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CAS No. : | 88887-87-0 | MDL No. : | MFCD11109576 |
Formula : | C4H10ClN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GHILZUOTUJGCDH-UHFFFAOYSA-N |
M.W : | 107.58 | Pubchem ID : | 12953687 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 28.94 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.83 |
Log Po/w (WLOGP) : | 1.24 |
Log Po/w (MLOGP) : | 0.76 |
Log Po/w (SILICOS-IT) : | 0.83 |
Consensus Log Po/w : | 0.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.03 |
Solubility : | 10.0 mg/ml ; 0.0933 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.96 |
Solubility : | 11.8 mg/ml ; 0.11 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.58 |
Solubility : | 28.0 mg/ml ; 0.26 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
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 |
---|---|---|
92% | With hydrogenchloride In 1,4-dioxane at 20℃; | (2) To a solution of the compound obtained in the above step (1) (4.66 g) in 1,4-dioxane (10 mL) was added a solution of 4N hydrochloric acid in dioxane (10 mL) , and the mixture was stirred at room temperature overnight. To the reaction mixture was added diisopropylether, and the precipitated crystals were collected by filtration to give 1-methylcyclopropylamine hydrochloride (2.69 g, yield: 92percent) as a colorless solid. MS (APCI) m/z; 72 [M+H] + |
50% | With hydrogenchloride In 1,4-dioxane at 20℃; for 1 h; | Step B: Preparation of l-methylcyclopropanamine hydrochloride.; A solution of l-methylcyclopropylcarbamate (250 mg, 1.46 mmol) in HCl (4N dioxane, 3.65 rnL, 14.6 mmol) was stirred at ambient temperature for 1 hour. It was then concentrated, triturated with ether, and filtered, giving the product as white solid (78 mg, 50percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: With diphenyl phosphoryl azide; triethylamine In <i>tert</i>-butyl alcohol at 75℃; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 20℃; for 2 h; |
1-Methylcyclopropane carboxylic acid (73.3 g, 0.73 mol), diphenyiphosphorylazde (221.7 g, 0.81 mol) and triethylamine (148.1 g, 1.46 mol) were stirred in tert-butanol(330 mL) and heated at 75 00 overnight. The reaction mixture was cooled to room temperature, poured into a mixture of ethyl acetate (750 mL) and water (1500 mL)stirred for 15 mm. The resulting precipitate was removed by filtration and the phases separated. The aqueous layer was extracted with ethyl acetate (2 x 750 mL) andcombined organic extracts were washed with water (750 mL), dried (MgSO4)concentrated to give a pale brown solid (88 g). The solid was suspended in 1 ,4-dioxane (295 mL) and 4 M hydrochloric acid (366 mL) was added. The reaction mixture was stirredroom temperature for 2 h. Diethyl ether was added and the mixture chilled in a methanol/ice bath for 15 mm. The precipitate was collected by filtration, washing with diethyl ether (2220 mL) before drying the filter cake for 10 mm to give 1-methylcyclopropanamine hydrochloride as a shiny white solid (40.5 g, 0.38 mol, 51percent).1H NMR (0D013): O 1.32 (5, 3H), 0.75-0.68 (m, 2H), 0.60-0.51 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a stirred solution of 1 -methylcyclopropane-1 -carboxylic acid (2 g, 19.98 mmol, 1 equiv) in t-butanol (10 ml_) was added DPPA (4.8 ml_, 22.17 mmol, 1 .1 equiv) and Triethyl amine(5.6 ml_ 40.18 mmol, 2 equiv) at room temperature, resulting reaction mixture was stirred at 75°C for 16h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1 , 4-Dioxane (30ml_), and 4N HCI (40 ml_) was added and the mixture was stirred for 3h. The reaction mixture was concentrated to obtain crude product. The crude product was washed with diethyl ether to obtain 1 -methylcyclopropan-1 -amine hydrochloride as brown solid (1 .2 g, 85percent yield).1H NMR (400 MHz, DMSO-d6) delta ppm 0.62-0.51 (m, 2 H), 0.94-0.83 (m, 2 H), 1 .37 (s, = 3 H), 8.42 (s, 3 H). | |
51% | 1-Methylcyclopropane carboxylic acid (73.3 g, 0.73 mol), diphenyiphosphorylazde (221.7 g, 0.81 mol) and triethylamine (148.1 g, 1.46 mol) were stirred in tert-butanol(330 mL) and heated at 75 00 overnight. The reaction mixture was cooled to room temperature, poured into a mixture of ethyl acetate (750 mL) and water (1500 mL)stirred for 15 mm. The resulting precipitate was removed by filtration and the phases separated. The aqueous layer was extracted with ethyl acetate (2 x 750 mL) andcombined organic extracts were washed with water (750 mL), dried (MgSO4)concentrated to give a pale brown solid (88 g). The solid was suspended in 1 ,4-dioxane (295 mL) and 4 M hydrochloric acid (366 mL) was added. The reaction mixture was stirredroom temperature for 2 h. Diethyl ether was added and the mixture chilled in a methanol/ice bath for 15 mm. The precipitate was collected by filtration, washing with diethyl ether (2220 mL) before drying the filter cake for 10 mm to give 1-methylcyclopropanamine hydrochloride as a shiny white solid (40.5 g, 0.38 mol, 51percent).1H NMR (0D013): O 1.32 (5, 3H), 0.75-0.68 (m, 2H), 0.60-0.51 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 0 - 20℃;Heating / reflux; | To the compound obtained in Referential Example 37 (4.46 g) in methylene chloride (20 mL) was added <strong>[88887-87-0]1-methylcyclopropylamine hydrochloride</strong> (J. Org. Chem., vol. 54, p. 1815 (1989)) (1.89 g) under ice cooling, and the thus-obtained mixture was stirred at room temperature overnight. Additional <strong>[88887-87-0]1-methylcyclopropylamine hydrochloride</strong> (1.89 g) was added thereto, and the thus-obtained mixture was stirred at room temperature for 20 hours, followed by heating under reflux for 5 hours with stirring. After methylene chloride and water were added to the reaction mixture, the organic layer was separated, and was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methanol : methylene chloride = 1:49), to thereby give the title compound (944 mg).1H-NMR(CDCl3) delta:0.40-0.50(2H, m), 0.68-0.73(2H, m), 1.16(3H, s), 2.88-2.94(2H, m), 3.03(2H, t, J=5.7Hz), 3.89(2H, br.s), 8.60(1H, s). MS(ESI)m/z:195(M+H)+. | |
In dichloromethane; water; | [Referential Example 102] 5-(1-Methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine: 1-Methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol. 54, p. 1815) (1.89 g) was added to dichloromethane (20 ml) containing 4-(2-methane-sulfonyloxyethyl)-5-methanesulfonyloxymethylthiazole(4.46 g) under ice cooling, and the mixture was stirred overnight at room temperature. 1-Methylcyclopropylamine hydrochloride (1.89 g) was additionally added, and the mixture was stirred for 20 hours at room temperature and 5 hours under refluxing. Dichloromethane and water were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane = 1:49) to obtain the title compound (944 mg) as a pale yellow oil. 1H-NMR (CDCl3) delta: 0.40-0.50(2H,m), 0.68-0.73(2H,m), 1.16(3H,s), 2.88-2.94(2H,m), 3.03(2H,t,J=5.7Hz), 3.89(2H,br.s), 8.60(1H,s). MS (ESI) m/z: 195(M+H)+. | |
In dichloromethane; at 0 - 20℃;Heating / reflux; | [Referential Example 38] 5-(1-Methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine: 1-Methylcyclopropylamine hydrochloride (J. Org. Chem., 1989, Vol. 54, p. 1815) (1.89 g) was added to methylene chloride (20 ml) containing the compound obtained in Referential Example 37 (4.46 g) under ice cooling, and the mixture was stirred overnight at room temperature. 1-Methylcyclopropylamine hydrochloride (1.89 g) was additionally added, and the mixture was stirred for 20 hours at room temperature and 5 hours under refluxing.. Methylene chloride and water were added to the reaction mixture to separate an organic layer.. The organic layer was dried over anhydrous sodium sulfate.. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:methylene chloride = 1:49) to obtain the title compound (944 mg).1H-NMR (CDCl3) delta: 0.40-0.50(2H,m), 0.68-0.73(2H,m), 1.16(3H,s), 2.88-2.94(2H,m), 3.03(2H,t,J=5.7Hz), 3.89(2H,br.s), 8.60(1H,s). MS (ESI) m/z: 195(M+H)+. |
In dichloromethane; at 20℃; for 25h;Heating / reflux; | Under ice cooling, <strong>[88887-87-0]1-methylcyclopropylamine hydrochloride</strong> (J. Org. Chem., 54, 1815(1989)) (1.89 g) was added to methylene chloride (20 ml) containing the compound (4.46 g) obtained in Referential Example 33. The resulting mixture was stirred overnight at room temperature. 1-Methylcyclopropylamine hydrochloride (1.89 g) was added further and the resulting mixture was stirred for 20 hours at room temperature and for 5 hours while heating under reflux. Methylene chloride and water were added to the reaction mixture. The organic layer thus separated was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography (methanol:methylene chloride = 1:49) on a silica gel column, whereby the title compound (944 mg) was obtained.1H-NMR(CDCl3)delta: 0.40-0.50(2H,m), 0.68-0.73(2H,m), 1.16(3H,s), 2.88-2.94(2H,m), 3.03(2H,t,J=5.7Hz), 3.89(2H,br.s), 8.60(1H,s). MS(ESI)m/z: 195(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In dichloromethane; at 20℃; for 2h; | Methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl (243 mg, 1.00 mmol) was addedto a solution of di-2-pyridyl thionocarbonate (232 mg, 1.00 mmol) in dichloromethane (5 ml).The reaction mixture was stirred at room temperature for 2 hours. 1-Methylcyclopropylaminehydrochloride (113 mg, 1.05 mmol) was added in one portion, followed by triethylamine (146//L, 1.05 mmol). Stirring was continued overnight at room temperature. Purification by flashcolumn chromatography (SiO2, ethyl acetate/heptane 60/40) yielded the title compound (318mg, 89percent yield) as a white solid.1H NMR (300 MHz, CDCI3): d- 0.55-1.09 (3 x br.s, 4H), 1.43 (s, 3H), 3.44 (br.s, 3H),7.04 (br.s, 2H), 7.28 (m, 1H), 7.39 (m, 4H), 7.73-8.38 (3 x br.s, 3H); HPLC-MS (Method A):mlz = 357 (M+H)+; Rt = 3.11 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate; at 120℃; for 0.0833333h;Microwave heating; | Example 10 N-cyclopropyl-4-methyl-3- [6- (4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3 (4H)- yl] benzamide (AZ12239931); Phosphorus oxychloride (0.11 ml) was added to a mixture of 4-methyl-3- [6- (4- isopropylpiperazin-1-yl)-4-oxoquinazolin-3 (4H)-yl] benzoic acid (0.30 g), 1- methylcyclopropylamine hydrochloride (0.13 g) and pyridine (5 ml) and the resultant was heated to 120°C for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9: 1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g); NMR Spectrum : (CDC13) 0.76 (m, 4H), 1.09 (d, 6H), 2.20 (s, 3H), 2.20 (s, 3H), 2.72 (m, 5H), 3.35 (m, 4H), 6.61 (s, 1H), 7.43 (m, 2H), 7.66 (m, 3H), 7.78 (m, 2H); Mass Spectrum: M+H+ 460. The 4-methyl-3- [6- (4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3 (4H)-yl] benzoic acid used for the starting material was prepared as follows:- Using an analogous procedure to that described paragraph (B) in the portion of Example 1 which is concerned with the preparation of starting material N-isopropylpiperazine was reacted with 5-fluoro-2-nitrobenzoic acid to give methyl 3- [ (5-fluoro-2- nitrobenzoyl) amino]-4-methylbenzoate to give methyl 4-methyl-3-[5-(4-isopropylpiperazin- 1-yl)-2-nitrobenzoyl] amino} benzoate ; NMR Spectrum: (DMSOd6) 0.99 (d, 6H), 2.34 (s, 3H), 2.55 (m, 4H), 2.71 (m, 1H), 3.50 (m, 4H), 3.85 (s, 3H), 7.07 (m, 2H), 7.39 (d, 1H), 7.71 (m, 1H), 8.06 (d, 1H), 8.20 (m, 1H), 9.96 (s, 1H); Mass Spectrum : M+H+ 441. Using an analogous procedure to that described paragraph (C) in the portion of Example 1 which is concerned with the preparation of starting materials, methyl 4-methyl-3- { [5- (4-isopropylpiperazin-l-yl)-2-nitrobenzoyl] amino} benzoate was reduced to methyl 3- { [2- amino-5- (4-isopropylpiperazin-1-yl) benzoyl] amino}-4-methylbenzoate ; Mass Spectrum: M+H+ 411. Using an analogous procedure to that described in Example 1, methyl 3- { [2-amino-5- (4-isopropylpiperazin-1-yl) benzoyl] amino}-4-methylbenzoate was reacted with triethylorthoformate to give methyl 4-methyl-3- [6- (4-isopropylpiperazin-l-yl)-4- oxoquinazolin-3 (4H)-yl] benzoate; NMR Spectrum: (DMSOd6) 1.00 (d, 6H), 2.15 (s, 3H), 2.59 (m, 4H), 2.68 (m, 1H), 3.24 (m, 4H), 3.85 (s, 3H), 7.45 (d, 1H), 7.60 (m, 3H), 7.95 (m, 1H), 8. 00 (m, 1H), 8.05 (d, 1H); Mass Spectrum : M+H+ 421. Methyl 4-methyl-3- [6- (4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3 (4H)-yl] benzoate 7.56 g) was dissolved in a mixture of methanol (135 ml) and water (45 ml). 2N NaOH (36 ml) added and stirred at room temperature for 1 hour. The pH was adjusted to 2-3 using 2N HC1 and the solvent evaporated in vacuo. The oil was triturated with a mixture of ethyl acetate (100 ml) and iso-hexane (100 ml) and the solid collected by filtration and dried under vacuum at 40°C for 16 hours to give the title compound (9.9 g); NMR Spectrum : (DMSOd6) 1.33 (d, 6H), 2.14 (s, 3H), 3.15 (m, 2H), 3.46 (m, 5H), 3.98 (m, 2H), 7.55 (m, 2H), 7.68 (m, 2H), 7.89 (m, 1H), 7.98 (m, 1H), 8.18 (t, 1H), 11.56 (s, 1H); Mass Spectrum: M+H+ 407. Using an analogous procedure to that described paragraph (A) in the portion of Example 6 which is concerned with the preparation of starting material, cyclobutylamine was reacted with 4-methyl-3- [6- (4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3 (4H)-yl] benzoic acid to give N-cyclobutyl-4-methyl-3- [6- (4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3 (4H)- yl] benzamide (AZ12239932); NMR Spectrum: (CDC13) 1.11 (d, 6H), 1.75 (m, 2H), 1.93 (m, 2H), 2.23 (s, 3H), 2.41 (m, 2H), 2.75 (m, 5H), 3.38 (m, 4H), 4.57 (m, 1H), 6.30 (d, 1H), 7.26 (s, 1H), 7.44 (m, 2H), 7.66 (m, 2H), 7.79 (m, 2H); Mass Spectrum: M+H"460. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 18h; | A) A stirred mixture of 2-amino-5-methoxybenzoic acid (4 g), trimethylorthoformate (3.93 ml), and acetic acid (0.137 ml) in toluene (100 ml) was heated under reflux for 2 hours. 3-amino-4-methyl-N- (l-methylcyclopropyl) benzamide (4.39 g) was added to the reaction mixture and stirring continued in refluxing toluene for 16 hours. The reaction mixture was allowed to cool and then was diluted with ethyl acetate. The organic solution was then washed with IN HC1 solution, 2N NaOH solution (x 2), brine, dried (magnesium sulfate) and concentrated to a cream coloured solid. The solid was dissolved in ethyl acetate and the insoluble material removed by filtration. Iso-hexane was added to the filtrate and concentrated to give 3- (6-methoxy-4-oxoquinazolin-3 (4H)-yl)-4-methyl-N- (l- methylcyclopropylbenzamide (4.3 g); NMR Spectrum : (DMSOd6) 0.59 (m, 2H), 0.72 (m, 2H), 1.35 (s, 3H), 2.12 (s, 3H), 3.89 (s, 3H), 7.50 (m, 2H), 7.56 (m, 1H), 7.72 (d, 1H), 7.83 (s, 1H), 7.88 (d, 1H), 8.17 (s, 1H), 8.63 (s, 1H) ; Mass Spectrum : M+Na+ 486. The 3-amino-4-methyl-N- (l-methylcyclopropyl) benzamide used as starting material was prepared as follows:- To a stirred suspension of 4-methyl-3-nitrobenzoic acid (9.06 g) in methylene chloride (50 ml) at 0°C was added oxalyl chloride (8. 7 ml) and DMF (1 drop), the reaction was stirred for 3 hours at room temperature. The reaction mixture was concentrated and the residue resuspended in methylene chloride (200 ml), cooled to 0°C and N, N-diisopropylethylamine (19. 2ml) and (1-methylcyclopropyl) amine hydrochloride (5.95 g) added. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated and the residue resuspended in ethyl acetate (200 ml). The organic layer was washed 2N HC1 (2 x 300 ml), saturated aqueous NaHCO3 solution (2 x 200 ml), brine (200 ml), dried (magnesium sulphate) and concentrated to yield the 4-methyl-N- (l-methylcyclopropyl)-3-nitrobenzamide as a yellow oil (10.72 g); NMR Spectrum: (DMSOd6) 0.68 (m, 4H), 2.54 (s, 3H), 2.54 (s, 3H), 7.55 (m, 1H), 8. 04 (m, 1H), 8.39 (m, 1H), 8.87 (s, 1H); Mass Spectrum: M+H+ 235. A suspension of 4-methyl-N- (1-methylcyclopropyl)-3-nitrobenzamide (10.72 g) and 10percent palladium on carbon (300 mg) in ethanol (200 ml) was agitated under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through diatomaceous earth (Celite ) and the filtrate evaporated to dryness and triturated with iso-hexane to give the title compound as a solid (8.32 g); NMR Spectrum: (DMSOd6) 0.64 (m, 4H), 2. 08 (s, 3H), 2.08 (s, 3H), 4.91 (s, 2H), 6.91 (m, 2H), 7.04 (d, 1H), 8.27 (s, 1H) ; Mass Spectrum : M+H 205. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride; In 1,4-dioxane; at 20℃; | (2) To a solution of the compound obtained in the above step (1) (4.66 g) in 1,4-dioxane (10 mL) was added a solution of 4N hydrochloric acid in dioxane (10 mL) , and the mixture was stirred at room temperature overnight. To the reaction mixture was added diisopropylether, and the precipitated crystals were collected by filtration to give 1-methylcyclopropylamine hydrochloride (2.69 g, yield: 92%) as a colorless solid. MS (APCI) m/z; 72 [M+H] + |
50% | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1h; | Step B: Preparation of l-methylcyclopropanamine hydrochloride.; A solution of l-methylcyclopropylcarbamate (250 mg, 1.46 mmol) in HCl (4N dioxane, 3.65 rnL, 14.6 mmol) was stirred at ambient temperature for 1 hour. It was then concentrated, triturated with ether, and filtered, giving the product as white solid (78 mg, 50%). |
With hydrogenchloride; methanol; water; at 50℃; for 6h; | The (l-methylcyclopropyl)amine hydrochloride used as starting material was prepared as follows :-Diphenylphoshoryl azide (10.5 ml) was added to a stirred mixture of 1- methylcyclopropane carboxylic acid (4.88 g) and triethylamine (6.8 ml) in anhydrous tert- butanol (100 ml) under an argon atmosphere. The mixture was heated to 5O0C and stirred for 15 minutes. The reaction mixture was then heated to 1000C and stirred for 16 hours. The reaction mixture was evaporated, dissolved in diethyl ether and washed with a saturated NaHCO3 solution, water and dried (magnesium sulfate) to give tert-butyl(l- EPO <DP n="86"/>methylcyclopropy^carbamate as a solid (3.61 g); NMR Spectrum: (DMSOdbeta) 0.45 (n, 2H), 0.58 (m, 2H), 1.22 (s, 3H)5 1.37 (s, 9H), 7.01 (s, IH)./ert-Butyl(l-methylcyclopropyl)carbamate (3.60 g) was dissolved in 10% HCl in methanol (20 ml) and heated to 5O0C for 6 hours. The reaction mixture was evaporated in vacuo and diethyl ether added. The mixture was evaporated to give (1- methylcyclopropyl)amine hydrochloride as a solid (2.24 g); NMR Spectrum: (DMSOd6) 0.60 (m, 2H), 0.92 (m, 2H), 1.35 (s, 3H)3 8.45 (s, 3H). |
With hydrogenchloride; methanol; at 50℃; for 6h; | a) The product gave the following data; NMR Spectrum: (DMSOd6) 0.61 (m, 2H), 0.74 (m, 2H), 1.37 (s, 3H), 2.13 (s, 3H), 2.24 (s, 3H), 2. 48 (m, 4H), 3.28 (m, 4H), 7.50 (m, 2H), 7.64 (m, 2H), 7.82 (s, 1H), 7.89 (m, 1H), 8.08 (s, 1H), 8.65 (s, 1H) ; Mass Spectrum: M+H 432. The (1-methylcyclopropyl) amine hydrochloride used as starting material was prepared as follows :- Diphenylphoshoryl azide (10.5 ml) was added to a stirred mixture of 1- methylcyclopropane carboxylic acid (4.88 g) and triethylamine (6.8 ml) in anhydrous tert- butanol (100 ml) under an argon atmosphere. The mixture was heated to 50C and stirred for 15 minutes. The reaction mixture was then heated to 100C and stirred for 16 hours. The reaction mixture was evaporated, dissolved in diethyl ether and washed with a saturated NaHCO3 solution, water and dried (magnesium sulphate) to give the title compound as a solid (3. 61 g); NMR Spectrum: (DMSOd6) 0.45 (m, 2H), 0.58 (m, 2H), 1.22 (s, 3H), 1.37 (s, 9H), 7.01 (s, 1H). tert-Butyl (1-methylcyclopropyl) carbamate (3.60 g) was dissolved in 10% HC1 in methanol (20 ml) and heated to 50C for 6 hours. The reaction mixture was evaporated in vacuo and diethyl ether added. The mixture was evaporated to give the title compound as a solid (2.24 g); NMR Spectrum : (DMSOd6) 0.60 (m, 2H), 0.92 (m, 2H), 1.35 (s, 3H), 8. 45 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.45 g (77%) | Preparation of 1-Methylycyclopropylamine Hydrochloride Water (190 mL) and 50percent sodium hydroxide (104.9 mL; 160 g; 2.0 mol) were combined and cooled to below 5° C. 1-Methylcyclopropanecarboxamide (60.4 g; 82percent solids; 49.6 g 100percent basis; 0.5 mol) was added and washed in with 60 mL water. The reaction was placed in an ice-acetone bath and the addition of aqueous sodium hypochlorite (12.68percent aqueous solution; 268 mL; 0.55 mol; 1.1 equiv) was begun. The addition was carried out over 30 minutes such that the temperature was maintained between 0 and 5° C. The mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was allowed to warm to ambient temperature and stir for 2 hours at which point all solids had dissolved. GC analysis of an aliquot indicated no caboxamide reactant present. One mL of 2 M sodium thiosulfate was added to destroy any excess oxidant and the reaction mixture was heated to 60° C. for 2 hours to decompose the carbamate intermediate. A distillation head was fitted to the flask and material boiling from ambient temperature up to a head temperature of 91° C. (43.78 g) was collected. The distillate contained an approximate 84:16 weight:weight mixture of 1-methylcyclopropylamine and water, respectively. The distillate was dissolved in 173 mL of n-butanol and cooled in an ice-water bath. Concentrated hydrochloric acid was added such that the temperature remained below 20° C. A Dean-Stark trap was placed on the flask and the mixture heated. A total of 39 mL of water were removed (head temperature at end of water removal was 111.5° C.). The trap was drained and an additional 77 mL of butanol distilled (final pot temperature was 125° C.). The heating mantle was removed from the flask and heptane (228 mL) was slowly added to the hot solution. Product crystallized at 109° C. The temperature at end of the heptane addition was 70° C. The resulting slurry was allowed to cool to ambient temperature and then cooled to 0-5° C. for 1 hour. The resulting glistening white solid was collected, washed with heptane (3*50 mL) and air-dried to afford 41.45 g (77percent) of 1-methylcyclopropaneamine hydrochloride, mp 203-204° C. 1H NMR (DMSO) delta8.35(bs, 3H); 1.38(s, 3H); 0.9 (t, 2H); 0.62(t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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15% | With sodium methylate; In 1-methyl-pyrrolidin-2-one; at 90℃; for 16h; | Preparation 44:6-Chloro-N4-(1-methylcyclopropyl)pyrimidine-2.4-diamine; 2-amino-4,6-dichloropyrimidine (508 mg, 3.1 mmol) was added to a suspension of <strong>[88887-87-0]1-methylcyclopropylamine hydrochloride</strong> (1.0 g, 9.3 mmol) and sodium methoxide (502mg, 9.30 mmol) in NMP (3 ml). The resulting mixture was heated at 90° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and the resulting precipitate filtered off, washed with further water (20 ml) and dried in vacuo to give the title compound as a colourless solid (280 mg, 15percent). 1H NMR (400 MHz, CDCl3): delta 6.71 (1H, s), 1.37 (3H, s), 0.83-0.79 (2H, m), 0.72-0.65 (2H, m) ppm. MS (ESI) m/z 199 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3 : 1 -methy lcyclopropyl- 1 -amine hydrochloride; v CONHBr NH2 I" - X . HCiA suspension of the N-bromo-l-methylcyclopropanecarboxamide from above in water (7mL) was treated with NaOH (900mg; 22.50mmol). The mixture was stirred at 250C for 2hr. The now homogenous solution was acidified to pHl with IN HCl and lyophilized. The solid residue was digested in ethanol, cooled and filtered. Evaporation afforded the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a nitrogen atmosphere 1.74 g KF is dissolved in 25 mL methanol at 35° C. while stirring. The resulting clear solution is evaporated to dryness and 16 mL NMP is added. Half of the added NMP is again distilled off under vacuum at 70° C. 8 mL NMP is added while flushing with nitrogen. To the white suspension is added 0.11 g cetyltrimethylammoniumbromide and 2.57 g 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide while flushing with nitrogen. The reactor is equipped with a condenser, N2-addition, and a heating facility. The temperature is raised to 140° C. while stirring. 24 h later additional 0.11 g cetyltrimethylammoniumbromide is added. After 30 h additional pretreated (as mentioned above) 0.58 g KF is added. After 48 h the mixture is cooled to room temperature and 2.8 mL triethylamine and 1.61 g methylcyclopropylamine hydrochloride is added. The temperature is raised to 70° C. and the mixture is stirred for another 24 h at 70° C. After cooling a white precipitate is filtered off. The filter cake is washed with 2.x.2.5 mL NMP. The filtrate is added drop wise to a solution of 3.7 g sodium acetate, 1.15 mL acetic acid, and 50 mL water. The pH of the resulting mixture was measured to 12.2 after addition of the NMP solution. Additional 0.6 mL acetic acid is added. A white, greasy precipitate is formed and is filtered off. To the filtrate is added 0.9 mL acetic acid. The pH is now 4.5. Additional 25 mL water is added to the solution. A white precipitate is formed. The solution is cooled on an ice bath and filtered. After drying of the filter cake to constant weight, 1.41 g of 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide crystals designated form D was obtained. 1H-NMR (DMSO-d6): delta 0.65-0.80 (m, 4H), 1.36 (s, 3H), 7.11 (s, 1H), 7.78 (br s,1H), 10.71 (br s,1H). [0192] The polymorph D is characterised by having a DSC thermogram as shown in FIG. 32 and a powder X-ray diffractogram (PXRD) as shown in FIG. 33. The melting point of polymorph D from 2-butanol is 248.0° C. (onset). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | 4-fluor o-2-(4-fluorop henyl)-5-(4~methoxy-2-methyl-5-(l - methylcyclopropylcarbamoylJphenyl^N-methylpyrazolofljS-alpyridine-S- carboxamide. To a solution containing 1-methylcycloprorhoanamine hydrochloride (0.012 g, 0.12 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol), 5-(4-fluoro-2- (4-fluorophenyl)-3 -(methylcarbamoyl)pyrazolo[ 1 ,5 -a]pyridin-5 -yl)-2-methoxy-4- methylbenzoic acid (0.040 g, 0.089 mmol) and DMF (0.60 mL) was added HATU (0.067 g, 0.18 mmol) in one portion. The solution was maintained at room temperature for Ih and concentrated. The resultant residue was purified using preparative HPLC (Waters- Xbridge, 50 x 100 mm, 5 micron, Cl 8 column; 0.1 M TFA, 0-100percent B (B = 10percent H2O/CH3OH)/ A (A - 90percent H2O/ CH3OH), 12 min. gradient, analysis time 20 min.) afforded 4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy- 2-methyl-5 -( 1 -methylcyclopropylcarbamoylJphenyO-N-methylpyrazolof 1,5- a]rhoyridine-3~carboxamide as a white solid. Preparative HPLC retention time: 11.7 min. IH NMR (400 MHz, CHLOROFORM-*/) delta ppm 8.35 (d, J-7.03 Hz, 1 H), 8.14 (s, 1 H), 8.10 (s, 1 H), 7.79 - 7.89 (m, 2 H), 7.12 - 7.21 (m, 2 H), 6.92 (s, 1 H), 6.75 (t, J=6.78 Hz, 1 H), 5.97 (d, ./=3,76 Hz, 1 H), 4.03 (s, 3 H), 2.98 (d, 7=5.02 Hz, 3 H), 2.32 (s, 3 H), 1.50 (s, 3 H), 0.82 - 0.89 (m, 2 H), 0.68 - 0.78 (m, 2 H). LCMS retention time: 2.232 min. LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C 18, 3.0 x 50 mm column using a SPD-10AV UV- Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100percent solvent A / 0percent solvent B to 0percent solvent A / 100percent solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10percent CH3OH / 90percent H2O / 10 mM TFA and solvent B was 10percent H2O / 90percent CH3OH MO mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.166667h; | Step C: Preparation of (RV5 -(2-(5 -fluoropyridin-3 -vDpyrrolidin- 1 -ylVN-d - methylcyclopropyl)pyrazolo[ 1 ,5-a"|pyrimidine-3-carboxamide.; To a DMF (0.6 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (Preparation I, 10.5 mg, 0.0321 mmol) and HATU (14.6 mg, 0.0385 mmol) was added l-methylcyclopropanamine hydrochloride (4.14 mg, 0.0385 mmol) and DIEA (0.0168 mL, 0.0962 mmol). After stirring for 10 minutes, the reaction mixture was directly purified by reverse-phase chromatography (5 to 50percent acetonitrile/water) to yield the final product as white solid (10 mg, 82percent). LCMS (apci) m/z = 381.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred colorless solution of 2-((lr,4r)- 4-hydroxycyclohexylamino)-4-(methylthio)pyrimidine-5-carbonitrile (0.700g, 2.65 mmol) in NMP (10 mL) was added mCPBA (1.306 g, 5.83 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h until completion of the reaction as indicated by LCMS. The reaction mixture was carried on to the next step without further purification. MS (ESI) m/z 281.4 [M+l] + and 297.2 [M+l] +. To the reaction mixture of 2-((lr,4r)-4- hydroxycyclohexylamino)-4-(methylsulfinyl)pyrimidine-5 -carbonitrile and 2-(( 1 r,4r)-4- hydroxycyclohexylamino)-4-(methylsulfonyl)pyrimidine-5 -carbonitrile from the previous step was added DIEA (2.78 mL, 15.89 mmol) and 1-methylcyclopropanaminehydrochloride (0.627 g, 5.83 mmol). The reaction was stirred at 90 °C for 16 h. Upon- 169 -ATI-2514175vl completion of reaction as indicated by LCMS and TLC the reaction mixture was concentrated and purified by silica gel chromatography using a gradient of 0percent - 80percent ethyl acetate in hexanes. The product fractions were combined and concentrated to afford 2-((ls,4s)-4-hydroxycyclohexylamino)-4-(l-methylcyclopropylamino)pyrimidine-5- carbonitrile (0.147g, 19percent yield) as a pale yellow solid. MS (ESI) m/z 288.2 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine; at 20℃; for 16h; | Preparation 113 N-(1-Methylcyclopropyl)methanesulfonamide To a stirred solution of <strong>[88887-87-0]1-methylcyclopropan-1-amine hydrochloride</strong> (0.100 g, 0.9 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.108 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a yellow oil (0.105 g, 76percent). 1H NMR (300 MHz, CDCl3) delta 4.68 (br s, 1H), 3.02 (s, 3H), 1.50 (s, 3H), 1.02-0.94 (m, 2H), 0.71-0.64 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 33 4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride (Cpd 33) To a solution of l-(2,4-dimethoxybenzyl)-10-formyl-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid (Example 22, step 9, 120 mg, 0.24 mmol) in dichloroethane (3 mL) was added 1-methylcyclopropanamine hydrochloride (60 mg, 0.5 mmol) followed by AcOH (20 mu, 0.35 mmol). After stirring at room temperature for 10 min, NaBH(OAc)3 (80 mg, 0.36 mmol) was added. The reaction was stirred at room temperature 1.5 h and monitored by LC/MS until the starting aldehyde was completely consumed. The dichloroethane was then removed and the residue was dissolved in MeOH (10 mL) and several drops of TFA to generate a homogeneous mixture that was filtered through a PTFE micron filter and purified directly by preparative HPLC to provide the product as a TFA salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Example 66 4-hydroxy-7,9-dimethyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride (Cpd 66) To a solution of l-(2,4-dimethoxybenzyl)-10-formyl-4-hydroxy-7,9-dimethyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid (Example 62, step 10, 145 mg, 0.28 mmol) in dichloroethane (3 mL) was added 1-methylcyclopropanamine hydrochloride (45.0 mg, 0.42 mmol) followed Et3 (60 mu^, 0.43 mmol). The mixture was stirred for 5 min at room temperature, then AcOH (30 mu^, 0.52 mmol) was added. After stirring at room temperature for 5 min, NaBH(OAc)3 (90 mg, 0.43 mmol) was added. The reaction was stirred overnight at room temperature. The dichloroethane was then removed and the residue was dissolved in MeOH (5 mL) and several drops of TFA to generate a homogeneous mixture that was filtered through a PTFE micron filter and purified directly by preparative HPLC to provide the product as a TFA salt (124.4 mg, 65percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.2 mg | The procedure of Example 9 was followed, using 1-methylcyclopropariamine hydrochloride (33 mg, 0.31 mmol, ChemBridge Corp.) and N,N- diisopropylethylamine (64 muL, 0.37 mmol) in the substitution step, which was carried out at 55°C for 2.5 hours. The product was obtained as the free base (6.2 mg, 33percent). 'H MR (400 MHz, d6-DMSO) 8 12.13 (s, IH), 8.83 (s, IH), 8.69 (s, IH), 8.42 (s, IH), 7.60 (d, J= 3.6 Hz, IH), 7.39 (s, IH), 7.08 (d, J= 3.6 Hz, IH), 7.01 (s, IH), 4.99 (tt, J= 8.4, 4.6 Hz, IH), 3.77 (d, J = 6.4 Hz, 2H), 3.42 (s, 2H), 3.10 - 2.94 (m, 2H), 2.81 (p, = 7.3 Hz, IH), 2.71 - 2.54 (m, 3H), 2.41 - 2.30 (m, 2H), 2.25 - 2.09 (m, 2H), 2.07 - 1.91 (m, 2H), 1.78 - 1.57 (m, 2H), 1.20 (s, 3H), 0.48 (dd, J= 5.7, 4.2 Hz, 2H), 0.30 (dd, J= 5.8, 3.8 Hz, 2H). ,9F NMR (376 MHz, d6-DMSO) delta -67.28 (s). LCMS (M+H)+: 606.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | In ethanol; at 86℃; for 20h;Sealed tube; Inert atmosphere; | In a sealed reaction vessel purged with nitrogen, a mixture of 1 , 1 -dimethylethyl 1 - oxa-6-azaspiro[2.5]octane-6-carboxylate (1.05 g, 4.92 mmol), ethanol (8 mL) andl- methylcyclopropanamine hydrochloride (0.7 g, 9.84 mmol) was heated at 85 °C affording a clear yellow solution. After 20 h, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure to afford the title compound (1.7 g, 61percent), which was used in next step without further purification. MS(ES)+ m/e 285 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | To an ice cooled stirred solution of <strong>[88887-87-0]1-methylcyclopropylamine hydrochloride</strong> salt (2 g, 18.6 mmol) in anhydrous THF (15 mE) was added sodium hydride (60 wt percent dispersion in oil, 1.48 g, 37.2 mmol) at 00 C., the reaction was then stirred at room temperature for 1 hout The resulting suspension was added to a solution of ethyl (3,5-dichioropy- ridazin-4-yl)imidoformate (Preparation 40, 2 g, 9.3 mmol) in anhydrous THF (5 mE) in another flask at 0°C. drop -wise and stirred at room temperature for 16 hours. The reaction mixture was quenched with crushed ice and extracted with EtOAc (2x20 mE). The organic layer was washed with water (10 mE) and saturated brine solution (10 mE) then dried over Na2 504 filtered and concentrated in vacuo. The residue was purified by silica gel colunm chromatography eluting with hexane:EtOAc 60:40 to afford the title compound as a white solid in 15percent yield, 340 mg.10734] ?H NMR (400 MHz, CDC13): oe ppm 0.73-0.75 (m, 2H), 0.90-0.93 (m, 2H), 1.55 (s, 3H), 5.96 (br s, 1H), 7.43,7.79 (d, 1H), 8.88 (s, 1H).10735] ECMS (System 7): Rt=2.74 minutes MS m/z 245 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.1% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 198 give 6-(4-(4-cyanophenyl)-5-hydroxy-lH-pyrazol-l-yl)-N-(l- methylcyclopropyl)nicotinamide [0892] Combined EDC (56.3 mg, 0.294 mmol), HOBT (39.7 mg, 0.294 mmol) and 6-(4-(4- cyanophenyl)-5 -hydroxy- lH-pyrazol-l-yl)nicotinic acid (45 mg, 0.147 mmol) in DMF (0.8 mL) then added 1 -methylcyclopropanamine hydrochloride (47.4 mg, 0.441 mmol) and Hunig's base (0.180 mL, 1.028 mmol) and stirred at 20°C for 16 h. The reaction mixture was diluted with 100 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (27 mg, 51.1 percent yield) as a yellow solid. XH NMR (400 MHz, DMSO-i/6) delta ppm 0.60 - 0.68 (m, 2 H) 0.73 - 0.81 (m, 2 H) 1.40 (s, 3 H) 7.75 (d, J=8.6 Hz, 2 H) 8.06 - 8.16 (m, 2 H) 8.35 (dd, J=8.6, 2.3 Hz, 1 H) 8.46 (d, J=8.8 Hz, 1 H) 8.54 (s, 1 H) 8.82 - 8.90 (m, 2 H) 13.53 (br. s., 1 H). MS m/z 360 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In dichloromethane; at 20℃; | To a stirred solution of 1- methylcyclopropan-1 -amine hydrochloride salt (429 mg, 3.99 mmol, 1.00 equiv) and triethylamine (268 mg, 2.65 mmol, 1.00 equiv) in CH2CI2 (6 mL) was added trimethylsilyl isocyanate (366 mg, 3.18 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature overnight and was quenched by the dropwise addition of CH3OH (2 mL) at 0 °C. The resulting solution warmed to room temperature and stirred for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was precipitated from OmicronEta:Epsilon20 (1 :40) affording 300 mg (66percent) of the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In diethyl ether; ethanol; water; at 20℃; for 0.833333h; | Into a 2 L 4-necked round-bottom flask, was placed a suspensionhydrochloride (110 g, 925.23 mmoi, 1.00 equiv., 90percent) in Et20 (1000 ml). This was followed by theaddition of a solution of NaOH (49 g, 1.23 mol, 1.20 equiv.) in H20 (200 ml). This was followed by the addition of a solution of ox alic acid (92.5 g, 1,03 mol, I .00 equiv.) in Et20/EtOH (400 ml), which was added dropwise with stirring, while maintaining the contents at room temperature over a time period of 20 minutes. The resulting solution was allowed to react, with stirring, for 3() minuteswhile the temperature was maintained at room temperature. A filtration was performed. The solid was washed 2 times with 200 nil of Et20. This resulted in the title compound as a solid. LC-MS (+ES1) m? = 72. ?H NMR (400 MHz, D20) 6 0.64 (2H, d), 0.85 (2H, d), 1.3.4 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a 1 0 L 4necked roundbottom flask purged and niaintaned with an inert atmosphere of mtrogen, was placed a suspension of Mg (351.2 g, 14.63 mol, 2.5() equiv.) in Et20 (4000 ml). To the above was added ethyl bromide (1595 g, 14.63 mol, 2.50 equiv.) dropwise with stirring, while warn:iing to a temperature of 30-35°C over a time period of 3 hours. The reaction mixture was stirred at refiux temperature for 30 minutes to give mixture A. into a 10 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed acetonitrile (240 g, 5.85 mol, I .00 equiv.) in Et20 (4 L). To the mixture was added Ti(Oi-Pr)4 (1828.6 g. 5.15 mol, 1.10 equiv., 80percent). Addition of mixture A above was followed, which was added dropwse while maintained at atemperature of 30-35°C. The reaction mixture was stirred at 30°C for 1.5 hours. To the above was added BF3?Et20 (1680 g, 11.61 mol, 47percent) dropwise with stirring, while wanuing to a temperature of 30-35°C over a time period of 60 minutes. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction mixture was cooled to -.10°C. Adjustment of the pH to 9.0 was accomplished by the addition of NaOH. Themixture was dried over NaCO3. The final product was purified by distillation under reduced pressure (760 mm Hg) and the fraction was collected at 50-60°C, which was then reacted with HC1 gas. This resulted in the title compound as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | C.70.2. Synthesis of 2-{(1 S)-2-[(2,6-dichlorophenyl)acetyl]-1-methyl-1 , 2,3,4- tetrahydroisoquinolin-5-yl}-2,2-difluoro-N-(1-methylcyclopropyl)acetamide 159. To a solution of 2-[(1 S)-2-[2-(2,6-dichlorophenyl)acetyl]-1-methyl-3,4-dihydro-1 H- isoquinolin-5-yl]-2,2-difluoro-acetic acid a128 (280 mg, 0.65 mmol) and 1- methylcyclopropanamine hydrochloride (75 mg, 0.66 mmol) in DMF (4 mL) was added BOP (325 mg, 0.72 mmol) and the reaction mixture is stirred for 5 min. Then, DIPEA (0.5 mL, 3 mmol) was added and the reaction mixture was stirred overnight at 60 °C. DIPEA (0.5 mL, 3 mmol) was added again to the reaction mixture which was stirred at 90 °C for 2 days. The reaction mixture was then diluted with EtOAc (50 mL) and successively washed with water (100 mL), 1 N aqueous solution of HCI (100 mL), brine (100 mL) and water (100 mL). The organic layer was dried over MgS04, filtered and concentrated under vacuum. The residue was purified by reverse phase chromatography (basic mode, LCMS prep) to give 35 mg of 2-{(1 S)-2-[(2,6-dichlorophenyl)acetyl]-1-methyl-1 ,2,3,4-tetrahydroisoquinolin-5-yl}-2,2- difluoro-N-(1 -methylcyclopropyl)acetamide 159 as a solid. Yield: 1 1 percent. LCMS (ES+): 481/483/485 (M+H)+, 95percent purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 20℃; | To a solution of N,N-diisopropylethylamine (0.14 mL, 0.81 mmol) in THF (5 mL) cooled in an ice bath, was added a mixture of 1 -methylcyclopropanamine hydrochloride (0.05 mL, 0.40 mmol) and 1 -chloroisoquinoline-7-sulfonyl chloride (100 mg, 0.38 mmol) in DCM (3 mL) and the mixture stirred overnight at room temperature. The mixture was diluted with water (30 mL) and extracted with DCM (2 x 30 mL). The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness. The crude product mixture was purified by prep HPLC (high pH) to give the desired product (48 mg, 0.16 mmol, 42%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | A suspension of 2,4-dioxo-1 1H-3,1 -benzoxazine-6-sulfonyl chloride (261 mg, 1 mmol) in DMF (2 mL) was treated with 1 -methylcyclopropanamine hydrochloride (0.1 1 g, 1 mmol) and cooled to -10 °C in an ice/MeOH bath. The solution was treated over 5 min with triethylamine (0.31 mL, 2.2 mmol). 2-(2-Pyridyl)ethylamine (0.16 mL, 1 .3 mmol) in DMF (2 mL) was added to the reaction mixture at 0 °C. More triethylamine (0.31 mL, 2.2 mmol) was added and the reaction mixture stirred at ambient temperature overnight. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water, passed through a hydrophobic frit and evaporated to dryness. Flash chromatographic purification over silica (CH2CI2/ ether/MeOH/Et3N eluent) of the residue afforded 2-amino-5-[(1 -methylcyclopropyl)sulfamoyl]-N-[2-(2- pyridyl)ethyl]benzamide (257 mg, 0.686 mmol, 69percent). 1 H NMR (300 MHz, CHLOROFORM-d) delta ppm 8.73 - 8.69 (m, 1 H), 8.14 - 8.08 (m, 2H), 7.86 - 7.78 (m, 1 H), 7.68 - 7.62 (m, 1 H), 7.39 -7.32 (m,1 H), 7.33 (d, J=8.2 Hz, 1 H), 6.68 (d, J=8.7 Hz, 1 H), 6.14 (br s, 2H), 5.32 (br s, 1 H), 3.89 - 3.81 (m, 2H), 3.28 - 3.22 (m, 2H), 1 .23, (s, 3H), 0.86 - 0.78 (m, 2H), 0.48-0.42 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | A suspension of 2,4-dioxo-1 1H-3,1 -benzoxazine-6-sulfonyl chloride (261 mg, 1 mmol) in DMF (2 mL) was treated with 1 -methylcyclopropanamine hydrochloride (0.1 1 g, 1 mmol) and cooled to -10 °C in an ice/MeOH bath. The solution was treated over 5 min with triethylamine (0.31 mL, 2.2 mmol). 3-Aminopropionitrile (0.1 mL, 1 .3 mmol) in DMF (2 mL) was added to the reaction mixture at 0 °C. More triethylamine (0.31 mL, 2.2 mmol) was added and the reaction mixture stirred at ambient temperature overnight. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined extracts were washed with water, passed through a hydrophobic frit and evaporated to dryness. Flash chromatographic purification over silica (CH2CI2/ ether/MeOH/Et3N eluent) of the residue afforded 2-amino-N-(2-cyanoethyl)-5-[(1 - methylcyclopropyl)sulfamoyl]benzamide (87 mg, 0.27 mmol, 27percent). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 7.86 - 7.84 (m, 1 H), 7.80 - 7.76 (m, 2H), 7.61 - 7.56 (m, 1 H), 6.66 (d, J=8.7 Hz, 1 H), 3.68 - 3.58 (m, 2H), 2.72 - 2.66 (m, 2H), 1 .19, 1 .16, (s, 3H), 0.75-0.68 (m, 2H), 0.46-0.38 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane;Cooling; | To a solution of N,N-diisopropylethylamine (0.49 mL, 2.79 mmol) in THF (10 mL) and DCM (6 mL) cooled in an ice bath, was added a mixture of I methylcyclopropanamine hydrochloride (0.2 g, 1 .87 mmol) and then portionwise 1 -(2,2- difluoroethyl)-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo-quinazoline-6-sulfonyl chloride (0.39 g, 0.93 mmol). After stirring overnight, the solvent was evaporated and the residue purified by prep hplc to give the desired product (58 mg, 0.128 mmol, 14percent) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | Quinazolinedione sulfonyl chloride derivative (1 eq), amine (2-3 eq) and triethylamine (2-3 eq) in DCM was stirred at ambient temperature and monitored by LCMS; reaction times vary from 1 h to overnight. The reaction mixture was diluted with 2 M HCI (5 mL) and DCM (5 mL) and stirred vigorously for 10 min, then filtered through a hydrophobic frit, the organic layer was concentrated to dryness. Alternatively, the reaction mixture was evaporated to dryness. The crude product was purified by automated column chromatography or prep. HPLC, high pH, to yield the desired product. For Examples 5 and 204, pyridine was used without addition of triethylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In dichloromethane; at 34℃; for 2.25h; | 3-Methyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride (12 g, 43.7 mmol) and 1 -methylcyclopropanamine hydrochloride (5.16 g, 48 mmol) were slurried in dichloromethane (120 mL) at 20 C. Triethylamine (13.4 mL, 96 mmol) was added over 15 min: this was exothermic and the temperature was allowed to rise to 34 C. As the reaction cooled, a precipitate formed. After stirring for 2 h the reaction was complete by HPLC. 1 M hydrochloric acid (100 mL) was added and stirred for 25 min. The product was filtered from the biphasic mixture and washed with water (100 mL). The solid was dried in the vacuum oven to give 3-methyl-N-(1 -methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6- sulfonamide (12.03 g, 0.039 mol, 89%).1 H NMR (300MHz, DMSO-d6) delta = 1 1 .83 (br. s, 1 H), 8.32 (d, J = 2.2 Hz, 1 H), 8.13 (s, 1 H), 7.99 (dd, J = 2.2, 8.6 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 1 .06 (s, 3H), 0.62 - 0.55 (m, 2H), 0.42 - 0.35 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane; at 20℃; for 3.16h; | Triethylamine (8.1 g, 80.1 mmol) was added to a stirred solution of 1 - methyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride (1 1 .3 g, 36.4 mmol) in dichloromethane (250 mL). 1 -Methylcyclopropanamine hydrochloride (4.3 g, 40.0 mmol) was added portionwise over 10 min and the reaction mixture was stirred at room temperature for 3 h. TLC showed the reaction to be complete. The reaction mixture was poured onto water (250 mL) and filtered to give the desired product 1 -methyl-N-(1 - methylcyclopropyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonamide (10.5 g, 0.034 mol, 93%).1 H NMR (300MHz, DMSO-d6) delta = 1 1 .83 (br. s, 1 H), 8.35 (d, J = 2.4 Hz, 1 H), 8.17 (s, 1 H), 8.06 (dd, J = 2.3, 8.8 Hz, 1 H), 7.61 (d, J = 8.9 Hz, 1 H), 3.48 (s, 3H), 1 .07 (s, 3H), 0.64 - 0.55 (m, 2H), 0.44 - 0.35 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | A suspension of compound 2,4-dioxo-1 H-3,1 -benzoxazine-6-sulfonyl chloride (10 g, 38.3 mmol) in DMF (100 mL) was treated with 1 -methylcyclopropanamine hydrochloride (4.1 g, 38.3 mmol) and cooled to -10 °C in an ice/MeOH bath. Triethylamine (8.51 g, 87.5 mmol) was added to the mixture and the resulting solution was stirred at -10 °C for 1 h. (1 -Methyl-1 H-pyrazol-4-yl)methanamine (8.45 g, 57.5 mmol) in DMF (10 mL) was added to the mixture at 0 °C, followed by triethylamine (1 1 .6 g, 1 15 mmol) and the reaction mixture was stirred at room temperature for 3 h. Water (200 mL) was added to the reaction mixture, then extracted with EtOAc (2 chi 100 mL). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by automated column chromatography SiO2 (Biotage, 120 g, eluent: 0-80percent EtOAc in petroleum ether) to give 2-amino-5-[(1 -methylcyclopropyl)sulfamoyl]-N-[(1 - methylpyrazol-4-yl)methyl]benzamide (4.7 g, 12.9 mmol, 34percent).1H NMR (300MHz, DMSO-d6) delta = 8.83 (t, J = 5.7 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.58 (s, 1 H), 7.55 (s, 1 H), 7.46 (dd, J = 2.2, 8.7 Hz, 1 H), 7.35 (s, 1 H), 7.09 (br. s, 2H), 6.79 (d, J = 8.8 Hz, 1 H), 4.22 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 1 .04 (s, 3H), 0.65 - 0.51 (m, 2H), 0.36 - 0.29 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of compound 2,4-dioxo-1 H-3,1 -benzoxazine-6-sulfonyl chloride (10 g, 38.3 mmol) in DMF (100 mL) was treated with 1 -methylcyclopropanamine hydrochloride (4.1 g, 38.3 mmol) and cooled to -10 °C in an ice/MeOH bath. Triethylamine (8.51 g, 87.5 mmol) was added to the mixture and the resulting solution was stirred at -10 °C for 1 h. (1 -Methyl-1 H-pyrazol-4-yl)methanamine (8.45 g, 57.5 mmol) in DMF (10 mL) was added to the mixture at 0 °C, followed by triethylamine (1 1 .6 g, 1 15 mmol) and the reaction mixture was stirred at room temperature for 3 h. Water (200 mL) was added to the reaction mixture, then extracted with EtOAc (2 chi 100 mL). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated. The crude product was purified by automated column chromatography SiO2 (Biotage, 120 g, eluent: 0-80percent EtOAc in petroleum ether) to give 2-amino-5-[(1 -methylcyclopropyl)sulfamoyl]-N-[(1 - methylpyrazol-4-yl)methyl]benzamide (4.7 g, 12.9 mmol, 34percent).1H NMR (300MHz, DMSO-d6) delta = 8.83 (t, J = 5.7 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.58 (s, 1 H), 7.55 (s, 1 H), 7.46 (dd, J = 2.2, 8.7 Hz, 1 H), 7.35 (s, 1 H), 7.09 (br. s, 2H), 6.79 (d, J = 8.8 Hz, 1 H), 4.22 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 1 .04 (s, 3H), 0.65 - 0.51 (m, 2H), 0.36 - 0.29 (m, 2H),Prepared from 2,4-dioxo-i H-3,i -benzoxazine-6-sulfonyl chloride, 1-methylcyclopropanamine hydrochloride and aminoacetonitrile bisulfate.1H NMR (300MHz, ODd3) O = 7.19 (s, 1H), 7.99 (d, J= 2.2 Hz, 1H), 7.67(dd, J= 2.1, 8.8 Hz, 1H), 7.22 - 7.16 (m, 1H), 6.73 (d, J= 8.8 Hz, 1H), 5.06 (br. s, 1H),4.32 (d, J = 5.7 Hz, 2H), 1 .23 (s, 2H), 0.81 - 0.76 (m, 2H), 0.50 - 0.45 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diisopropylamine; In dichloromethane; at 20℃; | Quinazolinedione sulfonyl chloride derivative (1 eq), amine (2-3 eq) and triethylamine (2-3 eq) in DCM was stirred at ambient temperature and monitored by LCMS; reaction times vary from 1 h to overnight. The reaction mixture was diluted with 2 M HCI (5 mL) and DCM (5 mL) and stirred vigorously for 10 min, then filtered through a hydrophobic frit, the organic layer was concentrated to dryness. Alternatively, the reaction mixture was evaporated to dryness. The crude product was purified by automated column chromatography or prep. HPLC, high pH, to yield the desired product. For Examples 5 and 204, pyridine was used without addition of triethylamine.Prepared from 7-fluoro-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo-1 H- quinazoline-6-sulfonyl chloride, 1 -methylcyclopropanamine hydrochloride and diisopropylamine in place of triethylamine. Intermediate S4-G2 N-(1-Cyanocyclopropyl)-7-fluoro-3-[(1-methylpyrazol-4-yl)methyl]-2,4- dioxo- 1H-quinazoline-6-sulfonamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 40℃; for 2h;Inert atmosphere; | To a stirred solution of (2,3,4,5,6-pentafluorophenyl) 1 -chloro-3-[(3- methylisoxazol-5-yl)methyl]-4-oxo-phthalazine-6-sulfonate (900. mg, 1 .72 mmol) and 1 - methylcyclopropanamine hydrochloride (204.09 mg, 1 .9 mmol) in DMF (20 mL) at ambient temperature, under nitrogen, was added triethylamine (0.53 mL, 3.79 mmol) the reaction mixture was heated at 40 °C for 2 h. The reaction mixture was evaporated to dryness and partitioned between DCM (10 mL) and water (10 mL). The organic phase was collected and evaporated to dryness, the crude product was purified by automated column chromatography (SiO2, RediSep, 12 g) eluent 0-70percent EtOAc in iso-hexane to afford 1 -chloro- N-(1 -methylcyclopropyl)-3-[(3-methylisoxazol-5-yl)methyl]-4-oxo-phthalazine-6-sulfonamide (400.0 mg, 0.98 mmol, 57percent). 1 H NMR (300MHz, DMSO-d6) delta = 8.65 (d, J = 8.0 Hz, 1 H), 8.57 (s, 1 H), 8.37 (dd, J = 2.1 , 8.6 Hz, 1 H), 8.26 (d, J = 8.5 Hz, 1 H), 6.43 (s, 1 H), 5.45 (s, 2H), 2.20 (s, 3H), 1 .08 (s, 3H), 0.64 - 0.57 (m, 2H), 0.47 - 0.39 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 2h; | General procedure: To a magnetically stirred solution of perfluorophenyl 1 -substituted-3-(isoxazol- 3-ylmethyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (1 .0 mmol) in DMF (8.0 mL) at 20 °C was added 1 -methylcyclopropanamine hydrochloride (1 .2 mmol) followed by triethylamine (2.4 mmol), and the resulting mixture was stirred at 60 °C for 2 h. The solvent was removed in vacuo to give the crude product as a residue, which was purified by automated column chromatography over silica gel eluting with a gradient of 0 to 80percent (v/v) EtOAc in hexane to give the desired product as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In dichloromethane; at 20℃; for 1h; | 1 -Methylcyclopropanamine hydrochloride (281 .1 mg, 2.61 mmol) and triethylamine (726.6 uL, 5.23 mmol) were added sequentially to a stirring solution of methyl 2-bromo-5-chlorosulfonyl-benzoate (745. mg, 2.38 mmol) in DCM (15 mL) at ambient temperature. The reaction mixture was stirred for 1 h then 2 M HCI (10 mL) was added and the reaction mixture stirred vigorously for 15 min. The organic phase was separated using a hydrophobic frit and evaporated to dryness. The crude product was purified by automated column chromatography SiO2 (RediSep, 24 g) eluent 30% EtOAc in iso-hexane to yield methyl 2-bromo-5-[(1 -methylcyclopropyl)sulfamoyl]benzoate (630.2 mg, 1 .81 mmol, 76%). 1 H NMR (300MHz, CDCI3) delta = 8.32 - 8.30 (m, 1 H), 7.86 - 7.79 (m, 2H), 4.99 (s, 1 H), 3.99 (s, 3H), 1 .25 (s, 3H), 0.82 - 0.75 (m, 2H), 0.57 - 0.50 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In dichloromethane; at 20℃; for 1h; | 1 -Methylcyclopropanamine hydrochloride (386.2 mg, 3.59 mmol) and triethylamine (997.9 uL, 7.18 mmol) were added sequentially to a stirring solution of 4- bromo-3-(methylcarbamoyl)benzenesulfonyl chloride (1 .02 g, 3.26 mmol) in DCM (20 mL) at ambient temperature. The reaction mixture was stirred for 1 h then 2M HCI (10 mL) was added and the mixture stirred for 10 min. The mixture was passed through a hydrophobic frit and the resulting organic phase collected. The acidic aqueous phase was neutralised to pH 7 with saturated aq. NaHC03, extracted with EtOAc (25 mL), the organic phase separated and passed through a hydrophobic frit. The combined organic phase was evaporated to dryness. The resulting crude product was purified by automated column chromatography SiO2 (Biotage, 24 g) eluent 0-75% EtOAc in iso-Hexane, to yield 2-bromo-N-methyl-5-[(1 - methylcyclopropyl)sulfamoyl]benzamide (510 mg, 1 .47 mmol, 45%). 1 H NMR (300MHz, CDCI3) delta = 8.00 (dd, J = 0.8, 2.0 Hz, 1 H), 7.78 - 7.75 (m, 2H), 6.06 (br. s, 1 H), 5.06 (br. s., 1 H), 3.05 (d, J = 4.9 Hz, 3H), 1 .26 (s, 3H), 0.81 - 0.76 (m, 2H), 0.56 - 0.49 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide; at 60℃; for 1.5h; | 1-Methylcyclopropanamine hydrochloride (193.65 mg, 1 .8 mmol) and triethylamine (417.01 uL, 3 mmol) were added to a solution of (2,3,4,5,6-pentafluorophenyl) 4-chloro-2-[(3-methylisoxazol-5-yl)methyl]-1 -oxo-isoquinoline-7-sulfonate (625. mg, 1 .2 mmol) in DMF (10 mL) at ambient temperature, the reaction mixture was heated at 60 °C for 1 .5 h. The reaction mixture was cooled then water (50 mL) and EtOAc (50 mL) were added, the organic phase was separated and the aqueous phase further extracted with EtOAc (50 mL). The combined organic phase was washed with water (50 mL), separated, passed through a hydrophobic frit and evaporated to dryness. The crude product was triturated with a minimal volume of EtOAc, to yield 4-chloro-N-(1 -methylcyclopropyl)-2-[(3-methylisoxazol- 5-yl)methyl]-1 -oxo-isoquinoline-7-sulfonamide (442 mg, 1 .08 mmol, 90percent). H NMR (300MHz, DMSO-d6) delta = 8.67 (d, J = 2.4 Hz, 1 H), 8.35 (s, 1 H), 8.23 (dd, J = 2.0, 8.6 Hz, 1 H), 8.21 (s, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 6.36 (s, 1 H), 5.34 (s, 2H), 2.19 (s, 3H), 1 .06 (s, 3H), 0.67 - 0.51 (m, 2H), 0.44 - 0.36 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.7% | With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 1h; | 8-Bromo-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo- 1H -quinazoline-6-sulfonyl chloride (1 .0 g, 2.31 mmol) was added to a stirred solution of 1 -methylcyclopropanamine hydrochloride (372 mg, 3.46 mmol), N,N-diisopropylethylamine (1 .23 mL, 6.92 mmol) and 4- dimethylaminopyridine (282 mg, 2.31 mmol) in DMF (8 mL), and the resulting mixture was agitated at 60 °C for 60 min. LCMS revealed TM (rt = 0.79 mins, 94percent), as well as several minor impurities. The mixture was cooled to ambient temperature and evaporated to dryness to give a residue which was purified by automated column chromatography (SiO2; RediSep - 24 g; 0 to 10percent MeOH in DCM) to afford the desired product (850 mg, 1 .82 mmol, 78.7percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 22h; | A suspension of 3-methyl-2-oxo-1 H-quinoline-6-sulfonyl chloride (40 mg, 0.12 mmol) and 1 -methylcyclopropanamine hydrochloride (20 mg, 0.19 mmol) in DCM (1 mL) was treated with triethylamine (0.05 mL, 0.37 mmol) and stirred at RT. After 1 h, 1 mL DMF was added to fully dissolve the reagents, after 3 h a further portion of triethylamine (0.05 mL, 0.37 mmol) was added and the mixture was stirred for 18 h and then diluted with water (2 mL) and DCM (10 mL). The aqueous layer was re-extracted with DCM, and the combined organic extracts were washed with water, dried (hydrophobic frit) and concentrated. Purification by flash column chromatography, eluting with EtOAc - 5% MeOH/EtOAc afforded 3-methyl-N-(1 -methylcyclopropyl)-2-oxo-1 H-quinoline-6-sulfonamide (20 mg, 0.068 mmol, 55%) as a white solid. 1H NMR (300MHz, DMSO-d6) delta = 12.10 (br. s., 1 H), 8.05 (d, J=2.1 Hz, 1 H), 8.00 (br. s., 1 H), 7.96 - 7.92 (m, 1 H), 7.78 (dd, J=2.0, 8.6 Hz, 1 H), 7.41 (d, J=8.7 Hz, 1 H), 2.1 1 (d, J=1 .0 Hz, 3H), 1 .04 (s, 3H), 0.64 - 0.53 (m, 2H), 0.40 - 0.30 (m, 2H) LCMS: high pH - found 293.1 [M+H]+ T= 0.86 min, 100% purity by UV; low pH - found 293.1 [M+H]+ T= 0.85 min, 100% purity by UV |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a magnetically stirred solution of 8-bromo-1 -methyl-3-[(3-methylisoxazol-5- yl)methyl]-2,4-dioxo-quinazoline-6-sulfonyl chloride (700 mg, 1 .56 mmol) and 1 - methylcyclopropanamine hydrochloride (185 mg, 1 .72 mmol) in DMF (20 mL) at 20 °C under nitrogen was added triethylamine (0.73 mL, 3.43 mmol), and the resulting mixture was stirred at 20 °C for 2 h. The solvent was removed in vacuo and the resulting residue was purified by automated column chromatography (SiO2; RediSep - 24 g; 0 to 5percent MeOH in DCM) to afford the desired product (560 mg, 1 .16 mmol, 74percent) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.166667h; | A solution of 3-[(1 -methylpyrazol-4-yl)methyl]-2-oxo- 1H -quinoline-6-sulfonyl chloride (43 mg, 0.13 mmol) , 1 -methylcyclopropanamine hydrochloride (21 mg, 0.19 mmol), N,N-diisopropylethylamine (0.07 mL, 0.38 mmol) and 4-dimethylaminopyridine (16 mg, 0.13 mmol) in DMF (1 mL) was stirred at RT for 10 min. The reaction mixture was concentrated to dryness and purified by automated column chromatography, eluting with DCM - 10percent MeOH/DCM, to afford the desired product N-(1 -methylcyclopropyl)-3-[(1 -methylpyrazol-4- yl)methyl]-2-oxo- 7H-quinoline-6-sulfonamide (30 mg, 0.081 mmol, 63percent) as a white powder. Example 4873-Bromo-N-( 1 -methylcyclopropyl)-2-oxo- 1 H-quinoline-6-sulfonamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.333333h; | solution of 3-bromo-2-oxo- 1H -quinoline-6-sulfonyl chloride (150 mg, 0.23 mmol), 1 -methylcyclopropanamine hydrochloride (38 mg, 0.35 mmol), N,N- diisopropylethylamine (0.12 mL, 0.7 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) in DMF (2 mL) was stirred at room temperature for 20 min. The reaction mixture was then concentrated to dryness to give an oily residue, which was purified by automated column chromatography (DCM - 10percent MeOH/ DCM- weak chromophore) to afford 3-bromo-N-(1 - methylcyclopropyl)-2-oxo- 7H-quinoline-6-sulfonamide (46 mg, 0.13 mmol, 55percent) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 2h; | General procedure: This was taken up in acetonitrile (2 mL) and treated with 1 - methylcyclopropanamine hydrochloride (0.54 mmol) and diisopropylethylamine (1 .44 mmol) and stirred at 60 °C for 2 h. The cooled reaction mixture was then diluted with EtOAc (10 mL) and water (5 mL) and layers separated. The aqueous layer was re-extracted with EtOAc and the combined organics were passed through a hydrophobic frit and concentrated. Purification by prep. HPLC, high pH, afforded the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Triethylamine (1 .18 mL, 8.47 mmol) was added to a stirring solution of 3- fluoro-4-nitrobenzenesulfonyl chloride (2.03 g, 8.47 mmol) and 1 -methylcyclopropanamine hydrochloride (91 1 .43 mg, 8.47 mmol) in DCM (40 mL) at 0 C. After 5 min pyridine (0.68 mL, 8.47 mmol) was added dropwise and the reaction mixture allowed to warm to ambient temperature, and stir overnight. Water (50 mL) was added, the organic layer was separated, and the aqueous layer extracted with DCM (2 x 10 mL). The organics were combined, passed through a hydrophobic frit and evaporated to dryness. The crude product was purified by automated column chromatography, SiO2, eluent 0-50% EtOAc in iso-hexane, to yield 3-fluoro-N-(1 -methylcyclopropyl)-4-nitro-benzenesulfonamide (1 .44 g, 5.26 mmol, 62%). 1H NMR (300MHz, CDCI3) delta = 8.19 (t, J = 7.7 Hz, 1 H), 7.88 - 7.79 (m, 2H), 5.10 (s, 1 H), 1 .30 (s, 3H), 0.83 - 0.72 (m, 2H), 0.69 - 0.49 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38 mg | With triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 1h; | Chlorosulfonic acid (2.0 mL) was added to 1 ,8-naphthalimide (200 mg, 0.690 mmol) and the resulting solution stirred at 80 °C for 5 h under nitrogen. The reaction mixture was left to stand overnight and then added in drops to a stirred slurry of ice/water (approx 30 mL). After the addition was complete EtOAc (40 mL) was added and the mixture stirred for 5 min. The EtOAc layer was isolated by passing through a hydrophobic frit and the aqueous phase washed with EtOAc (2 x 40 mL). The EtOAc extracts were combined and dried over anhydrous MgS04. The solution was filtered and a mixture of 1 -methylcyclopropanamine hydrochloride (148 mg, 1 .37 mmol) and triethylamine (348 mg, 3.43 mmol) in EtOAc/DCM (10 mL) was added dropwise with stirring. After 1 h at ambient temperature water (30 mL) was added and the mixture stirred for 5 min. The organic layer was separated and the aqueous layer washed with EtOAc (2 x 40 mL). The combined EtOAc extracts were concentrated under reduced pressure and the crude residue flash chromatographed over silica and then subsequently purified by prep HPLC (high pH) to give the desired product (38 mg, 0.1 15 mmol, 17percent) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Methyl 6-chlorosulfonyl-3-[(1 -methylpyrazol-4-yl)methyl]-2,4-dioxo-1 H- quinazoline-8-carboxylate (550 mg, 1 .33 mmol) was added to a stirred solution of 1 - methylcyclopropanamine hydrochloride (143 mg, 1 .33 mmol) and N,N-diisopropylethylamine (0.52 mL, 2.93 mmol) in DMF (10 mL), and the resulting mixture was agitated at ambient temperature for 12 h. The solvent was removed in vacuo and the resulting residue was purified by automated column chromatography (SiO2; RediSep - 4 g; 0 to 80percent EtOAc in hexane) to afford the desired product (350 mg, 0.782 mmol, 59percent) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11 mg | With triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 1h; | Chlorosulfonic acid (2.0 mL) was added to 2-[(1 -methylpyrazol-4- yl)methyl]benzo[de]isoquinoline-1 ,3-dione (200 mg, 0.69 mmol) and the resulting solution stirred at 80 °C for 5 h under nitrogen. The reaction mixture was left to stand overnight and then added in drops to a stirred slurry of ice/water (approx 30 mL). After the addition was complete EtOAc (40 mL) was added and the mixture stirred for 5 min. The EtOAc layer was isolated by passing through a hydrophobic frit and the aqueous phase washed with EtOAc (2 x 40 mL). The EtOAc extracts were combined and dried over anhydrous MgS04. The solution was filtered and a mixture of 1 -methylcyclopropanamine hydrochloride (148 mg, 1 .37 mmol) and triethylamine (348 mg, 3.43 mmol) in EtOAc/DCM (10 mL) was added in drops with stirring. After 1 h at ambient temperature water (30 mL) was added and the mixture stirred for 5 min. The organic layer was separated and the aqueous layer washed with EtOAc (2 x 40 mL). The combined EtOAc extracts were concentrated under reduced pressure and the crude residue flash chromatographed over silica and then subsequently purified by prep HPLC (high pH) to give the desired product (1 1 mg, 0.026 mmol, 3.8percent) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
254 mg | With triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 1h; | Chlorosulfonic acid (4.0 mL) was added to 2-[(3-methylisoxazol-5- yl)methyl]benzo[de]isoquinoline-1 ,3-dione (466 mg, 1 .59 mmol) and the resulting solution stirred at 80 °C for 3 h under nitrogen. The reaction mixture was added dropwise to a stirred slurry of ice/water (approx 30 mL). After the addition was complete EtOAc (40 mL) was added and the mixture stirred for 5 min. The EtOAc layer was isolated by passing through a hydrophobic frit and the aqueous phase washed with EtOAc (2 x 40 mL). The EtOAc extracts were combined and dried over anhydrous MgS04. The solution was filtered and a mixture of 1 -methylcyclopropanamine hydrochloride (343 mg, 3.19 mmol) and triethylamine (1 .1 1 mL, 7.97 mmol) in EtOAc/DCM (10 mL) was added in drops with stirring. After 1 h at ambient temperature water (30 mL) was added and the mixture stirred for 5 min. The organic layer was separated and the aqueous layer washed with EtOAc (2 x 40 mL). The combined EtOAc extracts were concentrated under reduced pressure and the residue was triturated with MeOH/diethyl ether to give the desired product (254 mg, 0.697 mmol, 37.5percent) as an off- white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Microwave irradiation; | Example 8-8 5-methyl-N-(1-methylcyclopropyl)-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-amine 7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine (100 mg, 0.294 mmol, INTERMEDIATE a8) was added to a suspension of 1-methylcyclopropanamine hydrochloride (95 mg, 0.883 mmol) and potassium carbonate (122 mg, 0.883 mmol) in N,N-dimethylformamide (3 mL). The vessel was flushed with argon, and then the mixture was stirred and heated in a microwave (100° C., 300 W, 1 hour). The reaction mixture was partitioned between water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated. Purification of the residue by preparative-HPLC (column: Waters XBridge® C18, 19*150 mm, 5 mum; mobile phase A: water/10 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 45percent B to 58percent B in 8 minutes; 254 nm) provided the titled compound (17.7 mg, 16.1percent). MS(ESI+) m/z 375.1 [M+H]+; 1H NMR (400 MHz, CD3OD) delta ppm 1.01 (m, 2H), 1.09 (m, 2H), 1.56 (s, 3H), 1.78 (d, 3H), 2.64 (s, 3H), 4.51 (q, 1H), 6.30 (s, 1H), 6.58 (s, 1H), 7.55 (d, 2H), 7.63 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.8% | With caesium carbonate; potassium iodide; In 1,4-dioxane; at 130℃; for 4h; | Example 9-7 2-[1-(5-chloropyridin-2-yl)ethyl]-5-methyl-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidin-7-amine 7-Chloro-2-[1-(5-chloropyridin-2-yl)ethyl]-5-methylpyrazolo[1,5-a]pyrimidine (80 mg, 0.260 mmol, INTERMEDIATE a9) was added to a suspension of 1-methylcyclopropanamine hydrochloride (140 mg, 1.302 mmol), potassium iodide (43.2 mg, 0.260 mmol) and cesium carbonate (255 mg, 0.781 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 130° C. for 4 hours. This reaction mixture was concentrated under vacuum, and the crude residue was purified by preparative-HPLC (column: Waters XBridge® C18, 19*150 mm, 5 mum; mobile phase A: water/0.05percent NH4HCO3, mobile phase B: acetonitrile; flow rate: 20 mL/minute; gradient: 30percent B to 70percent B in 10 minutes; 254 nm) to provide the titled compound (22.1 mg, 24.8percent). MS(ESI+) m/z 342.1 [M+H]+; 1H NMR (400 MHz, CD3OD) delta ppm 0.89 (m, 2H), 0.98 (m, 2H), 1.51 (s, 3H), 1.77 (d, 3H), 2.50 (s, 3H), 4.50 (q, 1H), 6.17 (s, 1H), 6.27 (s, 1H), 7.40 (d, 1H), 7.79 (dd, 1H), 8.49 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In ethanol; at 80℃; for 16h;Inert atmosphere; Cooling with ice; | TEA (1 .8 mL, 12.66 mmol) was added to a stirred solution of 4-chloro-3-nitropyridine (1 .0 g, 6.32 mmol) in EtOH (20 mL) followed by addition of the HCI salt of 1 -methylcyclopropanamine (0.74 g, 6.96 mmol) under N2 atmosphere, at an ice cooled condition. The resulting mixture was stirred at 80 00 for 16 h, then concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The afforded crude product was purified by silica gel column chromatography using 30percent EtOAc in hexane, which gave the title compound (410 mg, 60percent) as a solid. MS (ES+) 193.6 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In tetrahydrofuran; | A solution of 4-[5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl]benzoyl chloride (1.5 g, 1.0 eq.),1-methylcyclopropanamine hydrochloride (0.58 g, 1.0 eq.) and triethylamine (3 ml, 3 eq.) in tetrahydrofuran (50 ml) was stirred overnight, before it was quenched by the addition of waterand the product was extracted into methylen chloride. The combined organic layers weresuccessively washed with diluted aqueous solutions of hydrochloric acid and sodiumbicarbonate, successively, dried over sodium sulfate and freed from solvent under reducedpressure to afford the title compound (1.0 g, 59percent). 1H NMR (400 MHz, CDCb, 298 K): o [ppm]=8.19 (d, 2H), 7.88 (d, 2H), 6.52 (s, broad, 1H), 1.61 (s, 1H), 1.50 (s, 3H), 0.89 (m, 2H), 0.78 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | To a solution of (3S,4S)-1-cyclohexyl-4-[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]- amino}-piperidine-3-carboxylic acid (21.7 mg, 0.05 mmol) in DMF (0.55 ml_) is added 1- methylcyclopropan-1 -amine hydrochloride (1 1 .3 mg, 0.1 mmol). DIPEA (0.028 ml_, 0.16 mmol) is then added followed by HATU (20 mg, 0.052 mmol). The reaction mixture is stirred overnight at RT. The crude mixture is directly purified by prep. LC-MS with method E. LC-MS method D: tR = 0.66 min; [M+H]+ = 487.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
473 mg | With sodium hydride; In tetrahydrofuran; 2,2,2-trifluoroethanol; mineral oil; for 168h;Cooling with ice; | Preparation Example 45 To 2,2,2-trifluoroethanol (12 mL) was added sodium hydride (a 60percent oil dispersion, 340 mg) under ice-cooling, followed by stirring for 20 minutes. To the reaction mixture was added <strong>[88887-87-0]1-methylcyclopropaneamine monohydrochloride</strong> (1 g) at the same temperature, and a solution of (2S)-2-(4-chloro-2-fluorophenyl)oxirane (1.39 g) in 2,2,2-trifluoroethanol (5 mL) was added thereto. The reaction mixture was stirred for 7 days and then concentrated. To the obtained residue was added ethyl acetate, water was added thereto, followed by performing liquid separation, and the organic layer was washed with brine. The organic layer was then dried over anhydrous sodium sulfate, the insoluble materials were then separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 100:0 to 0:100) to obtain (1S)-1-(4-chloro-2-fluorophenyl)-2-[(1-methylcyclopropyl)amino]ethanol (473 mg) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With N-ethyl-N,N-diisopropylamine; at 50℃; for 1h; | Compound 86 (6.90 g, 26.9 mmol) was dissolved in diisopropylethylamine (10 mL,57.3 mmol) followed by the addition of <strong>[88887-87-0]1-methylcyclopropan-1-amine hydrochloride</strong> (87, 3.20 g,29.7 mmol). The reaction was heated to 50°C for 1 hour before being diluted with diethyl ether(200 mL) and washed with 1M HC1 in water (2 x 200 mL). The organic phase was collected,washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, andconcentrated. Compound 88 was isolated by column chromatography (40percent ethyl acetate in hexanes) as a clear oil (3.25g, 43percent yield). MS ES+: 282.247 (expected 282.106). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution of 2-((5-(ethoxycarbonyl)-2-methylthiazol-4-yl)oxy)acetic acid (92, 173mg, 0.704 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.369 mL, 2.11 mmol) in N,Ndimethylformamide (4.0 mL) was added HATU (291 mg, 0.774 mmol). After stirring for 10mi <strong>[88887-87-0]1-methylcyclopropan-1-amine hydrochloride</strong> (87, 91 mg, 0.85 mmol) was added. After 2 hours at room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes to give the desired product as an off-white solid, ethyl 2-methyl-4-(2-((1-methylcyclopropyl)amino)-2- oxoethoxy)thiazole-5-carboxylate (93, 150.3 mg, 72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6 mg | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 16h;Inert atmosphere; | A suspension of 5-bromo-7-(pyridin-4-yl)isoquinoline (3) (30 mg, 0.105 mmol), 1-methylcyclopropan-1 -amine hydrochloride (28.3 mg, 0.263 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3 9.7 mg, 0.0105 mmol), 2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl (BINAP, 6.5 mg, 0.0105 mmol) and sodium tert- butoxide (44.3 mg, 0.462) in toluene (1 .5 mL) was heated under N2 at 90°C for 16 h, cooled to room temperature and concentrated. The residue was diluted in MeOH and filtered, then purified by mass-triggered preparative reverse phase HPLC with 10-90percent acetonitrile/water to afford the title compound (6 mg). 1 H NMR (400 MHz, Chloroform-d) delta 9.24 (s, 1 H), 8.74 (s, 2H), 8.49 (s, 1 H), 7.69 - 7.60 (m, 2H), 7.59 - 7.56 (m, 1 H), 7.52 - 7.46 (m, 1 H), 7.39 - 7.36 (m, 1 H), 1 .52 (s, 3H), 0.98 - 0.92 (m, 2H), 0.88 - 0.81 (m, 2H). LCMS (m/z [M+H]+): 276. |
Tags: 88887-87-0 synthesis path| 88887-87-0 SDS| 88887-87-0 COA| 88887-87-0 purity| 88887-87-0 application| 88887-87-0 NMR| 88887-87-0 COA| 88887-87-0 structure
[ 97291-62-8 ]
trans-2-Methylcyclopropanamine hydrochloride
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[ 178033-78-8 ]
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[ 174886-05-6 ]
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[ 22287-35-0 ]
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[ 26562-81-2 ]
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[ 97291-62-8 ]
trans-2-Methylcyclopropanamine hydrochloride
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[ 178033-78-8 ]
(S)-1-Cyclopropylethan-1-amine hydrochloride
Similarity: 0.72
[ 174886-05-6 ]
1-Methylcyclobutanamine hydrochloride
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