamide is admixed under argon at room temperature with HATU (1.5 eq.) and N,N-diisopropylethylamine (2.5 eq.). After 30 minutes, 1.1 equivalents of the appropriate amine are added. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is concentrated, and the residue is purified by means of preparative HPLC.; According to General Method 3, 88 mg (approx. 0.15 mmol) of the compound from Example 9A and 19 mg (0.14 mmol) of (methylsulphonyl)acetic acid were reacted. Diastereomer separation of 38 mg of the residue by Method 1C gave 2 mg of Example 3. LC-MS (Method 1B): Rt=1.05 min; MS (ESIpos): m/z=492 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With thionyl chloride; ammonium acetate; In ethanol; for 16h;Reflux; | Add 500 ml of ethanol to a 500 ml three-necked flask, 12.4 g of 2- (methylsulfonyl) acetic acid and 18.2 g of ammonium acetate, heated to 50 C,10.0 g of 3-ethoxy-4-methoxybenzaldehyde was added dropwise, heating reflux reaction. Cooled to below 10C, 40 g of thionyl chloride was added dropwise and heated under reflux for 16 hours to distill off ethanol. To the residue was added 50 ml of dichloromethane and the pH was adjusted to 6-7 with 5 mol / L NaOH solution.The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined and concentrated to give 14.2 g of a colorless oil,HPLC purity 98%, yield 78%. |
Tags: 2516-97-4 synthesis path| 2516-97-4 SDS| 2516-97-4 COA| 2516-97-4 purity| 2516-97-4 application| 2516-97-4 NMR| 2516-97-4 COA| 2516-97-4 structure
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P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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