Structure of 57297-29-7
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CAS No. : | 57297-29-7 |
Formula : | C4H9ClN2 |
M.W : | 120.58 |
SMILES Code : | N=C(C1CC1)N.[H]Cl |
MDL No. : | MFCD00053010 |
InChI Key : | JRYOZJIRAVZGMV-UHFFFAOYSA-N |
Pubchem ID : | 2781916 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 32.49 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.87 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.49 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.07 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.5 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.37 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.49 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.83 |
Solubility | 17.8 mg/ml ; 0.148 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.11 |
Solubility | 9.43 mg/ml ; 0.0782 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.1 |
Solubility | 95.1 mg/ml ; 0.789 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.69 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.48 |
* 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 |
---|---|---|
75% | With potassium carbonate; In 1,2-dimethoxyethane; for 3h;Heating / reflux; | Example 14 Preparation of 2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers / ethyl acetate: 20 / 1) to yield 2.1 g (75 percent) of the pure product having as a colorless liquid; 1H NMR (CDCl3); delta = 2.10 ppm (m, N=C(=N)-CH). |
2.1 g (75%) | With potassium carbonate; In 1,2-dimethoxyethane; | EXAMPLE 14 Preparation of 2-cyclopropyl-4-(3-trifluoromethylphenoxy)pyrimidine 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers/ethyl acetate: 20/1) to yield 2.1 g (75percent) of the pure product having as a colorless liquid; 1H NMR (CDCl3); delta=2.10 ppm (m, N=C(=N)-CH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | EXAMPLE 2 Preparation of 5-benzyloxy-6-oxo-2-cyclopropyl-1,6-dihydropyrimidine-4-carboxylic Acid tert-butyl Ester NaOMe (6.8 mL, 25 wt percent solution in MeOH, 30 mmol) was added to a solution of cyclopropane-1-caboximidamide HCl (1.21 g, 10.0 mmol) and fumarate reagent 1a (4.60 g, 15.0 mmol) in MeOH (16.6 mL) at 0° C. The mixture was warmed to room temperature, then stirred for 30 hours. After dilution with MeOH (5 mL) and cooling to 0° C., 1N HCl (40 mL) was added and the product was precipitated from the mixture. The solid was washed with 10 mL of cold 9:1H2OMeOH and dried giving 3.14 g of the title product (92percent isolated yield) of >98percent pure (HPLC area percent purity at 210 nm) as a white crystalline solid with a melting point of 164.0-164.5° C. 1H-NMR (400 MHz, CDCl3) d 12.98 (1H, br s), 7.46-7.49 (2H, m), 7.30-7.38 (m, 3h), 5.24 (2H, s), 1.89-1.95 (1H, m), 1.52 (9H, s), 1.24-1.29 (2H, M), 1.05-1.10 (2H, m); 13C NMR (100 MHz, DMSO-d6) 164.3, 159.7, 159.5, 145.7, 139.4, 137.3, 128.6, 128.3 (2 peaks), 82.6, 73.4, 27.9, 13.5, 10.0 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium acetate; | EXAMPLE 62 Synthesis of 2-cyclopropyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide, 48.1 mg (0.399 mmol) of cyclopropyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate, in the same manner as that of Example 61. Yield: 90.4 mg (0.205 mmol) (77percent) MS (ESI, m/z) 440 (M+H)+ 438 (M-H)- 1H-NMR (CDCl3): 1.06-1.14 (2H, m), 1.17-1.22 (2H, m), 1.73 (2H, quint), 2.22-2.30 (1H, m), 2.48 (2H, t), 2.53 (3H, s), 3.31 (2H, q), 5.48 (1H, br t), 7.06-7.08 (2H, m), 7.15-7.20 (1H, m), 7.24-7.29 (2H, m), 7.39-7.40 (1H, m), 7.66-7.68 (2H, m). |
With sodium acetate; | Example 62 Synthesis of 2-cyclopropyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 100 mg (0.266 mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide, 48.1 mg (0.399 mmol) of cyclopropyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of sodium acetate, in the same manner as that of Example 61. Yield: 90.4 mg (0.205 mmol) (77percent) MS (ESI, m/z) 440 (M+H)+ 438 (M-H)- 1H-NMR (CDCl3): 1.06-1.14 (2H, m), 1.17-1.22 (2H, m), 1.73 (2H, quint), 2.22-2.30 (1H, m), 2.48 (2H, t), 2.53 (3H, s), 3.31 (2H, q), 5.48 (1H, br t), 7.06-7.08 (2H, m), 7.15-7.20 (1H, m), 7.24-7.29 (2H, m), 7.39-7.40 (1H, m), 7.66-7.68 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With sodium acetate; | EXAMPLE 90 Synthesis of 4-(3-chloro-4-methoxyphenyl)-2-cyclopropyl-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.419 mmol) of 2-acetyl-3-(3-chloro-4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 76.0 mg (0.629 mmol) of cyclopropyl-carbamidine hydrochloride and 68.9 mg (0.840 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 54.7 mg (0.125 mmol) (31percent) MS (ESI, m/z) 436 (M+H)+ 1H-NMR (CDCl3): 1.04-1.11 (2H, m), 1.17-1.22 (2H, m), 1.72 (2H, quint), 2.23-2.32 (1H, m), 2.45 (2H, t), 2.54 (3H, s), 3.32 (2H, q), 3.85 (3H, s), 5.47 (1H, br s), 6.90 (1H, d), 7.04-7.07 (1H, m), 7.15-7.20 (1H, m), 7.23-7.26 (3H, m), 7.70 (1H, dd), 7.88 (1H, d). |
With sodium acetate; | Example 90 Synthesis of 4-(3-chloro-4-methoxyphenyl)-2-cyclopropyl-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.419 mmol) of 2-acetyl-3-(3-chloro-4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 76.0 mg (0.629 mmol) of cyclopropyl-carbamidine hydrochloride and 68.9 mg (0.840 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 54.7 mg (0.125 mmol) (31percent) MS (ESI, m/z) 436 (M+H)+ 1H-NMR (CDCl3): 1.04-1.11 (2H, m), 1.17-1.22 (2H, m), 1.72 (2H, quint), 2.23-2.32 (1H, m), 2.45 (2H, t), 2.54 (3H, s), 3.32 (2H, q), 3.85 (3H, s), 5.47 (1H, br s), 6.90 (1H, d), 7.04-7.07 (1H, m), 7.15-7.20 (1H, m), 7.23-7.26 (3H, m), 7.70 (1H, dd), 7.88 (1H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium acetate; | EXAMPLE 92 Synthesis of 2-cyclopropyl-4-(2,4-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.467 mmol) of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide, 84.4 mg (0.700 mmol) of cyclopropyl-carbamidine hydrochloride and 77.1 mg (0.940 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 92.9 mg (0.233 mmol) (49percent) MS (ESI, m/z) 400 (M+H)+ 1H-NMR (CDCl3): 1.01-1.07 (2H, m), 1.13-1.18 (2H, m), 1.37-1.47 (2H, m), 2.22-2.30 (9H, m), 2.55 (3H, s), 3.15 (2H, q), 5.22 (1H, br t), 6.97-7.05 (3H, m), 7.13-7.28 (5H, m). |
With sodium acetate; | Example 92 Synthesis of 2-cyclopropyl-4-(2,4-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide: The title compound was obtained by using 150 mg (0.467 mmol) of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide, 84.4 mg (0.700 mmol) of cyclopropyl-carbamidine hydrochloride and 77.1 mg (0.940 mmol) of sodium acetate, in the same manner as that of Example 1. Yield: 92.9 mg (0.233 mmol) (49percent) MS (ESI, m/z) 400 (M+H)+ 1H-NMR (CDCl3): 1.01-1.07 (2H, m), 1.13-1.18 (2H, m), 1.37-1.47 (2H, m), 2.22-2.30 (9H, m), 2.55 (3H, s), 3.15 (2H, q), 5.22 (1H, br t), 6.97-7.05 (3H, m), 7.13-7.28 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; | EXAMPLE 1 Preparation of ethyl 6-amino-5-bromo-2-cyclopropyl-4-pyrimidinecarboxylate (Compound 1) and methyl 6-amino-5-bromo-2-cyclopropyl-4-pyrimidinecarboxylate (Compound 2) Step A: Preparation of 2-cyclopropyl-6- (diethoxymethyl)-4 (lI)-pyrimidinone To a mixture of ethyl 4,4-diethoxy-3-oxobutanoate (prepared according to the method of E. Graf, R. Troschutz, Synthesis, 1999,7, 1216; 10.0 g, 46 mmol) and cyclopropane- carboximidamide monohydrochloride (Lancaster Synthesis, 5.0 g, 41 mmol) in methanol (100 mL) was added a methanol solution of sodium methoxide (5. 4 M, 8.4 mL, 46 mmol). The reaction mixture was stirred overnight. The solvent was removed with a rotary evaporator. Dichloromethane was added and the mixture was filtered. The solvent from the filtrate was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) (35-100percent ethyl acetate in hexanes as eluant) to afford the title compound as a white solid (4.67 g). 1H NMR (CDC13) 8 6.55 (s, 1H), 5.10 (s, 1H), 3.61 (m, 4H), 1.91 (m, 1H), 1.23 (m, 8H), 1.09 (m, 2H). Additionally 3.24 g of an undehydrated product was obtained. This material could be converted to the title compound by refluxing it in methanol with a catalytic amount of pyridinium p-toluenesulfonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | A 500-mL jacketed reactor equipped with a pH meter, temperature probe and metering addition funnel was charged with denatured ethanol (contained 5 percent 2-propanol, 3O mL) and water (150 mL). The reaction mixture was stirred while diethyl oxalacetate, sodium salt (70 g, 0.33 mol) was added over 10 minutes. A solution of 25 percent aqueous NaOH (14 g, 56 mL, 0.35 mol) was metered into the stirring vortex over 1 h while maintaining the temperature in a range of 25 to 30 °C. The reaction mixture was stirred for an additional 30 minutes at 30 °C, and <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> (32 wt percent solution in water, 32 g, 0.267 mol) was added. A solution of 25 percent aqueous NaOH (31 g, 0.19 mol) was added at a temperature ranging from 30 to 35 0C over about 1 h so as to maintain the pH in the range of 10.5-11.5. Then the resulting orange mixture was gradually heated to 60 0C over a period of 1 h and held at the same temperature for additional 30 minutes. The reaction mixture was cooled to 45-50 0C, and hydrochloric acid (37 wt. percent in water, 50 mL, 0.60 mol) was added over 1 h at about 45 0C (CAUTION: foaming) until the pH reached to about 1.5. The reaction mixture was cooled to 5 °C and filtered. The resulting wet cake was washed with water (3 x 20 mL), suction-dried, and dried in a vacuum-oven at 70 0C for 16 h to afford 42 g (85 percent yield) of the title compound as a beige solid (97 percent purity by HPLC assay) decomposing at 235-236 0C.1H NMR (DMSO-J6) 6 6.58 (s, IH), 1.95 (m, IH), 1.0 (m, 4H). 13C NMR (DMSO-J6) delta 169.2, 169.0, 157.3, 116.8, 17.7, 14.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium methylate; In methanol; for 3.5h;Heating / reflux; | The title compound was prepared following a procedure described in US 4, 558, 039 using the tetrafluoroborate of Arnold's salt (N- (2-benzyloxy-3- (dimethylamino)-2- propenylidene)-N-methylmethanaminium tetrafluoroborate-Holy, A., Arnold, Z, Collect. Czech. Chem. Commun., EN, 38, 1973, 1371-1380). Cyclopropanecarboxamidine hydrochloride (2.0 g, 16.6 mmol) was dissolved in MeOH (10 mL). To this solution was added Arnold's salt (5.85 g, 18.3 mmol). A solution of NaOMe (2.15 g, 39.8 mmol) in MeOH (20 mL) was added in small portions and the reaction mixture was heated under argon to reflux temperature. After 3.5 h, the reaction mixture was allowed to cool to room temperature and the solvents were removed by evaporation. The solid material was washed with water, filtered off and dried under reduced pressure to give the subtitle compound (2.4 g, 64percent). APCI-MS m/z: 227.1 [MH +I. 'H-NMR (DMSO-D6): 6 8.44 (2H, s), 7.49-7. 29 (5H, m), 5.21 (2H, s), 2.14 (1H, m), 0.95 (2H, m), 0.89 (2H, m) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With triethylamine; In ethanol; for 1h;Reflux; | Example 196a 2-cyclopropylpyrimidin-4-amine 196a Cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) was dissolved in ethanol (25 mL) and triethylamine (1.26 g, 12.5 mmol), followed by the addition of 2-chloroacrylonitrile (870 mg, 10 mmol). The resulting orange-yellow solution was refluxed for 1h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase Combiflash to afford 196a (300 mg, 27percent) as a light brown solid. MS-ESI: [M+H]+ 136 |
With triethylamine; In ethanol; for 0.5h;Heating / reflux;Product distribution / selectivity; | Alternative Preparation Method for Step A]: Cyclopropylcarbamidine hydrochloride (7.61 g) was dissolved in ethanol (125 mL) and triethylamine (19.35 mL) and 2-chloro-acrylonitrile (5.52 mL) were added. The resulting orange-yellow solution was refluxed for 30 minutes. The mixture was cooled and left in a refrigerator over night. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/methanol 9:1) to give 2-cyclopropyl-pyrimidin-4-ylamine (4.2 g) as a light brown solid that was still contaminated with an unidentified component, but used without further purification. 1H NMR (delta, DMSO-d6, product signals only): 7.88 (d, 1H), 6.64 (br s, 2H), 6.16 (d, 1H), 1.89-1.82 (m, 1H), 0.87-0.81 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; at 20℃; for 0.25h; | Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60 °C for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HC1 solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro- 4, 6-pyrimidinediol 3 (3.6 g, 76 percent) is obtained as a white powder and used in the next step without further purification. 1H NMR (250 MHz, DMSO): 0.95 (m, 4H), 1.83 (m, 1H), 12.1 (bs, 2H); Sodium (0.417 g, 18.1 mmol) is dissolved in methanol (65 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (2.19 g, 18.1 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo to 30 ml. This free base is added to a solution of sodium (0.834 g, 36.2 mmol) in methanol (130 ml) under a nitrogen atmosphere, at room temperature. 2-ethoxy-4, 5-dihydro-3H-pyrrole-3- carboxylic acid ethyl ester (3.4 g, 18.1 mmol) in methanol is added and the mixture is stirred at 60 °C overnight. After cooling, the solvent is evaporated and the solid obtained is dissolved in water. The pH is adjusted at 5 with a 5 N HC1 solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-6,7-dihydro-5H- pyrrolo [2,3-d] pyrimidin-4-ol 48 (1.88 g, 59 percent) is obtained as a white powder and used in the next step without further purification. MS (MH+): 178. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | a 2-Cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-one Analogous to Scheme 1from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong>. Yield: 62percent. White solid, m/z (ISP) 252 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | A l-L reactor equipped with a thermocouple, subsurface gas feed line, hydrogen chloride cylinder, cylinder balance and nitrogen bubbler was flushed with nitrogen and charged with cyclopropanecarbonitrile (100 g, 1.5 mol), methanol (48 g, 1.5 mol) and toluene (400 mL). The reaction mixture was maintained at 15 °C under slight nitrogen positive pressure while feeding anhydrous hydrogen chloride (57 g, 1.55 mol) below the reaction mixture surface over 2 h. Then the reaction mixture was stirred for 16 h at 23 0C. EPO <DP n="24"/>Excess hydrogen chloride was purged by bubbling nitrogen below the reaction mixture surface and venting the effluent gas through a water scrubber over 2 h. The mixture was cooled to 5 °C, and then a solution of ammonia in methanol (240 mL of a 7 M solution, 1.7 mol) was added over 10 minutes while maintaining the temperature below 25 °C. After being allowed to stand an additional 1 h, the reaction mixture was distilled at reduced pressure to remove the excess methanol. The product was filtered, washed with toluene (100 mL), and suction-dried to give 17O g (94 percent yield) of the title compound as a solid. 1H NMR (DMSO-J6) delta 8.8 (br s, 4H), 1.84 (m, IH), 1.1 (m, 4H). | |
79.5% | Cyclopropylcarboxamidine hydrochloride (1) A solution of cyclopropanecarbonitrile (70 g, 1 .04 mol) in ethanol (50 mL) was added to a saturated solution of dry HCI gas in dry ethanol (93 g) along with slight cooling. The resulting mixture was then stirred at RT for 24 h. The thick suspension formed was diluted with ethanol (25 mL) and cooled with an ice-water bath. An ethanolic ammonia solution (103.2 g) was added slowly to the ethanol mixture over ~ 30 min. The cooling bath was then removed, and the mixture was stirred at 23 °C for another 24 h. The precipitated ammonium chloride by-product was filtered off, and washed with ethanol (25 mL). The filtrates were concentrated and diluted with methanol (25 mL). The product was precipitated from the methanol mixture by the addition of diethyl ether (100 mL). The suspension was stirred for 4 h, the precipitate was filtered off, washed with diethyl ether (50 mL), and dried under vacuum to afford 100 g (79.5percent) of the amidine (1 ). LCMS m/z 85 (M+1 ). H NMR (400 MHz, DMSO-d6) delta 8.86 (s, 2H), 8.72 (s, 2H), 1.84 (m, 1 H), 1.15-1 .06 (m, 4H). | |
67% | Hydrogen chloride gas was bubbled through a stirred solution of cyclopropylcarbonitrile (10.0 g, 0.15 mol) and methanol (6 ml, 0.15 mol) in dry ether (60 ml) at 0°C for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in methanol (125 ml). The solution was added to an ice-cold mixture of methanol (125 ml) and liquid ammonia (15 ml) and the mixture stirred for 1 hour. The resulting clear solution was evaporated to leave cyclopropylcarboxamidine hydrochloride salt as a white solid (12.0 g, 67percent). Characterising data for the compound are as follows: 1H nmr (400 MHz, d6-DMSO) deltaH 8.75 (2H, s), 8.64 (2H, s), 1.81 (1 H, quintet), 1.11 (4H, s) ppm. |
67% | Hydrogen chloride gas was bubbled through a stirred solution of cyclopropylcarbonitrile (10.0 g, 0.15 mol) and methanol (6 ml, 0.15 mol) in dry ether (60 ml) at 00C for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue dissolved in methanol (125 ml). The solution was added to an ice-cold mixture of methanol (125 ml) and liquid ammonia (15 ml) and the mixture stirred for 1 hour. The resulting clear solution was evaporated to leave cyclopropylcarboxamidine hydrochloride salt as a white solid (12.0 g, 67percent). 1H nmr (400 MHz, de-DMSO) deltaH 8.75 (2H, s), 8.64 (2H, s), 1.81 (1 H1 quintet), 1.11 (4H1 s) ppm. | |
7.3 g (61%) | EXAMPLE 5A Cyclopropanecarboximidamide Hydrochloride In analogy to the procedure for Example 3A, 6,71 g (100 mmol) cyclopropanecarbonitrile and proportionate amounts of the other reagents are used. Yield: 7.3 g (61percent) GC/MS (method A): retention time 3.42 min., m/z 85,1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | a 2-Cyclopropyl-10-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong>. Yield: 88percent. White solid, m/z (ISP) 270 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | a 10-Chloro-2-cyclopropyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropancarboxamidine hydrochloride. Yield: 83percent. White solid, m/z (ISP) 28 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | a 2-Cyclopropyl-5,7-dihydro-10-methyl-6H-pyrimido[5,4-d][1]benzazepin-6-one Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong>. Yield: 88percent. White solid, m/z (ISP) 266 (MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; potassium carbonate; In chloroform; water; argon; | EXAMPLE 28 A 1.32 g portion of bromine dissolved in 6.6 ml of chloroform was dropwise added gradually (spending about 60 minutes) to 36 ml of chloroform solution containing 3.55 g of 4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-isopropoxybenzanilide at room temperature. When disappearance of the color of bromine was confirmed, the reaction solution was washed with a saturated sodium bicarbonate aqueous solution. The resulting organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure and then evaporated to dryness using a vacuum pump. The thus obtained solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 5.0 g of cyclopropylcarbamidine hydrochloride and 8.02 g of potassium carbonate and subjected to 20 hours of heating under reflux in a stream of argon. The resulting reaction solution was mixed with water to effect phase separation, and the separated organic layer was dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was crystallized from toluene to obtain 2.96 g of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium ethanolate; In ethanol; at 80℃; for 2h; | Example 1; Preparation of tert-butyl 2-cvclopropyl-4-(3,3,3-trifluoropropoxyl-5,6,8,9-tetrahydro- 7H-pyrimido[4,5-d]azepine-7-carboxylate; [052] Step 1; Preparation of tert-butyl 2-cvclopropyl-4-hvdroxy-5,6,8,9-tetrahydro-7H - pyrimido[4,5-d]azepine-7-carboxylate; [053] Commercially available 1- tert-butyl 4-ethyl 5-oxoazepane-1 ,4-dicarboxylate (6.0 g, 21.0 mmol) and <strong>[57297-29-7]cyclopropanecarboximidamide hydrochloride</strong> (2.54 g, 21.0 mmol) were combined and dissolved in ethyl alcohol (21 mL ). Sodium ethoxide (21 weight percent solution in ethyl alcohol) (7.85 mL , 21.0 mmol) was added, and the mixture was heated at 80°C for 2 h. The contents of the reaction flask were cooled to 0°C and filtered. The solids were washed with cold methanol and dried in a 40°C vacuum oven to provide the title compound as an off-white solid (4.6 g, 72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium ethanolate; In ethanol; for 3h;Heating / reflux; | Step 2; Preparation of tert-butyl 2-cvclopropyl-4-hvdroxy-9-methyl-5,6,8,9- tetrahvdro-7/-/-pyrimido[4,5-d]azepine-7-carboxylate; [067] Sodium ethoxide solution (21 weight percent ethanol, 2.24 mL, 1.45 mmol) was added dropwise to a solution of 1- tert-butyl 4-ethyl 6-methyl-5-oxoazepane-1,4-dicarboxylate (290 mg, 0.97 mmol) in ethanol (6 mL). Cyclopropylcarbamidine hydrochloride (175 mg, 1.45 mmol) was added, and the mixture was heated at reflux for 3 h. The contents of the flask were cooled to rt, and the solvent was removed under reduced pressure. The residue was suspended in water and extracted with chloroform (2x). The organic layers were combined and concentrated to afford 200 mg (64percent) of crude product, which was EPO <DP n="21"/>used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium methylate; In methanol; water; | (a) The 2-cyclopropyl-4-hydroxy-6-methylpyrimidine to be employed as a starting material could be prepared, for example, as follows: STR6 78.3 g (0.65 mol) of cyclopropylamidine hydrochloride and then 76.4 g (0.65 mol) of acetoacetic acid methyl ester were added to a solution of 70 g (1.3 mol) of sodium methylate in 400 ml of methanol at room temperature. The mixture was stirred at room temperature for 18 hours, the solvent was then distilled off in vacuo and the residue was dissolved in 400 ml of water. The solution was adjusted to pH 4 by adding concentrated hydrochloric acid and, after cooling to 5°-10° C., the product which had precipitated was filtered off. 75 g (77percent of theory) of 2-cyclopropyl-4-hydroxy-6-methylpyrimidine were obtained in this manner in the form of a colorless powder with the melting point 187° C. STR7 | |
With sodium methylate; In methanol; at 20℃; for 18h; | 2-Cyclopropyl-6-methylpyrimidin-4-ol (B8.1) (0372) A mixture of <strong>[57297-29-7]cyclopropane-carboximidamide hydrochloride</strong> (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16.7 mmol) and CH3ONa (1.8 g, 33.4 mmol) in MeOH (200 mL) was stirred at rt for 18 h. Then the mixture was diluted with Sat. Na2SO3 (50 mL), then concentrated under reduced pressure. The residue was dissolved in 50 mL water, adjusted pH to 4. After cooling to 5° C., the solid was collected and dried in vacuum to give the title compound (2.0 g, 98percent) as a yellow solid. The crude product was used in the next step without further purification. LC-MS: [M+H]+=151.2. | |
With sodium methylate; In methanol; at 20℃; for 18h; | A mixture of cyclo propanecarboximidamide hydrochloride (2.0 g, 16.7 mmol), methyl 3-oxobutanoate (1.9 g, 16.7 mmol) and CH3ONa (1 .8 g, 33.4 mmol) in MeOH (200 mL) was stirred at rt for 18 h.Then the mixture was diluted with Sat. Na2503 (50 mL), then concentrated under reduced pressure. The residue was dissolved in 50 mL water, adjusted pH to 4. After cooling to 5°C, the solid was collected and dried in vaccum to give the title compound (2.0 g, 98percent) as a yellow solid. The crude product was used in the next step without further purification. LC-MS: [M+H] = 151.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
sodium ethanolate; In ethanol; | EXAMPLE 18 2-Cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile In analogy to the procedure described in example 15 the Z and/or E 2-cyano-3-methylsulfanyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acrylic acid ethyl ester [example 13 a)] was treated with cyclopropylcarbamidine hydrochloride in ethanol in the presence of sodium ethylate at reflux to yield the 2-cyclopropyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile as colorless solid; m.p. >200° C.; MS: [M]+=307. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(ii) Cyclopropanecarboxamidine hydrochloride from cyclopropanecarbonitrile. Hydrogen chloride reaction time: 6 days Ammonia reaction time: 16 hours Melting point: 55-58°C 1H NMR CDCl3): 0.85 (m); 1.2 (m); 1.7 (m) Infra red (paraffin mull): 3400, 3200, 1650, 1460, 1380, 1310, 1150, 1040, 940 cm1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In ethanol; at 20℃; | Ethyl cyclopropanecarboximidate monohydrochloride (40.5 g 0.27 mol) was added portionwise to a saturated solution of ammonia in ethanol (50 mL). A further portion of ethanol (33 mL) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol to give the title composition (83 mL). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In ethanol; toluene; at 20℃;Heating / reflux; | A portion (-40.4 mL) of the ethanol solution of <strong>[57297-29-7]cyclopropanecarboximidamide monohydrochloride</strong> as prepared in Example 1 was added to a portion (-210 mL) of the solution of the sodium salt of ethyl 4,4-diethoxy-3-oxobutanoate as prepared in Example 2. The mixture was allowed to stir overnight at room temperature. The mixture was boiled for about 2 h and then allowed to cool to room temperature. The mixture was evaporated under reduced pressure, and the residue was redissolved in toluene (200 mL). A solution of ammonium chloride (0.68 g, 12.7 mmol) in water (30 mL) was added. After stirring for 10 minutes, the aqueous phase was removed. The organic phase was dried and evaporated to leave the product as pale yellow solid (27.27 g, 88 percent yield). Product recrystallized from hexanes melted at 111.5-112.0 °C.IR (nujol) 1674, 1602, 1400, 1316, 1153, 1116, 1099, 1068, 1003, 965, 860 cm-1.- EPO <DP n="16"/>1H NMR (CDCl3) delta 6.54 (d, J= 0.4 Hz, IH), 5.10 (d, J= 0.4 Hz, IH), 3.70-3.57 (m, 4H),1.98-1.92 (m, IH), 1.27-1.05 (m, 10H). MS m/e (M+ + 1) calcd. 239.1396, obsd. 239.1395. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | In ethanol; for 120h;Heating / reflux; | To a suspension of 1 g (3.48 mmol) of 2,5-diamino-3-chloro-4-methylamino-benzoic acid methyl ester (synthesis described in example H7) in 153 ml of EtOH, is added 866 mg (6.97 mmol) of <strong>[57297-29-7]cyclopropane carboxamidine hydrochloride</strong>. After 24 hours of reaction under reflux, 866 mg (6.97 mmol) of <strong>[57297-29-7]cyclopropane carboxamidine hydrochloride</strong> were added more and the reaction is stirred under reflux 2 days more. Again 433 mg (3.48 mmol) of <strong>[57297-29-7]cyclopropane carboxamidine hydrochloride</strong> is added and after again 2 days of reaction under reflux, the reaction is stopped and the solvent is evaporated. The residue is suspended in EtOAc and the precipitate is filtrated. The filtrate obtained is evaporated and purified by flash chromatography on silica gel and gives 100 mg (0.36 mmol, 10percent) of a brown solid. LC/MS: 280 / 282 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | NaH (60percent purity, 41 .9 g,) is added in portions to EtOH (800 mL) at 0 °C. The resulting mixture is warmed to ambient temperature and the cyclopropanecarboxamidine hydrochlorid (93.5 g,) isadded in portions. The reaction is warmed to 50 °C and maintained at this temperature for 0.5 h and then cooled to ambient temperature before mucobromic acid (100 g,) is added in EtOH while keeping the internal temperature below 55 °C. The mixture is allowed to cool to ambient temperature and stirred for additional 16 h. All solid components are removed by filtration and the resulting solution is concentrated under reduced pressure. Aq. HCI (1 mol/L) is added, the aqueous phase is washed with EtOAc (3x), the combined organic extracts are dried over MgSO4 and the solid parts removed by filtration. The residue is concentrated under reduced pressure and the resulting solid titrated with (iPr)20. The solids are collected by filtration and dried yielding the title compound (68.0 g, yield 72 percent) as a colorless solid.1 NMR (400 MHz, CDCI3): 6 = 8.91 (s, 1H), 2.38?2.26 (m, 1H), 1.34?1.14 (m, 4H) ppm; MS (ESI) mlz 244.9 [M + Hj. | |
72% | NaH (60percent purity, 41 .9 g) is added in portions to EtOH (800 mL) at 0 °C. The resulting mixture is warmed to ambient temperature and the cyclopropanecarboxamidine hydrochlorid (93.5 g,) is added in portions. The reaction is warmed to 50 °C and maintained at this temperature for 0.5 hand then cooled to ambient temperature before mucobromic acid (100 g) is added in EtOH while keeping the internal temperature below 55 °C. The mixture is allowed to cool to ambient temperature and stirred for additional 16 h. All solid components are removed by filtration and the resulting solution is concentrated under reduced pressure. Aq. HCI (1 mol/L) is added, the aqueous phase is washed with EtOAc (3x), the combined organic extracts are dried overMg504 and the solid parts removed by filtration. The residue is concentrated under reduced pressure and the resulting solid titrated with (iPr)20. The solids are collected by filtration and dried yielding the title compound (68.0 g, yield 72 percent) as a colorless solid.1H NMR (400 MHz, CDCl3): 6 = 8.91 (s, 1H), 2.38 ?2.26 (m, 1H), 1.34?1.14 (m, 4H) ppm; MS (ESI) mlz 244.9 [M + Hj. | |
With sodium ethanolate; In ethanol; at 20 - 56℃; | 5-Bromo-2-cyclopropylpyrimidine was prepared by the method of Budesinsky, Z., Coll.Czech. Chem. Commun., 1949,14, 223-235. Cyclopropanecarboximidamidehydrochloride (2.5 g, 20.7 mmol) was dissolved in EtOH (4 mL), freshly prepared 4.1M"NaOEf irTEtOH (478 niC) was"~added followe'dTSy mucobrbmic aci<T(2'.7 g, 10.3"mm6l)r "The mixture was heated to 56 °C for 30 minutes, more NaOEt in EtOH (4.1M, 3.2 mL)was added and the reaction was stirred at 56 °C for another 15 minutes and then at roomtemperature overnight. The solvent was evaporated off, aqueous HC1 (2M, 10 mL) wasadded and the brown solid was filtered off. The aqueous layer was extracted three timeswith dichloromethane. The combined organic layers were dried and concentrated to give abrown oil that together with the solid gave crude intermediate 5-bromo-2-cyclopropylpyrimidine-4-carboxylic acid (1.6 g). The crude intermediate was heated at140 °C for 8 minutes to give a brown sticky oil that was then partly dissolved indichloromethane. The solution was decanted from the mixture and concentrated to givethe subtitle compound as an oil (673 mg).^-NMR (CDC13): 5 8.61 (2H, s); 2.25 (1H, m); 1.13 (4H, m).APCI-MS m/z: 199/201 1:1 [MH1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; In ethanol;Heating / reflux; | 3,4-dichlorobenzaldehyde (2.0 g, 11.43 mmol), ethyl cyanoacetate (1.29 g, 5 11.43 mmol), <strong>[57297-29-7]cyclopropanecarboxamidine hydrochloride</strong> (1.38 g, 11.43 mmol), and potassium carbonate (1.58 g, 11.43 mmol) were refluxed in ethanol (40 mL) overnight. The stirbar was removed and water was added. The precipitate was filtered and washed with water to give 2.17 g (62percent) of the title compound as a white powder. MS m/z calculated for (M + H)+ 306, found 306. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5% | Reference Example 10; 2-cyclopropyl-4 -isobutyl-6-methoxypyrimidine-5- carbaldehyde; (step 1); To a solution of methyl 5-methyl-3-oxohexanoate(14.3 g) synthesized by a known method (WO2006/090915) and cyclopropylcarbamidine monohydrochloride (10.9 g) in ethanol (180 mL) was added sodium ethoxide (18.5 g) at room temperature, and the mixture was heated under reflux for 4 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and acidified with 6N hydrochloric acid at 0°C. The resultant product was extracted 3 times with ethyl acetate, and the organic layer was washed with brine.' The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50-67percent ethyl acetate/hexane) and crystallized from ethyl acetate-IPE to give 2-cyclopropyl-6-isobutylpyrimidine- 4-ol (1.31 g, 7.5percent) as. a white powder.1H-NMR (300MHz, CDCl3): deltapsi.91 (6H, d, J=6.4Hz), 1.03- 1.12 (2H, m) , 1.14-1.22 (2H, m) , 1.86-1.95 (IH, m) , 1.99-2.10 (IH, m) , 2.31 (2H, d, J=7.2Hz), 6.05 (IH, s), 13.38 (IH, br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In methanol; acetone; tert-butyl alcohol; at 0 - 20℃; for 4h; | EXAMPLE 29; Tetrahydro-furan-3-carboxylic Acid [(S)-3-[5-(2-cyclopropyl-4,6-dimethyl-pyrimidine-5-carbonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-1-(3-fluoro-phenyl)-propyl]-amide (I-48); step 1-; A solution of 126 (0.5 g, 2.904 mmol) and 128 (0.21 g, 1.742 mmol) in MeOH/acetone (1.5 mL/2 mL) was cooled down to 0° C. and a solution of potassium-tert-butoxide solution in tert-butanol (1.75 mL, 3.485 mmol) was added drop wise. After the addition was complete the mixture was slowly warmed to RT. After 4 h the solvent was evaporated. The residue was partitioned between DCM and water. A few drops of 1M HCl were added to bring the pH to ca.7. The layers were separated and the aqueous layer was extracted with DCM. The combined extracts were washed with brine, combined, dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography which afforded a partially purified 130a, which was used in the following step without further purification. |
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