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CAS No. : | 4023-02-3 | MDL No. : | MFCD00210087 |
Formula : | C4H7ClN4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RBZRMBCLZMEYEH-UHFFFAOYSA-N |
M.W : | 146.58 | Pubchem ID : | 2734672 |
Synonyms : |
1H-Pyrazole-1-carboximidamide hydrochloride
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 36.75 |
TPSA : | 67.69 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.89 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.43 |
Log Po/w (WLOGP) : | 0.43 |
Log Po/w (MLOGP) : | 0.01 |
Log Po/w (SILICOS-IT) : | -0.72 |
Consensus Log Po/w : | 0.03 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.36 |
Solubility : | 6.33 mg/ml ; 0.0432 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.42 |
Solubility : | 5.59 mg/ml ; 0.0381 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.08 |
Solubility : | 122.0 mg/ml ; 0.83 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.74 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
43% | With hydrogenchloride In 1,4-dioxane for 1 h; Reflux | Pyrazole (1.634 g, 24 mmol) and cyanamide (1 g, 24 mmol) were dissolved in 1,4-dioxane (24 mL), and 4M-HCl (6 mL) dissolved in 1,4- dioxane then stirred under reflux for 1 hour. After completion of the reaction, the reaction product was recrystallized in an ice water bath under the condition of diethyl ether. Yield 43percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In water; acetone at 20℃; | To a solution of di-tert-butyldicarbonate (13.4 g, 61.5 mmol) in acetone (45 mL) were added lH-pyrazole-l-carboxamidine hydrochloride (9.0 g, 61.5 mmol, 1.0 equiv.) and 9.0 mL of water. K2CO3 (4.24 g, 30.6 mmol, 0.5 equiv.) in H20 (12.0 mL) was added dropwise for 30 min at room temperature. After 2 h, another portion of di-tert- butyldicarbonate (1.35 g, 6 mmol, 0.1 equiv.) was added and the solution was stirred overnight. The acetone was removed under reduced pressure and the resulting white solid was dissolved in 30.0 mL of water, and allowed to stir at 0 °C for 30 min. The precipitated tert-butyl (imino(lH-pyrazol-l-yl)methyl)carbamate was collected by filtration, washed with water, washed with hexane, and dried in vacuo to provide the title compound as a colorless solid (11.37 g, 88percent yield). FontWeight="Bold" FontSize="10" H NMR (CDCI3, 400 MHz): δ 9.06 (brs, 1H), 8.45 (d, J= 3.2 Hz, 1H), 7.67 (d, J= 0.8 Hz, 1H), 7.59 (brs, 1H), 6.39 (dd, J = 2.8, 1.6 Hz, 1H), 1.54 (s, 9H). |
74.8% | With dmap; triethylamine In tetrahydrofuran at 20℃; for 20 h; | Step 1: Preparation of tert-butyl (1H-pyrazol-1-ylcarbonoimidoyl)carbamate To a solution of (Boc)2O (61 g, 0.28 mol) in THF (1 L) was added DMAP (17 g, 0.14 mol) and Et3N (42 g, 0.42 mol). After stirring for 30 min, 1H-pyrazole-1-carboximidamide hydrochloride (20 g, 0.14 mol) was added and the mixture was stirred at 20° C. for 20 hrs. The reaction was then concentrated in vacuo and the residue was dissolved in EtOAc (500 mL). The solution was washed with aq. NH4Cl (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc (200 mL) to afford the title compound (22 g, 74.8percent yield) as white solid that was used as-is in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.9% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2.66667 h; | (Example 8)Synthesis of tert-butyl (tert-butoxycarbonyliminopyrazol- 1-yl-methyl)carbamate [compound (H)]Step F-I: N,N-dimethylformamide (350 ml) and N. N- diisopropyl ethylamine (125 ml) were added to tert- butyl( iminopyrazol-1-yl-methyl)carbamate lH-pyrazole-1- <n="80"/>carboxamidine hydrochloride (100 g) , and then a N.N- dimethylformamide (50 ml) solution of ditert-butyl dicarbonate (152 g) was added over 40 minutes at room temperature. After the mixture was stirred for 2 hours at the same temperature, water (500 ml) was added, the mixture was extracted with toluene (500 ml), and organic layer 1 and aqueous layer 1 were separated. Organic layer 1 was further washed twice with water (300 ml), and organic layer 2 was separated. Aqueous layer 1 was extracted with toluene (500 ml), and organic layer 3 was separated. Organic layer 2 and organic layer 3 were combined, and the solvent was distilled off under reduced pressure until the amount of the solution became approximately 300 ml. Hexane (500 ml) was added to the resulting solution at room temperature, the mixture was stirred for 30 minutes, followed by stirring for 30 minutes under ice-cooling, and then crystals were filtered. The crystals were washed with hexane (100 ml), and then dried under reduced pressure to give the title compound (120.3 g. 83.9percent yield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In water; acetone; at 20℃; | To a solution of di-tert-butyldicarbonate (13.4 g, 61.5 mmol) in acetone (45 mL) were added lH-pyrazole-l-carboxamidine hydrochloride (9.0 g, 61.5 mmol, 1.0 equiv.) and 9.0 mL of water. K2CO3 (4.24 g, 30.6 mmol, 0.5 equiv.) in H20 (12.0 mL) was added dropwise for 30 min at room temperature. After 2 h, another portion of di-tert- butyldicarbonate (1.35 g, 6 mmol, 0.1 equiv.) was added and the solution was stirred overnight. The acetone was removed under reduced pressure and the resulting white solid was dissolved in 30.0 mL of water, and allowed to stir at 0 C for 30 min. The precipitated tert-butyl (imino(lH-pyrazol-l-yl)methyl)carbamate was collected by filtration, washed with water, washed with hexane, and dried in vacuo to provide the title compound as a colorless solid (11.37 g, 88% yield). FontWeight="Bold" FontSize="10" H NMR (CDCI3, 400 MHz): delta 9.06 (brs, 1H), 8.45 (d, J= 3.2 Hz, 1H), 7.67 (d, J= 0.8 Hz, 1H), 7.59 (brs, 1H), 6.39 (dd, J = 2.8, 1.6 Hz, 1H), 1.54 (s, 9H). |
74.8% | With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 20h; | Step 1: Preparation of tert-butyl (1H-pyrazol-1-ylcarbonoimidoyl)carbamate To a solution of (Boc)2O (61 g, 0.28 mol) in THF (1 L) was added DMAP (17 g, 0.14 mol) and Et3N (42 g, 0.42 mol). After stirring for 30 min, 1H-pyrazole-1-carboximidamide hydrochloride (20 g, 0.14 mol) was added and the mixture was stirred at 20 C. for 20 hrs. The reaction was then concentrated in vacuo and the residue was dissolved in EtOAc (500 mL). The solution was washed with aq. NH4Cl (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc (200 mL) to afford the title compound (22 g, 74.8% yield) as white solid that was used as-is in the next step. |
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; ethyl acetate; | Step 1 Manufacture of N-tert-butoxycarbonyl-pyrazole-1-carboxamidine To a solution of di-tert-butyl dicarbonate (7.43 g, 33 mmol) in 100 ml dichloromethane 11.3 ml of N,N-diisopropylethylamine (66 mmol) and 4.40 g of 1H-pyrazole-1-carboxamidine hydrochloride (30 mmol) were added. The solution was agitated for 3 h at room temperature and then evaporated to dryness. The obtained white solid was dissolved in 200 ml ethylacetate, the organic phase was washed with 5 % (w/w) sodium hydrogen carbonate, dried over magnesium sulfate and finally evaporated to dryness. The residue was dissolved in boiling hexane. The solution was allowed to stand at room temperature over night and then at 4C for 24 hours. The crystals thus formed were recovered by filtration and washed in cold hexane (0C). After drying, 5.28 g of white crystals were obtained (25 mmol yield=84 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In neat (no solvent) at 25℃; for 1.5h; Sonication; | 4.2. General procedure of ultrasound-assisted guanylation ofamines with 1H-pyrazole-1-carboxamidine hydrochloride General procedure: In a cylindrical reaction ask with a at bottom, the amine(1.0 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride(1.05 mmol) were placed. The mixture was subjected to ultrasound in a 36.6 or 480 kHz thermo-controlled ultrasonic bath. Control experiments without ultrasound irradiation were carried out with magnetic stirring of ca. 840 rpm. After the reaction, the mixture was dissolved in ethanol (1/1 (v/v), 5 mL). The resultant ethanolic solution was subjected to GC analysis to estimate the yield of the guanidine. |
90% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | |
86% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 26h; |
84% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 4h; Ambient temperature; | |
80% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | General procedure. General procedure: Subsituted guanidines were prepared according to the literatureprocedure.1 To a stirred solution of 1H-pyrazole-1-carboxamidine hydrochloride (1.00 g; 6.8mmol; 1.00 equiv.) and DIPEA (1.24 mL; 7.2 mmol; 1.05 equiv.) in MeCN (25 mL),benzylamine (782 μL; 7.2 mmol; 1.05 equiv.) was added. The reaction mixture was stirred atambient temperature overnight and precipitated solid filtered and washed with MeCN andEt2O to obtain pure product 4c as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 6h; | 1.1d Id: Preparation of tert-butyl (3J?)-3-[(Z)-amino(imino)methyl]ammo}piperidme-l- carboxylate hydrochloride To a mixture of tert-btyl (5i?)-3-ammopiperidine-l -carboxylate (10 g, 49.9 mmol) and pyrazole carboxamidine hydrochloride (7.31 g, 49.9 mmol) was added Hunig's base (8.72 ml, 49.9 mmol) and DMF (30 ml). The reaction was heated at 70° C for 18 hours. The reaction was then cooled to room temperature and quenched by adding 700 ml of diethyl ether and stirring at room temperature for 24 hours. Product separated out as a white solid, which was filtered, washed, and dried (13 g, 94%). 400 MHz 1H NMR (DMSO-dβ) δ: 7.67 (d, J= 8.8 HZ, IH), 6.9-7.6 (br. s, 4H), 3.55 (br.s, 2H), 2.8-3.6 (m, 4H), 2.8-2.9 (m, IH), 1.6-1.7 (m, IH), 1.39 (s, 9H), 1.2-1.3 (m, IH). LCMS: 243 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 6h; | 3.3e 3e: Preparation of tert-butyl 4-[amino(imino)methyl]amino}piperidine-l-carboxylate hydrochlorideTo a mixture of tert-butyl 4-aminopiperidine-l-carboxylate (8.93 g, 44.6 mmol) and pyrazole carbox-amidine hydrochloride ( 6.536 g, 44.6 mmol) was added Hunig's base (7.77 ml, 44.6 mmol) and DMF (25 ml). The reaction was heated at 60° C for 15 hours. The reaction was then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separated out as a white solid, which was filtered, washed and dried (10.9 g, 88%). M.p. = 169-172° C; 400 MHz 1H NMR (DMSO-dβ) δ: 8.09 (d, J= 8.8 HZ, IH), 6.9-7.9 (br. s, 3H), 3.83 (d, /= 13.6 Hz, 2H), 3.63 (m, IH), 2.88 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 1.25 (m, 2H); LCMS: 243 [M+H]; calc. for CnH22N4O2- 1.06 HCl 0.2 H2O: C 46.39, H 8.31, N 19.68; found C 46.43, H 8.31, N 20.68. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 6h; | E38.1 To a solution of spiro[naphtha[1,2-b][1,4]oxathiine-2,4'-piperidine]-5,6-dione (0.500 g, 1.66 mmol) in dimethylformamide (10 mL) was treated with pyrazole carboxamide hydrochloride (0.243 g, 1.66 mmol) and diisopropylethylamine (0.289 mL, 1.66 mmol). The reaction was heated at 60° C. for 6 hours, then cooled to room temperature. The reaction mixture was diluted with ether (100 mL) and vigorously stirred for one hour. The supernatant was decanted, more ether was added. This process was repeated until a solid was formed. The solid was collected, washed with ether, and dried under high vacuum to give a purple solid (0.503 g, 88%). M.p.=262-264° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.87 (m, 2H), 7.73 (t, J=7.6 Hz, 1H), 7.67 (br. s, 3H), 7.56 (t, 1H), 3.87 (d, J=13.6 Hz, 2H), 3.38 (m, 2H), 3.34 (s, 2H), 2.06 (d, J=13.6 Hz, 2H), 1.85 (m, 2H); LCMS: 344 [M+H]. |
88% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 6h; | E38.1 E38.1. Synthesis of 5.6-dioxo-5 ,6-dihvdro-lη-spiroriiaρhtho[ 1 ,2-bl [1 ,41oxathiine-2,4'-piperidine1- 1 '- carboximidamidinium chloride (Compound 254)To a solution of spiro[naphtha[l,2-δ][l,4]oxathiine-2,4'-piperidine]-5,6-dione (0.500 g, 1.66 mmol) in dimetliylformamide (10 mL) was treated with pyrazole carboxamidine hydrochloride (0.243 g, 1.66 mmol) and diisopropylethylamine (0.289 mL, 1.66 mmol). The reaction was heated at 60 0C for 6 hours, then cooled to room temperature. The reaction mixture was diluted with ether (100 mL) and vigorously stirred for one hour. The supernatant was decanted, more ether was added. This process was repeated until a solid was formed. The solid was collected, washed with ether, and dried under high vacuum to give a purple solid (0.503 g, 88 %). M.p. = 262-2640C; 400 MHz 1H NMR (DMSOd6) δ: 7.87 (m, 2H), 7.73 (t, J= 7.6 Hz, IH), 7.67 (br. s, 3H), 7.56 (t, IH), 3.87 (d, /= 13.6 Hz, 2H), 3.38 (m, 2H), 3.34 (s, 2H), 2.06 (d, J = 13.6 Hz, 2H), 1.85 (m, 2H); LCMS: 344 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In acetonitrile at 70℃; for 4h; | 7 Method 7Methyl (1 S,3R)-3-carbamimidamidocyclopentane-l-carboxylateMethyl (IS, 3R)-3-aminocyclopentane-l-carboxylate hydrochloride (Method 6; 1.29 g, 7.18 mmol) was dissolved in acetonitrile (35 ml) and treated with triethylamine (3.0 ml, 21.52 mmol). lH-Pyrazole-1-carboxamidine hydrochloride (2.1 g, 14.33 mmol) was added and the reaction mixture heated at 70C (internal temperature) for 4 hrs. The reaction mixture was allowed to cool overnight and then evaporated to a yellow viscous oil, which was treated with sat. aq. NaHCO3 (-50 ml). The mixture was shaken before standing for 30-40 mins. The resultant precipitate produced was collected by suction filtration, washed with water and dried under suction for 2 hrs, before being transferred to a vacuum oven and dried under vacuum, at 550C, for 3 hrs to give the title compound as a white solid (1.61 g, 100%). NMR (400.132 MHz,) 1.44 - 1.62 (m, 2H), 1.81 - 1.98 (m, 3H), 2.26 (m, IH), 2.80 (m, IH), 3.61 (s, 3H), 3.82 (m, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Pyrazole-1-carboximidamide hydrochloride (739mg, 5.04 mmol) was added to a stirred solution of tert-butyl 3-aminoazepane-l -carboxylate (541 mg, 2.52 mmoi) and triethylamine (0.7 ml, 5.04 mmol) in acetonitrile (15 ml). The mixture was heated at reflux for 3.5 hrs then cooled to ambient temperature, filtered and washed with acetonitrile and dried under high-vacuum to give the title compound as a colourless solid (179 mg, 28%). The <n="116"/>acetonitrile filtrate was evaporated in vacuo, the gum obtained was dissolved in DCM and sat. aq. sodium bicarbonate was added and the mixture was left to stand at ambient temperature for 16 hrs. The precipitated solid was filtered and dried in vacuo to give additional title compound as a colourless solid (192 mg, 30%). NMR (400.132 MHz) 1.41 (m, 9H), 1.68 (m, 3H), 3.37 (m, 8H), 7.81 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine at 20 - 100℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 26h; | |
85% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | General procedure. General procedure: Subsituted guanidines were prepared according to the literatureprocedure.1 To a stirred solution of 1H-pyrazole-1-carboxamidine hydrochloride (1.00 g; 6.8mmol; 1.00 equiv.) and DIPEA (1.24 mL; 7.2 mmol; 1.05 equiv.) in MeCN (25 mL),benzylamine (782 μL; 7.2 mmol; 1.05 equiv.) was added. The reaction mixture was stirred atambient temperature overnight and precipitated solid filtered and washed with MeCN andEt2O to obtain pure product 4c as an off-white solid. |
82% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; |
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | ||
With triethylamine In acetonitrile at 60℃; | 8.2 Step 2: Preparation of compound 8 General procedure: 1 -benzylguanidine HCl 10 (0.1 g, 0.68 mmol) was dissolved in MeCN (5 M), benzylamine derivative 9 (0.58 mmol) and Et3N (0.07 mL, 0.69 mmol) followed by stirring at 60 °C. After completion of the reaction, the reaction product was recrystallized under diethyl ether to give the product. Yield 50-73%. | |
With triethylamine In acetonitrile at 60℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 2h; | 197 Example 197 [00682] AMD7074: Preparation of 1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]guanidine (hydrobromide salt). A heterogeneous mixture of the amine (140 mg, 0.385 mmol), 1H-pyrazole-1-carboxanidine hydrochloride (55 mg, 0.38 mmol), and DIEA (0.067 mL, 0.38 mmol) in THF (0.19 mL) was stirred at room temperature under nitrogen atmosphere for 2 hours. Diethyl ether (5 mL) was added to the mixture, then decanted (4×) to give a colourless oil that was dried in vacuo at room temperature to give the corresponding guanidine hydrochloride salt (170 mg, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; | 19.d d) Preparation of 3-(t-butyldimethylsiloxy)-N-(N-carboxamidino-3-aminopropyl)-7α-(1-hydroxy-1-methylethyl)-6,14-endo-ethenotetrahydronororipavine Ref: Michael S. Bernatowicz, Youling Wu and Gary R. Matsueda, Journal of Organic Chemistry, 1992 57 2497-2502 To a mixture of 3-(t-butyldimethylsiloxy)-N-(3-aminopropyl)-7α-(1-hydroxy-1-methylethyl)-6,14-endo-ethenotetrahydronororipavine (0.196 g, 0.37 mmol), diisopropylethylamine (0.065 ml, 0.37 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (0.055 g, 0.37 mmol) was added anhydrous dimethylformamide (2 ml), and the reaction mixture was stirred at room temperature under nitrogen for overnight.. The reaction mixture was evaporated to dryness under reduced pressure, and the crude product was chromatographed on silica gel. (Yield=0.191 g, 88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | |
100% | With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; | 1.A A. To a mixture OF PYRAZOLE-1-CARBOXYIMIDINE (1.46 g, 10 MMOL), benzylmethylamine (1.21 g, 10 mmol), and N,N-diisopropylethylamine (1.74 mL, 10 mmol) was added DMF (5 mL). The reaction mixture was stirred at room temperature overnight. Ether (50 mL) was added, and the product which became an oil was at the bottom of the flask. The mixture was sonicated and the top ether layer was decanted. This process was repeated several times until the product solidified. The solid was dried under high vacuum overnight to provide the title compound (2.0 g, 100%) as a white solid. MS (ES+) m/z (M+H) += 164. 33. 1H NMR (400 MHz, CD30D) : 8 2. 91 (s, 3H), 4. 51 (s, 2H), 7. 24 (m, 5H). HPLC: Retention time = 0.79 min (Method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In ethanol for 3h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In water for 1h; | 6; 29.2 To a solution of methyl 44aminomethyl) benzoate hydrochloride (5 g) in dry ethanol (25 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride (4.4 g) followed by DIPEA (13.0 mL) and the mixture was refluxed for 3 h. Ethanol was removed under vacuum. To the remaining viscous oil saturated solution of NaHC03 (50 mL) was slowly added under vigorous stirring followed by addition of 300 ml water (resultant pH 9). A white solid is formed and stirring was continued for lh. This material was filtered off, washed with water (200 mL) and tert-butyl methyl ether (50 mL), and dried to give the title compound 24 as a white powder (4.7 g, 91%).'H NMR (400 MHz, DMSO-d6) 8 (ppm): 7.91 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.39 (s, 2H), 3.83 (s, 3H), 3.80-2. 80 [m, 4H + 2H20 (determined by elemental analysis]). |
77% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | |
77% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 4h; Stage #2: With sodium hydrogencarbonate In water | 7.2 Step 2: Methyl (4-GUANIDINOMETHYL) benzoate; (40) [0204] To a stirred suspension of methyl 4-aminomethyl-benzoate hydrochloride (39,15. 7 g, 77.8 MMOL) and DIISOPROPYLETHYLAMINE (29.5 ML, 171.2 MMOL) in DMF (85.6 ml) at room temperature under nitrogen was added PYRAZOLE-L-CARBOXAMIDINE HYDROCHLORIDE (12.55 g, 85.6 MMOL). After 4 h the reaction mixture as a clear solution was concentrated to dryness under vacuum and saturated aqueous solution of NAHC03 (35 ml) was added to give a suspension. The solid was separated by filtration and washed with cold water. The mother liquor was concentrated to produce additional amount of a solid material which was also collected by filtration. Both solids were combined, triturated with H20 (50 ml), filtered off, washed with cold H20 and diethyl ether, and dried to afford the title compound 40 (12.32 g, 77% yield) as a white crystalline solid. 1H NMR: (400 MHz, DMSO-d6) 5 (ppm): 9.20-8. 00 (m, 4H), AB system (8 A = 7.91, DB = 7. 39, JAB = 8. 2 Hz, 4H), 4.39 (bs, 2H), 3.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one | 2.B Step B Step B Cyclization and Oxidation to the Pyrimidine Nucleus The product from Step A (100 mg, 0.052 mmol) was combined with 0.26 mmol of the pyrazole carboxamidine hydrochloride and 0.13 mmol NaHCO3 in 1 ml N-methylpyrrolidinone. The reaction mixture was shaken at 70° C. for 24 hours. Following cooling, the reaction was washed successively with water, methanol, DMF, methylene chloride and ether, then dried. Cleavage of a small amount of resin indicated that the desired dihydropyrimidine was present in high yield. The dried resin was then taken up in THF and 1.1 eq. of dicyanodichloroquinone (DDQ) was added. The resulting slurry was stirred for 0.5 hours at which time the resin was washed with DMF, 10% Na2HCO3, H2O, dimethylformamide (DMF), methanol (MeOH), methylene chloride and ether, then dried. Cleavage of a small amount of this resin with trifluoroacetic acid/methylene chloride indicated the presence of a pyrimidine in high yield. | |
With sodium hydrogencarbonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one | 2.B Step B Step B Cyclization and Oxidation to the Pyrimidine Nucleus The product from Step A (100 mg, 0.052 mmol), shown as compound 2 in FIG. 2, was combined with 0.26 mmol of the pyrazole carboxamidine hydrochloride and 0.13 mmol NaHCO3 in 1 ml N-methylpyrrolidinone. The reaction mixture was shaken at 70° C. for 24 hours. Following cooling, the reaction was washed successively with water, methanol, DMF, methylene chloride and ether, then dried. Cleavage of a small amount of resin indicated that the desired dihydropyrimidine, compound 3 in FIG. 2, was present in high yield. The dried resin was then taken up in THF and 1.1 eq of dicyanodicloroquinone (DDQ) was added. The resulting slurry was stirred for 0.5 hours at which time the resin was washed with DMF, 10% Na2HCO3, H2O, dimethylformamide (DMF), methanol (MeOH), methylene chloride and ether, then dried. Cleavage of a small amount of this resin with trifluoroacetic acid/methylene chloride indicated the presence of a pyrimidine in high yield, shown as compound 4 in FIG. 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile; | IIb present. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | 4.1.8 (2-(5-(4-Bromobenzyl)-1-(4-methoxybenzyl)-1,4,5,6-tetrahydro-4,6-dioxo-1,3,5-triazin-2-ylamino)ethyl)guanidine (11) [PC-25] General procedure: To a solution of intermediate ( 36) (0.17g, 0.37mmol) in CH3CN (10mL) at room temperature, DIPEA (0.13mL, 0.75mmol) and pirazole-1-carboxamidine hydrochloride (0.05g, 0.37mmol) were added. The reaction mixture was stirred for 12h at room temperature. The white solid formed was collected by centrifugation and washed twice with ethyl ether (2×10mL). The crude final compound was purified by reversed phase preparative HPLC. Yield 0.17g (93%) |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | ||
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | 2.G N-{2-[5-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine (Cpd 17). A crude mixture of Cpd 2e (390 mg, 0.98 mmol) was dissolved in acetonitrile (10 mL) and was treated with pyrazole-1-carboxamidine hydrochloride (143 mg, 0.98 mmol) and diisopropylethylamine (0.340 mL, 1.95 mmol). The reaction was allowed to proceed overnight at room temperature. Inspection of the reaction mixture showed that a white precipitate had formed and the precipitate was collected and dried by vacuum filtration. The solid collected afforded 307 mg of Cpd 17 as a white powder. M+ (ES+)=442.3. 1H NMR (DMSO, d6). δ 3.33 (m, 4H), 3.73 (s, 3H), 4.89 (s, 2H), 5.04 (s, 2H), 6.89-6.91 (d, 2H, J=8.66 Hz), 7.10-7.16 (t, 2H, J=8.91 Hz), 7.21-7.24 (d, 2H, J=8.63 Hz), 7.32-7.36 (dd, 2H, J=2.90, 5.57 Hz), 7.66 (s, 1H), 8.19 (s, 1H). |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | 2.G G. iV-{2-[5-(4-Fluoro-benzy])-l-(4-methoxy-benzyl)-4,6-dioxo-l,4,5,6- tetrahydro-[l,3,5]triazin-2-ylamino]-ethyl}-guanidine (Cpd 17). A crude mixture of Cpd 2e (390 mg, 0.98 mmol) was dissolved in acetonitrile (10 mL) and was treated with pyrazole-1-carboxamidine hydrochloride (143 mg, 0.98 mmol) and diisopropylethylamine (0.340 mL, 1.95 mmol). The reaction was allowed to proceed overnight at room temperature. Inspection of the reaction mixture showed that a white precipitate had formed and the precipitate was collected and dried by vacuum filtration . The solid collected afforded 307 mg of Cpd 17 as a white powder. M+ (ES+) = 442.3. 1H NMR (DMSO, J6). δ 3.33 (m, 4H), 3.73 (s, 3H), 4.89 (s, 2H), 5.04 (s, 2H), 6.89 - 6.91 (d, 2H, J= 8.66 Hz), 7.10 - 7.16 (t, 2H, J = 8.91 Hz), 7.21 - 7.24 (d, 2H, /= 8.63 Hz), 7.32 - 7.36 (dd, 2H, J = 2.90, 5.57 Hz), 7.66 (s, IH), 8.19 (s, IH). | |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | 2.G A crude mixture of Cpd 2e (390 mg, 0.98 mmol) was dissolved in acetonitrile (10 ml_) and was treated with pyrazole-1-carboxamidine hydrochloride (143 mg, 0.98 mmol) and diisopropyiethylamine (0.340 ml_, 1.95 mmol). The reaction was allowed to proceed overnight at room temperature. Inspection of the reaction mixture showed that a white precipitate had formed and the precipitate was collected and dried by vacuum filtration . The solid collected afforded 307 mg of Cpd 17 as a white powder. M+ (ES+) = 442.3. 1H NMR (DMSO, ofe). δ 3.33 (m, 4H), 3.73 (s, 3H), 4.89 (s, 2H), 5.04 EPO (s, 2H), 6.89-6.91 (d, 2H, J = 8.66 Hz), 7.10-7.16 (t, 2H, J = 8.91 Hz), 7.21-7.24 (d, 2H, J= 8.63 Hz), 7.32-7.36 (dd, 2H, J= 2.90, 5.57 Hz), 7.66 (s, 1H), 8.19 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3(c) Preparation of (endo)-N-(8-methyl-8-azabicyclo[3.2. l]oct-3-yl)guanidine hydrochloride; Prepared as described in example 3(a) with the addition of 1 mole equivalent of HCl to the diethyl ether quench prior to stirring.M.p. = 240-244 C; 300 MHz 1H NMR (DMSO-d6) delta: 10.98 (br. s, 1H), 8.31 (d, J= 6.3Hz, 1H), 7.51 (br. s, 3H), 3.76 (m, 3H), 2.6 (m, 5H), 2.4 (m, 2H), 2.2 (m, 2H), 1.85 (d, J = 15.4 Hz, 2H); LCMS: 183 [M+H]. CaIc. for C9H18N4 2 HCl: C 42.32, H 7.90, N 21.95; found C 39.78, H 7.91, N 22.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 18h; | 39.39d 39d: Preparation of tert-butyl (3 R)-3-[(Z)-amino(imino)methyl]amino}piperidine-1- carboxylate hydrochloride; To a mixture of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (10 g, 49.9 mmol) and pyrazole carboxamidine hydrochloride (7.31 g, 49.9 mmol) is added Hunig's base (8.72 ml, 49.9 mmol) and DMF (30 ml). The reaction is heated at 70° C for 18 hours. The reaction is then cooled to room temperature and quenched by adding 700 ml of diethyl ether and stirring at room temperature for 24 hours. Product separates out as a white solid, which is filtered, washed, and dried (13 g, 94%). 400 MHz 1H NMR(DMSO-d6) δ: 7.67 (d, J= 8.8 HZ, 1H), 6.9-7.6 (br. s, 4H), 3.55 (br.s, 2H), 2.8-3.6 (m,4H), 2.8-2.9 (m, 1H), 1.6-1.7 (m, 1H), 1.39 (s, 9H), 1.2-1.3 (m, 1H). LCMS: 243 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; | 16 To a solution of 4-(fluorophenyl)piperazine (100 mg, 0.56 mmol) and diisopropylethylamine (106 μL, 0.61 mmol) in ACN (2 mL) was added lH-pyrazole- 1-carboximidamide hydrochloride (89 mg, 0.61 mmol). The reaction stirred at room temperature overnight. A precipitate formed, which was collected via filtration and washed with ACN to obtain 4-(4-fluorophenyl)piperazine-l-carboximidamide as a white solid (119 mg, 97% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.77 (br s, 3H), 7.10-6.97 (m, 4H), 3.60 (dd, 4H, J =5.3, 4.7 Hz), 3.14 (dd, 4H, J =5.4, 4.7 Hz); 13CNMR (75.5 MHz, DMSO-d6): δ 157.9 (154.8), 156.3, 147.2, 118.0, 115.5 (115.2), 4 488..33,, 4444..77;; 1199FF NNMMRR ((228822..44 MMHHzz,, DDMMSSOO--dd66)):: δδ - -124.70-124.78 (m, IF); HRMS calcd for CnH15FN4: 223.13535 found 223.1353. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.9% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2.66667h;Product distribution / selectivity; | (Example 8)Synthesis of tert-butyl (tert-butoxycarbonyliminopyrazol- 1-yl-methyl)carbamate [compound (H)]Step F-I: N,N-dimethylformamide (350 ml) and N. N- diisopropyl ethylamine (125 ml) were added to tert- butyl( iminopyrazol-1-yl-methyl)carbamate lH-pyrazole-1- <n="80"/>carboxamidine hydrochloride (100 g) , and then a N.N- dimethylformamide (50 ml) solution of ditert-butyl dicarbonate (152 g) was added over 40 minutes at room temperature. After the mixture was stirred for 2 hours at the same temperature, water (500 ml) was added, the mixture was extracted with toluene (500 ml), and organic layer 1 and aqueous layer 1 were separated. Organic layer 1 was further washed twice with water (300 ml), and organic layer 2 was separated. Aqueous layer 1 was extracted with toluene (500 ml), and organic layer 3 was separated. Organic layer 2 and organic layer 3 were combined, and the solvent was distilled off under reduced pressure until the amount of the solution became approximately 300 ml. Hexane (500 ml) was added to the resulting solution at room temperature, the mixture was stirred for 30 minutes, followed by stirring for 30 minutes under ice-cooling, and then crystals were filtered. The crystals were washed with hexane (100 ml), and then dried under reduced pressure to give the title compound (120.3 g. 83.9% yield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; | |
82% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 0.166667h; | 3.1 Step 1; N-Benzyloxycarbonyl-1H-pyrrazole-1-carboxamidine; A solution of 1H-prazole-1-carboxamide hydrochloride (25.0 g, 170.55 mmol) and N,N-diisopropylethylamine (62.5 mL, 359 mmol) in 100 mL methylene chloride was cooled to 0° C. in an ice bath and stirred under nitrogen. To this reaction mixture was added benzyl chloroformate (26.34 mL, 170.55 mmol) in portions. The ice bath was removed, and the reaction mixture was stirred for 10 minutes. Methylene chloride (350 mL) was added, and the organic phase was washed successively with water, 5% aqueous KHSO4, water, and brine. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give 34.4 g (82%) of N-benzyloxycarbonyl-1H-pyrrazole-1-carboxamidine, which was used directly in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In water; at 20℃; for 48h; | 6A-Deoxy-6A-amino-beta-CDs (250 mg), 1H-pyazole carboxamidine hydrochloride (500 g), and N,N-diisopropylethylamine (2.0 mL) were mixed in water (2 mL) and the solution was stirred at room temperature for 48 h and then poured into acetone. The precipitate collected were dissolved in water (2 mL), and the aqueous solution was re-precipitatedby pouring into acetone to form a white precipitate. This dissolution precipitation process was repeated for another two times to afford compound 11 as a pale white solid. Yield:85percent 1H NMR (400 MHz, D2O)delta 5.17-5.04 (m, 7 H), 3.98 (dd, J=17.4, 8.0 Hz, 9 H), 3.87 (d,J=12.1 Hz, 12 H), 3.70- 3.54 (m, 14 H). 13C NMR (101 MHz, DMSOd6)delta 157.68, 157.64, 101.84, 101.71, 101.63, 101.44, 101.42, 101.41,97.32, 88.66, 87.72, 82.39, 82.30, 82.29, 82.27, 82.26, 81.03, 72.94,72.91, 72.86, 72.81, 72.61, 71.91, 71.75, 71.71, 71.68, 71.61, 70.40,70.38, 60.18, 42.08, 42.06, 42.05, 42.03, 42.01, 39.53. HR-MS: m/zcalcd for [M+H]+: 1176.4154, found: 1176.4155. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 5 - 20℃; Inert atmosphere; | 55 To a stirred solution of 14e (218 mg, 0.67 mmol) and lH-pyrazole-1-carboxamidine hydrochloride50 (196 mg, 1.34 mmol) in anhydrous DMF (5 mL) was added DIEA (479 mg, 0.65 mL, 3.7 mmol) under nitrogen at 50C. Stirring was continued at room temperature overnight. The reaction mixture was concentrated to dryness and the product was purified by column chromatography (silica gel 230- 400 mesh, elution with 4:1 :0.3 chlorofornrmethanoLNFLtOH). The desired fractions were combined, concentrated, and dried in vacuo to give a white solid: yield 219 mg (89%), MS: m/z 366 (M+H)+; 1HNMR (DMSO-d6) δ 8.34 (s, IH, H-8), 8.15 (s, IH, H-2), 7.48, 7.37, 7.28 (bs, NHs), 5.87 (d, IH, H-I', Jr>2.= 5.2 Hz), 5.50 (d, IH, 2'-OH, J2.-2H = 5.7 Hz), 5.28 (d, IH, 3'- OH, J3 -3 OH = 4.5 Hz), 4.65 (ddd, IH, H-2', Jr,2. = 5.2 Hz, J2,3. = 5.1 Hz, J2 -2OH = 5.7 Hz), 4.12 (ddd, IH, H-3', J2 >3.= 5.1 Hz, J3vr= 4.6 Hz, J3 -3OH = 4.5 Hz), 4.0-4.10 (bm, IH, H-4'), 3.30-3.50 (bm, 2H, 5'-CH2), 3.12-3.28 (bm, 2H, NH-CH2), 2.55-2.65 (bm, 2η, N(Cη3)-CH2), 2.25 (bs, 3η, N-CH3); UV λmax. nn^ pH 1, 256.3 (ε 10,900), pH 7, 259 (ε 11,300), pH 13, 259 (ε 11,000). Anal. (CI4H23N9O3-O-OSCHCI3J -SH2O) C, H, N. |
89% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 5 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | |
45% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 1 step 1 To a stirred solution of pyrazole-l-carboximidamide hydrochloride (48.00 g, 327.47 mmol) and [(4-methoxyphenyl)methyl](methyl)amine (49.52 g, 327.47 mmol) in DMF (480 mL) was added DIEA (44.44 g, 343.84 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature. Et20 (500 mL) was added, and the desired product beacame an oil at the bottom of the flask. The mixture was sonicated and the top ether layer was decanted. This process was repeated several times until the desired product solidified. The solid was dried under high vacuum to afford Af- [(4-m eth ox ypti en y 1 )m eth y 1 ] - A - methylguanidine hydrochloride (37.3g, 45%) as an off-white solid. MS ESI calculated for CioHieCINsO [M + H -HC1]+, 194.12, found 194.10. H NMR (400 MHz, CD OD) d 7.24- 7.21 (m, 2H), 7.02-7.21 (m, 2H), 4.56 (s, 2H), 3.81 (s, 3H), 2.99 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.25% | Stage #1: 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 0.333333h; Stage #2: diethyl 2-ethoxymethylenemalonate In ethanol Reflux; | 1 Example 1 Ethyl 4-hydroxy-2-pyrazol-1-ylpyrimidine-5-carboxylate (2) Pyrazole-1-carboximidamide hydrochloride(1eq)And N,N-diisopropylethylamine (2.2 eq) was added to 5 volumes of ethanol,Stir at room temperature for 20 min,Diethyl ethoxymethylidene malonate (1 eq) was added and the mixture was warmed to reflux and allowed to react overnight.After the reaction was completed, about half of the volume of ethanol was distilled off under reduced pressure, and the mixture was extracted twice with water and ethyl acetate.Adjust the pH of the water layer to 3-4, precipitate a large amount of white insoluble matter, and filter.After drying, 2 white powders were obtained.The yield was about 90.25%. |
88.3% | With triethylamine In ethanol at 20℃; Reflux; | 4.1.2. Synthesis of ethyl 4-hydroxy-2-pyrazol-1-yl-pyrimidine-5-carboxylate (3) A solution of 100.0 g 2 (0.68 mol,1 eq) and 207.1 g TEA (2.04 mol,3 eq) in ethanol (500 mL)was stirred at room temperature for 0.5 h.147.5 g EMME (0.68 mol, 1 eq) was added and then heated to refluxuntil no 2 appeared on TLC. The mixture was cooled to roomtemperature, and then evaporated about half the volume of ethanolunder reduced pressure. The residue was extracted by 500 mLwater and 600mL ethyl acetate. The organic layer was washed with150 mL water twice, The aqueous extracts were combined andadjusted to pH 3e4 with stirring for 0.5 h. The precipitate was filtratedand washed with water (100 mL 2), then dried in vacuumto get 141.1 g 3 as a white powder with a yield of 88.3%. m.p.162.8e163.8 C; ESI-MS (m/z): 235.08 [MH]; 1H NMR (300 MHz,DMSO-d6) d 13.28 (br s, 1H), 8.59 (m, 2H), 7.96 (dd, J1 0.6 Hz,J2 1.5 Hz, 1H), 6.67 (dd, J1 1.5 Hz, J2 2.7 Hz, 1H), 4.26 (q,J 7.1 Hz, 2H), 1.29 (t, J 7.1 Hz, 3H). |
88.3% | With triethylamine In ethanol at 20℃; Reflux; | 4.1.2. Synthesis of ethyl 4-hydroxy-2-pyrazol-1-yl-pyrimidine-5-carboxylate (3) A solution of 100.0 g 2 (0.68 mol,1 eq) and 207.1 g TEA (2.04 mol,3 eq) in ethanol (500 mL)was stirred at room temperature for 0.5 h.147.5 g EMME (0.68 mol, 1 eq) was added and then heated to refluxuntil no 2 appeared on TLC. The mixture was cooled to roomtemperature, and then evaporated about half the volume of ethanolunder reduced pressure. The residue was extracted by 500 mLwater and 600mL ethyl acetate. The organic layer was washed with150 mL water twice, The aqueous extracts were combined andadjusted to pH 3e4 with stirring for 0.5 h. The precipitate was filtratedand washed with water (100 mL 2), then dried in vacuumto get 141.1 g 3 as a white powder with a yield of 88.3%. m.p.162.8e163.8 C; ESI-MS (m/z): 235.08 [MH]; 1H NMR (300 MHz,DMSO-d6) d 13.28 (br s, 1H), 8.59 (m, 2H), 7.96 (dd, J1 0.6 Hz,J2 1.5 Hz, 1H), 6.67 (dd, J1 1.5 Hz, J2 2.7 Hz, 1H), 4.26 (q,J 7.1 Hz, 2H), 1.29 (t, J 7.1 Hz, 3H). |
60% | With sodium methylate In ethanol at 75℃; for 0.666667h; | 3-e.A Intermediate 3-eStep A: Ethyl 4-hvdroxy-2-(lH-pyrazol-l-yl)pyrimidine-5-carboxylate (3-a) lH-pyrazole-l-carboximidamide hydrochloride, compound 2-a from Example 2, (22.11 g, 0.15mol) in EtOH (250ml) was added sodium methoxide (12.3g, 0.23mol) and diethylethoxymethylenemalonate, compound 2-b from Example 2, (30ml, 0.15mol). The reaction was heated for about 40 min at 75 °C and then cooled to room temperature. The mixture was filtered and the solid was washed with ethanol and ether and dried under vacuum to give compound 3-a (21g, 60%). :H NMR (DMSO-d6, 300ΜΗζ,):δ 8.50(m, 2H), 7.70(s, 1H), 6.47(m, 1H), 4.13(m, 2H), 1.24(m, 3H). |
60% | With sodium methylate In ethanol at 75℃; for 0.666667h; | 3-e.A Step A: Ethvl 4-hvdrorv-2 1H-Dvrazol-l-vnDvrimidine-5-carboxvlate (3-a¾1 H-pyrazole- 1 -carboximidamide hydrochloride, compound 2-a from Example 2, (22.11 g, O.lSmol) in EtOH (250ml) was added sodium methoxide (12.3g, 0.23mol) and diethylethoxymethylenemalonate, compound 2-b from Example 2, (30ml, 0.1 Smol). The reaction was heated for about 40 min at 75 °C and then cooled to room temperature. The mixture was filtered and the solid was washed with ethanol and ether and dried under vacuum to give compound 3-a (21 g, 60%). .H NMR (DMSO-d6, 300ΜΗζ,):δ 8.50(m, 2H), 7.70(s, 1H), 6.47(m, 1H), 4.13(m, 2H), 1.24(m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: C15H25F8NO5; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 264h; Inert atmosphere; Stage #2: trifluoroacetic acid | 6.8.1. 9b General procedure: To a solution of compound 7b (161.6 mg, 0.4 mmol) in DMF (0.4 mL), Hünig's base (0.14 mL, 0.8 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (117.3 mg, 0.8 mmol) were added and the reaction was stirred vigorously. Another addition of Hünig's base and 1H-pyrazole-1-carboxamidine hydrochloride was made at 72 h. Another aliquot of Hünig's base and 1Hpyrazole-1-carboxamidine hydrochloride was added at 6 days and every 24 h thereafter to drive the reaction to completion. NMR and MALDI confirmed the completion of the reaction at 11 days. The solvent was removed under reduced pressure. The crude product was obtained as a yellow gum, which was then suspended in H2O and passed through an IRN-78 ion-exchange column to neutralize the hydrochloride. The resulting crude product was separated with reverse phase chromatography (MeOH/H2O, 0.1% TFA) to afford a light yellow oil as the product in mono-TFA salt form (126.8 mg, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | To a solution of amine 12 (300 mg, 0.7 mmol) and 1H-pyrazole-1-carboxamidine (310 mg, 2.1 mmol) in anhydrous DMF (2 mL) was added N,N-diisopropylethylamine (0.36 mL, 2.1 mmol). The mixture was stirred at room temperature for 96 h. During this period, two additional batches of 1H-pyrazole-1-carboxamidine hydrochloride (103 mg, 0.7 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.7 mmol) in DMF (0.5 mL) were added at 48 h and 72 h, respectively. Methanol (15 mL), water (6 mL), and 10% NaOH solution (2 mL) were added, and the mixture was stirred for additional 12 h. Acetic acid was then added until pH 7.5. The solvent was removed by concentration under reduced pressure at 40 C. The residue was filtered, and the filtrate was applied to a column of Dowex 50WX8-200 (H+) resin and washed with water until neutralization. The column was then eluted with 1.5 N aqueous ammonium hydroxide, and the combined fractions were concentrated. The residue was recrystallized by isopropanol/water (3:1) to afforded zanamivir as a white solid (120 mg, 52%). Mp 252-254 C; +40.5 (c 1.0, H2O); 1H NMR (300 MHz, D2O): delta 5.61 (d, J=2.1 Hz, 1H), 4.44 (dd, J=2.1, 9.3 Hz, 1H), 4.37 (dd, J=1.2, 10.8 Hz, 1H), 4.21 (t, J=9.6 Hz, 1H), 3.92-3.98 (m, 1H), 3.88 (dd, J=3.7, 12 Hz, 1H), 3.61-3.67 (m, 2H), 2.02 (s, 3H); 13C NMR (75 MHz, D2O): delta 175.5, 170.3, 158.1, 150.4, 105.0, 76.5, 70.9, 69.2, 64.2, 52.2, 48.9, 23.1; Anal. Calcd for C12H20N4O7·1.17H2O: C, 40.78, H, 6.37, N, 15.85; found: C, 40.62, H, 6.37, N, 15.57; MS (ESI, m/z): 333.00 [M+H]+; ESI-HRMS calcd for C12H20N4O7Na [M+Na]+ 355.1230, found 355.1234. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: N<SUP>1</SUP>-((1R,2R)-2-(aminomethyl)-2,3-dihydro-1H-inden-1-yl)-N<SUP>2</SUP>-(4-chloro-3-fluorophenyl)-oxalamide; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 65℃; for 3h; Inert atmosphere; Stage #2: formic acid | |
75% | Stage #1: N<SUP>1</SUP>-((1R,2R)-2-(aminomethyl)-2,3-dihydro-1H-inden-1-yl)-N<SUP>2</SUP>-(4-chloro-3-fluorophenyl)-oxalamide; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 65℃; for 3h; Stage #2: formic acid In water; N,N-dimethyl-formamide; acetonitrile | 18 (+)-N’-(4-Chloro-3-fluorophenyl)-N2-Qrans-2-(guanidinomethyl)indan-1-yl)oxalamideformate salt To a solution of amine (+)-13 (25 mg, 0.080 mmol) in DMF (0.5 mL) was added i-Pr2NEt (56 jiL, 0.32 mmol), followed by carbamidine 13 (23 mg, 0.16 mmol). The mixture was then heated to 65 °C for 3 h, then cooled to room temperature and diluted with of CH3CN and the product purified via HPLC to afford 27 mg (75%) of the formate salt of (+)-4 as a white solid (‘H and ‘3C NMR consistent with (±)-4). [CL]D = +45.05 (c 0.28, MeOH); 99% ee by SFC (Chiralpak IC, 40% (0.5% NEt3/MeOH)/C02, 254 nm, 4 mL/min, 12 MPa): (1R,2R)-enantiomer [cf. (+)-4]: tr = 3.1 mm (major) and (1S,2S)- enantiomer [cf. (-)-4]: tr = 4.2 mm (minor). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h; | The synthesis of 4-methylpiperazine-1-carboximidamide To a solution of 1-methylpiperazine (2 g, 20.0 mmol) and 1 H-pyrazole-1-carboximidamide (2.92 g, 20.0 mmol) in DMF (5 mL) was added DIPEA (2.58 g, 2.0 mmol). The mixture was stirred at rt for 24 h, diluted with diethyl ether (80 mL) and stirred at rt 2 h. The resulting precipitate was collected and washed with diethyl ether (20 mL) and dried to give title product (2.2 g, yield 78%) as a white solid, which was used to next step without further purification. |
65% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 10h; Inert atmosphere; | 5.1.1.43. 4-Methyl piperazine-1-carboximidamide (9). To a stirring solution of methyl piperazine (500 mg, 4.5 mmol) in DMF (7.5 ml)was added amidinopyrazole hydrochloride (666 mg, 4.5 mmol) and DIPEA (0.8 ml, 4.5 mmol). The reaction was heated at 80 °C for 10 h.The mixture was concentrated in vacuo. The residue was dilutedwith CH2Cl2 and recrystallized with ether. The solid is filtered anddried in vacuo to afford a pale yellow solid (580 mg, 65%). 1H NMR (300 MHz, CDCl3) δ ppm 4.87 (s, 5H), 3.53 (t, J 5.19 Hz, 4H), 2.55 (t,J 5.06 Hz, 4H), 2.37 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 15h; | A mixture of <strong>[2523-55-9]trans-4-methylcyclohexanamine</strong> (1.13 g, 10.0 mmol), 1H-pyrazole-1-carboximidamide*HCl (1.48 g,10.0 mmol), DIPEA (1.65 mL, 10.0 mmol) and DMF (5.5 mL) was stirred at 60 C for 15 h. Then the reaction mixture was cooled down to rt, diluted with diethyl ether, and stirred at rt to complete crystallization. The obtained solid was collected by filtration, washed with diethyl ether (3×20 mL), and air-dried to give the product (1.61 g, 84%) as a white powder |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine In acetonitrile at 75℃; for 36h; | B16 Example B16 Preparation of compound 25 Compound 14 (0.365g, 0.79mmol) was added to a solution of N,N-diethylethanamine (0.55ml, 3.95mol) in acetonitrile (9ml). Then lH-pyrrazole-l-carboxamidine monohydrochloride (0.348g, 2.37mmol) was added and the resulting mixture was stirred 36 hours at 75°C. The resulting precipitate was filtered and washed with CH3CN. The solid was washed 3 times with water and dried under vacuum at 60°C, yielding 0.276g (69%) of compound 25. |
69% | With triethylamine In acetonitrile at 75℃; for 36h; | B16 Preparation of Compound 25 Compound 14 (0.365 g, 0.79 mmol) was added to a solution of N,N-diethylethanamine (0.55 ml, 3.95 mol) in acetonitrile (9 ml). Then 1H-pyrrazole-1-carboxamidine monohydrochloride (0.348 g, 2.37 mmol) was added and the resulting mixture was stirred 36 hours at 75° C. The resulting precipitate was filtered and washed with CH3CN. The solid was washed 3 times with water and dried under vacuum at 60° C., yielding 0.276 g (69%) of compound 25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | 4.1.8 (2-(5-(4-Bromobenzyl)-1-(4-methoxybenzyl)-1,4,5,6-tetrahydro-4,6-dioxo-1,3,5-triazin-2-ylamino)ethyl)guanidine (11) [PC-25] To a solution of intermediate ( 36) (0.17g, 0.37mmol) in CH3CN (10mL) at room temperature, DIPEA (0.13mL, 0.75mmol) and pirazole-1-carboxamidine hydrochloride (0.05g, 0.37mmol) were added. The reaction mixture was stirred for 12h at room temperature. The white solid formed was collected by centrifugation and washed twice with ethyl ether (2×10mL). The crude final compound was purified by reversed phase preparative HPLC. Yield 0.17g (93%); Rf(D) 0.42; HPLC K 5.52; mp 215-217°C; m/z 503.37 (M+H)+; 1H NMR (DMSO-d6): δ 7.52-6.89 (m, 8H), 4.98 (s, 2H), 4.87 (s, 2H), 3.73 (s, 3H), 3.39-3.28 (m, 4H); 13C NMR (DMSO-d6): 158.55, 156.91, 154.04, 153.27, 150.90, 136.66, 131.08 (2 carbon atoms), 129.77 (2 carbon atoms), 127.92 (2 carbon atoms), 126.99, 120.17, 113.87 (2 carbon atoms), 55.00, 44.28, 43.90, 36.98, 36.81; IR (nujol) 3396, 3149, 1724, 1666, 1578cm-1. Anal. Calcd. for C25H26BrF6N7O7 (502.36) C, 50.21; H, 4.82, N, 19.52. Found: C, 50.26; H, 4.83, N, 19.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | 4.1.8 (2-(5-(4-Bromobenzyl)-1-(4-methoxybenzyl)-1,4,5,6-tetrahydro-4,6-dioxo-1,3,5-triazin-2-ylamino)ethyl)guanidine (11) [PC-25] General procedure: To a solution of intermediate ( 36) (0.17g, 0.37mmol) in CH3CN (10mL) at room temperature, DIPEA (0.13mL, 0.75mmol) and pirazole-1-carboxamidine hydrochloride (0.05g, 0.37mmol) were added. The reaction mixture was stirred for 12h at room temperature. The white solid formed was collected by centrifugation and washed twice with ethyl ether (2×10mL). The crude final compound was purified by reversed phase preparative HPLC. Yield 0.17g (93%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 62℃; for 2h; | Stir a solution of <strong>[2338-18-3]2,3-dihydro-1H-inden-2-amine hydrochloride</strong> (197 g; 1.08 equiv; 1.16 moles), 1H-pyrazole-1-carboximidamide hydrochloride (158 g; 1.00 equiv; 1.08 moles) and diisopropylethylamine (400 g; 2.87 equiv; 3.09 moles; 539.74 mL) in acetonitrile (2 L) at 62 C. for 2 hours, during which time a white solid precipitates. Cool the mixture to 25 C., then filter and wash with 300 mL acetonitrile and 300 mL methyltert-butyl ether. Dry the product in air at 25 C. for 1 h to afford the title compound (200 g, 87%) as a white solid: MS (m/z): 176 (M+1). |
87% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 62℃; for 2h; | Synthesis of l-indan-2-ylguanidine hydrochloride.Stir a solution of 2,3-dihydro-lH-inden-2-amine hydrochloride (197 g; 1.08 equiv; 1.16 moles), lH-pyrazole-l-carboximidamide hydrochloride (158 g; 1.00 equiv; 1.08 moles) and diisopropylethylamine (400 g; 2.87 equiv; 3.09 moles; 539.74mL) in acetonitrile (2 L) at 62C for 2 hours, during which time a white solid precipitates. Cool the mixture to 25C, then filter and wash with 300 mL acetonitrile and 300 mL methyltert-butyl ether. Dry the product in air at 25 C for 1 h to afford the title compound (200g, 87%) as a white solid. MS (m/z): 176 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: C125H172N10*10ClH With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; methanol at 20℃; for 1h; Stage #2: 1H-pyrazole-1-carboximidamide hydrochloride In tetrahydrofuran; methanol at 20℃; for 24h; | |
95% | Stage #1: C125H172N10*10ClH With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; methanol at 20℃; for 1h; Stage #2: 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; methanol at 20℃; for 24h; | 2 Preparation of oligomeric oxime 4 With methanol (2 mL) and tetrahydrofuran (1 mL)The mixed solvent dissolves 44.4 mg (20.4 μmol) of Compound 3,150 microliters (861.2 micromoles) diisopropylethylamine was added and stirred at room temperature for 1 hour. Add another 130 mg (887 micromoles)1-pyrazole-1-carboxamidine hydrochlorideWith 150 μl (861.2 μmol) diisopropylethylamine, stir at room temperature for 24 hours. After concentration under reduced pressure, the residue was dissolved in DMSO (1 ml) and diluted with 10 ml of secondary water. The solution was added to a dialysis bag with a molecular weight cut-off of 500, dialyzed against secondary water for one week, and concentrated under reduced pressure. The residue was dried in a vacuum drying oven for 24 h to give 43.6 mg of product in 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | General procedure. General procedure: Subsituted guanidines were prepared according to the literatureprocedure.1 To a stirred solution of 1H-pyrazole-1-carboxamidine hydrochloride (1.00 g; 6.8mmol; 1.00 equiv.) and DIPEA (1.24 mL; 7.2 mmol; 1.05 equiv.) in MeCN (25 mL),benzylamine (782 μL; 7.2 mmol; 1.05 equiv.) was added. The reaction mixture was stirred atambient temperature overnight and precipitated solid filtered and washed with MeCN andEt2O to obtain pure product 4c as an off-white solid. |
71% | With triethylamine In acetonitrile at 60℃; | Compound 197.1. Pyrrolidine-l-carboximidamide hydrochloride Compound 197.1. Pyrrolidine-l-carboximidamide hydrochloride. Into a 100-mL round-bottom flask, was placed a solution of pyrrolidine (5.8 mL, 70.30 mmol) in CH3CN (30 mL). Triethylamine (9.8 mL, 70.17 mmol) and lH-pyrazole-l-carboximidamide hydrochloride (10.2 g, 69.59 mmol) was added to the reaction. The reaction mixture was stirred overnight at 60 °C. The product was collected by filtration to yield 7.5 g (71%) of the title compound as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With disodium hydrogenphosphate; In ethanol; at 85℃; for 10h; | To the stirred mixture of 4.18 g of pyrazole-1-carboxamidine hydrochloride (28.5 mmol) and 120 mL of ethanol 4.05 g of Na2HPO4 (28.5 mmol) and 4.12 g of Preparation 9a1 (23.78 mmol) were added, then it was stirred at 85 C for 10 h. The reaction mixture was cooled, concentrated under reduced pressure, and the crude product was purified via flashchromatography using heptane and EtOAe as eluents to give 4-(dimethoxymethyl)-2-(1H-pyrazol- I -yI)-pyrimidine.1H NMR (400 MHz, DM80-do): 8.92 (d, TH), 8.65 (d, 111), 7.87 (br s, IH), 7.50 (d, 1H),6.62 (dd, IH), 5.36 (s, 111), 3,38 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.9% | 1-amindinoparazole hydrochloride (2.0 g, 13.4 mmol) and 3,4-Dimethylphenethylamine (1.96 g, 13.4 mmol) were dissolved in DMF 4 ml and were agitated with the addition of diisopropylethylamine (7ml g, 4.02mmol) at room temperature for 16 hours. After the reactioncompleted, the solvent was removed by vacuum distillation and extracted with water and methylene chloride. The water layer was distilled under vacuum and purified with chromatograph using MC:MeOH=9: 1. The purified product was dissolved in a small amount of methanol and agitated with the addition of 12N HCl (0.9m1, 1 0.46mmol) at room temperature for 1 hour. Then, the product was added by ethylacetate 30 ml and agitated for 30 minutes. The produced solid was filtered, washed with ethylacetate and dried under vacuum to produce the title compound in white solid (0.85g, 27.9 %). 1H NMR (400 MHz, CD3OD) delta 7.06 (d, J=7.2Hz, 1H), 6.99 (m, 2H), 3.39 (t, J=7.6Hz,21-1), 2.85 (t, J=7.6Hz, 2H), 2.29 (d, J16Hz, 6H) LCMS: 192 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | 10 Synthesis of N-Pro-2-ynyl-guanidine (PG). Propargyl amine (0.12 g, 2 mmol), 1H-pyrazole-1-carboxamindine hydrochloride (0.29 g, 2 mmol) and triethylamine (0.26 g, 2 mmol) were dissolved in DMF (1 mL), and the mixture was stirred at room temperature for 16 h. Then, the reaction solution was poured into 10-fold ethyl ether (10 mL) to remove the DMF and other impurities. Dry under vacuum to yield an oily product. Obtained 0.24 g (yield=90%). 1H NMR [D2O, δ, ppm]: 3.85 (s, 2H, CH≡CH2-), 2.57 (s, 1H, CH≡CH2-); 13C{1H} NMR (D2O, δ, ppm): 165.08, 77.91, 73.92 and 30.88; HR ESI-MS (m/z) [M+H]+ calcd. for C4H8N3, 98.0718. found 98.0721. |
88% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 36h; | Preparation of BNM-IV-147 To a solution of (+)-(R,R)-BNM-III-170.2TFA (40 mg, 0.059 mmol) in DMF (400 1iL) at a room temperature were added DIPEA (22 μL, 0.124 mmol) and 1H-pyrazole-1- carboximidamide•HCl (18mg, 0.124 mmol). The resulting mixture was stirred at room temperature for 36 h. Were then added to the reaction vessel water (1.8 mL) and acetonitrile (0.3 mL), and the resulting solution (total volume: 2.5 mL) was submitted to HPLC in a single injection. Eluant: 90:10 to 60:40 water/acetonitrile. Gradient time: 15 min. Flow rate: 15 mL/min. Product retention time: 9.5 min. Product fractions were combined and the resulting solution was deep-frozen (-78 C) and lyophilized to afford the bis-TFA salt of (+)-(R,R)- BNM-IV-147 as a white powder (35 mg, 82%). 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1 H), 9.45 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 11.9 Hz, 1 H), 7.89 - 7.71 (m, 2 H), 7.61 (t, J = 8.6 Hz, 1 H), 7.51 (br. s., 5 H), 7.21 - 7.11 (m, 3 H), 7.07 (d, J = 7.9 Hz, 1 H), 5.17 (t, J = 8.5 Hz, 1 H), 4.56 (s, 2 H), 3.61 - 3.21 (m, 2 H + residual H2O), 3.12 (dd, J = 15.9, 7.9 Hz, 1 H), 2.91 (s, 3 H), 2.84 (q, J = 6.3 Hz, 1 H), 2.67 (dd, J = 15.5 Hz, 8.9, 1 H); 13C NMR (125 MHz, DMSO-d6) δ 160.0, 158.8, 158.4 (q, JCF = 32 Hz, TFA), 157.0, 156.8 (d, JCF = 244 Hz), 156.8, 142.2, 141.9, 138.4 (d, JCF = 10 Hz), 135.4, 130.7, 125.8, 124.0, 123.5, 117.4 (d, JCF = 3 Hz), 114.4 (d, JCF = 18 Hz), 108.5 (d, JCF = 26 Hz), 56.9, 52.6, 45.3, 42.9, 40.1, 36.1, 33.9; HRMS (ES+) m/z = 489.1929 ([M+H]+; calcd for C22H27N8O2ClF: 489.1930); +11.8 (c 0.16, CH3OH). |
82% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 36h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 1H-pyrazole-1-carboximidamide hydrochloride; ethyl isocyanate With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl acetamide at -10℃; for 0.75h; Cooling with ice; Stage #2: 1,1'-carbonyldiimidazole With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl acetamide at -5 - 20℃; for 2.5h; | 2.1 (1) Preparation of 3-ethyl-6-(1-pyrazolyl)-(1,3,5-triazine-2,4(1H,3H)-dione DBU (63.3 mL, 420 mmol) was added dropwise to mixture of 1-amidinopyrazole hydrochloride (58.6 g, 400 mmol), ethyl isocyanate (33.2 mL, 420 mmol), and DMA (240 mL) at -10° C. over 15 minutes, and the resulting mixture was stirred under ice-cooling for 30 minutes. 1,1′-Carbonyldiimidazole (97.2 g, 600 mmol) was added to the reaction mixture under ice-cooling, and then DBU (93 mL, 620 mmol) was added at -5° C. over 30 minutes. The reaction mixture was stirred under ice-cooling for 1 hour and then stirred at room temperature for 1 hour. 2 mol/L Hydrochloric acid (1.16 L) was added to the reaction mixture at 20° C. over 1 hour. The resulting powder was collected by filtration to give 3-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dione (73.0 g, yield: 88%) as pale brown powder. 1H-NMR (5 ppm TMS/CDCl3): 1.30 (6H, t, J=7.0 Hz), 4.02 (2H, q, J=7.0 Hz), 6.59 (1H, m), 7.34 (1H, m), 8.48 (1H, m), 9.79 (1H, brs). |
88% | Stage #1: 1H-pyrazole-1-carboximidamide hydrochloride; ethyl isocyanate With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl acetamide at -10℃; for 0.75h; Stage #2: 1,1'-carbonyldiimidazole With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl acetamide at -5 - 20℃; for 2.5h; Stage #3: With hydrogenchloride In N,N-dimethyl acetamide at 20℃; for 1h; | 2.1 Preparation of 3-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dione DBU (63.3 mL, 420 mmol) was added dropwise to mixture of 1-amidinopyrazole hydrochloride (58.6 g, 400 mmol), ethyl isocyanate (33.2 mL, 420 mmol), and DMA (240 mL) at -10°C over 15 minutes, and the resulting mixture was stirred under ice-cooling for 30 minutes. 1,1'-Carbonyldiimidazole (97.2 g, 600 mmol) was added to the reaction mixture under ice-cooling, and then DBU(93 mL, 620 mmol) was added at -5°C over 30 minutes. The reaction mixture was stirred under ice-cooling for 1 hour and then stirred at room temperature for 1 hour. 2 mol/L Hydrochloric acid (1.16 L) was added to the reaction mixture at 20°C over 1 hour. The resulting powder was collected by filtration to give 3-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dione (73.0 g, yield:88%) as pale brown powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; | 5 Synthesis and characterization of 1,1'-(((((1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9-oxo-9H-xanthene-3,6-diyl)bis(oxy))bis(2-hydroxypropane-3,1-diyl))bis(azanediyl)) bis(ethane-2,1-diyl))diguanidine (11) 4.5 Synthesis and characterization of 1,1'-(((((1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9-oxo-9H-xanthene-3,6-diyl)bis(oxy))bis(2-hydroxypropane-3,1-diyl))bis(azanediyl)) bis(ethane-2,1-diyl))diguanidine (11) 10 (70.7 mg, 0.110 mmol) was dissolved in 5 mL of DMF. Subsequently, N,N-diisopropylethylamine (DIEA) (0.0546 mL, 0.330 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (48.4 mg, 0.330 mmol) were added to the solution. The mixture was stirred at room temperature for 12 h. After the reaction completed, the mixture was diluted with a butanol solution, followed by liquid-liquid extraction 3 times with brine (3 * 50 mL). The organic phase was dried over anhydrous Na2SO4. Then, the solvent was evaporated, and HPLC-grade methanol was added for subsequent purification by reversed-phase HPLC (eluent: methanol with 0.1% v/v formic acid and ultrapure water with 0.1% v/v formic acid). 11 was obtained as a dark yellow solid in 68% yield (54.4 mg). 1H NMR (400 MHz, MeOD) δ 6.55 (s, 1H, Ar-H), 6.17 (s, 1H, Ar-H), 5.19-5.15 (m, 2H, 2 * CH), 4.31-3.95 (m, 8H, 3 * CH2, 2 * CH), 3.75 (s, 3H, OCH3), 3.51 (s, 4H, 2 * CH2), 3.27-3.07 (m, 10H, 5 * CH2), 1.79-1.75 (m, 6H, 2 * CH3), 1.66-1.63 (m, 6H, 2 * CH3); 13C NMR (101 MHz, MeOD) δ 182.88, 170.43, 163.46, 160.45, 159.19, 158.23, 156.23, 156.05, 145.15, 137.90, 132.03, 131.97, 124.88, 123.90, 112.92, 112.48, 104.62, 100.34, 90.72, 71.96, 71.58, 67.56, 67.43, 61.61, 52.28, 52.03, 48.15 (2 * CH3), 40.12, 40.03, 27.03, 26.11, 26.00, 22.36, 18.47, 18.31. HRMS (ESI): calculated for C36H54N8O8 [M+H] + 727.4143, found 727.4123. |
With N-ethyl-N,N-diisopropylamine at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The fragment comprising residues 8-9 (referring to Formula (I)) was assembled manually starting from 5.00 g (3 5 mmol) of MBHA resin (EMD Biosciences, catalog number 855006, 0.70 mmol/g). DCC or DIC/HOBt mediated couplings in DCM were employed. Single cycles of at least 2 h with a 2-4-fold excess of activated Boc-protected amino acids were used during the synthesis. The completeness of couplings was assessed with the ninhidrin test. Removal of the Boc protecting group was achieved with two consecutive washes (5 and 25 min.) of the peptide resin with 50% TFA/DCM containing 1% m-cresol. Neutralization of the peptide resin was accomplished with two 5 min. washes with 5% TEA/DCM. The following amino acid derivatives were used to assemble the residue numbers 8-9 resin-bound peptide: Boc-Gly-OH and Boc-Dab(Fmoc)-OH. After the fragment comprising residues numbered 8-9 was assembled, the resin was split and the synthesis was continued manually at a 0.5 mmol scale. (The remainder of this product was used in the synthesis of other compounds as described herein.) (0187) The fragment comprising residues numbered 2-7 (see Formula (I)) was subsequently assembled using synthetic methods described for the 8-9 fragment. The following derivatives were used in this segment: Boc-Pro-OH, Boc-Cys(Mob)-OH, Boc-Asn-OH, Boc-Gln-OH, Boc-Ile-OH and Boc-Phe-OH. The resin was split again and the synthesis was continued manually at a 0.13 mmol scale. The position 1 amino acid was introduced as Z(2-Cl)-Cys(Mob)-OH and the Fmoc group was removed with two consecutive washes with 25% piperidine in DMF (5 and 20 min., respectively). Fmoc-Lys(Boc)-OH was then coupled and the remaining fragment comprising residues numbered 10-18 (see Formula (I)) was subsequently assembled by Boc chemistry. The following amino acid derivatives were used to synthesize this fragment: Boc-Glu-NH2, Boc-Arg(Tos)-OH, Boc-Pro-OH, Boc-Ala-OH, Boc-Asn-OH, Boc-Gln-OH, Boc-Phe-OH, Boc-D-Tyr(Me)-OH and PhAc-OH. After the entire peptide sequence has been assembled the resin was washed thoroughly with DMF and treated with 25% piperidine in DMF (5 and 20 min) The resin was then washed with DMF, suspended in NMP/DMSO (1:1, v/v) and guanylated with 1H-Pyrazole-1-carboxamidine HCl (Aldrich 02729LB)/DIPEA. Finally, the resin was washed with DMF, MeOH and DCM and dried in vacuo. The peptide was cleaved from the resin with 20 mL of HF/anisole 20:1 (v/v) for 1.5 h at 0 C. The resin/crude peptide was washed with 100 mL of ethyl ether and the peptide was extracted with 100 mL of acetic acid/water 3:1, (v/v). The subsequent steps were the same as in the synthesis of compound 2. The fractions were pooled and lyophilized. 47.5 mg (0.018 mmol, 7% assuming 85% peptide content) of white peptide powder was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In acetonitrile for 3h; Reflux; | General procedure for guanylation of primary aliphatic amines General procedure: Amine and 1 (0.9-0.99 eq) was added to MeCN (3 mL/100 mg amine) on a 50- to 100-mg scale and refluxed for 2-3 h. After complete disappearance of 1 (by TLC w/ 70:30:3 CHCl3/MeOH/NH4OH) the reaction mixture was cooled down to room temperature. Furthermore, depending on whether the product precipitated out or not, the following was done: The reaction mixture was partially evaporated and added to Et2O (200 mL). The ether phase was decanted and the residual oil was washed with Et2O (3 x 200 mL), before it was added one last portion of Et2O (200 mL) and left for 48 h. The hard crystalline precipitate was then crushed and stirred with Et2O (3 x 100 mL) for 10 min each time. Decanting and drying afforded 2c as an off-white solid. |
69% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 12h; | General procedure. General procedure: Subsituted guanidines were prepared according to the literatureprocedure.1 To a stirred solution of 1H-pyrazole-1-carboxamidine hydrochloride (1.00 g; 6.8mmol; 1.00 equiv.) and DIPEA (1.24 mL; 7.2 mmol; 1.05 equiv.) in MeCN (25 mL),benzylamine (782 μL; 7.2 mmol; 1.05 equiv.) was added. The reaction mixture was stirred atambient temperature overnight and precipitated solid filtered and washed with MeCN andEt2O to obtain pure product 4c as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.9% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃; for 48.0h; | 16.16 g (55.96 mmol) of 2,2,5,7, 8-pentamethylchroman-6-sulfonyl chloride (Combi-Blocks, Inc., San Diego, CA) was dissolved in dioxane (200 mL), and 9.07 g (61.88 mmol) of lH-pyrazole-1- carboxamidine HCl dissolved in dioxane (200 mL) was added to the solution followed by 22 mL (2 eq.) of DIEA. The reaction mixture was stirred at room temperature for 48 hours, at which time all of the lH-pyrazole-1 -carboxamidine HCl had been consumed as confirmed via TLC. The dioxane was evaporated in vacuo and the remaining brown oil was redissolved into 200 mL DCM. The organic layer was washed with water (3 x 200 mL), dried over sodium sulfate and evaporated to give a brown solid. The crude material was recrystallized three times from ethanol to give 13.17 g (64.9% yield) of 1 as a white solid. lU NMR (500 MHz, CDCb) delta 8.21 (dd, J = 2.8, 0.7 Hz, 1H), 7.67 (dd, J = 1.6, 0.7 Hz, 1H), 6.40 (dd, J = 2.9, 1.6 Hz, 1H), 2.98 (s, 2H), 2.62 (s, 3H), 2.56 (s, 3H), 2.11 (s, 3H), 1.47 (s, 6H). 13C NMR (126 MHz, CDCb) delta 12.34, 17.86, 19.16, 28.48, 42.99, 86.67, 109.47, 117.74, 124.83, 128.92, 130.88, 132.98, 139.13, 143.44, 148.66, 159.41. HRMS (ESI): calculated mass (Ci7H23N403S) [M+H]1+: 363.1491, mass found m/z: 363.1510 [M+H]1+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: C106H140N10S With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; methanol at 20℃; for 1h; Stage #2: 1H-pyrazole-1-carboximidamide hydrochloride In tetrahydrofuran; methanol at 20℃; for 24h; | 10 Preparation of oligofluorene 10 The reaction scheme is shown in Fig.A mixture of 97 mg (51.6 micromoles) of compound 9 was dissolved in a mixed solvent of methanol (4 ml) and tetrahydrofuran (2 ml)And 400 μl (2.3 mmol) of diisopropylethylamine was added and stirred at room temperature for 1 hour.304 mg (2.07 mmol) of 1-pyrazole-1-carboxamidine hydrochloride and 400 μl (2.3 mmol) of diisopropylethylamine were added and the mixture was stirred at room temperature for 24 hours.After concentration under reduced pressure, the residue was dissolved in DMSO (2 mL) and diluted with 20 mL of secondary water.The solution was added to a dialysis bag with a molecular weight cutoff of 500,After dialysis with secondary water for one week,The residue was dried in a vacuum oven for 24 h to give 96.3 mg of product in 97% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine In 1,4-dioxane; water for 8h; Reflux; | 21 Experimental 21. 1-(2-Phenoxyethyl)guanidine [0332] A mixture of 2-phenoxyethan-1-amine (10 mmol, 1.0 equiv), 1H-pyrazole-1-carboxamidine hydrochloride (15 mmol, 1.5 equiv, 1 M) and DIPEA (1.5 equiv) in 1,4-dioxane/H20 (2:1) was refluxed for 8 hours, cooled down to r.t. and evaporated to dryness. Anorange oily residue was treated with water and resulting solution was saturated with solid K2C03 to induce the precipitation of free guanidine. Formed precipitate was filtered off, washed withcold water and dried on a rotary evaporator to afford a title compound. Yield: 0.878 g (49%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃; for 96h; | A 100 mL round-bottom flask flask was charged with a solution of tert-butyl N- [[(2S)-pyrrolidin-2-yl]methyl]carbamate (1 g, 4.993 mmol) in DMF (3 mL), then was added pyrazole-1-carboxamidine hydrochloride (0.7319 g, 4.993 mmol) and N,N- diisopropylethylamine (0.6453 g, 4.993 mmol). The reaction was stirred at ambient temperature for 4 days, then diluted with 50 mL of diethyl ether. The mixture was stirred for 2 h, then the solvents were decanted to leave an oil. This was taken up in 2 mL of ethanol, then the solution was diluted with 25 mL of ethyl acetate and 10 mL of hexanes. The solvents were decanted, and the residue was dried in vacuo to give tert-butyl N-[[(2S)-1-carbamimidoylpyrrolidin-2- yl]methyl]carbamate hydrochloride (1.058 g, 76 % yield) as an off-white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 1H-pyrazole-1-carboximidamide hydrochloride With potassium hydroxide In N,N-dimethyl-formamide Green chemistry; Stage #2: 1-ethoxy-4-isothiocyanatobenzene In N,N-dimethyl-formamide at 20℃; Green chemistry; | General experimental procedure for the preparation of 1-[(N-arylthiocarbamoyl)amidino]pyrazoles (2a-g) by method B (mechanochemical method) General procedure: Powdered potassium hydroxide (112 mg, 2 mmol) was added to 1-amidinopyrazole hydrochloride (1) (292 mg, 2 mmol) in an agate mortar and the mixture was ground with an agate pestle for 1-3 min. To this mixture, aryl isothiocyante (2 mmol) was added and the grinding continued at room temperature for 15-20 min. The oily emulsion first formed subsequently solidified and the solid was worked up by triturating with petroleum ether, followed by water. The product was collected by filtration and purified by crystallization from an ethanol-water mixture (1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Under an argon atmosphere, to a solution of tert-butyl N-(5-aminopentyl)carbamate (300 mg, 1.46 mmol) in dichloromethane (15 mL) were added triethylamine (0.206 mL, 1.48 mmol) and 1-amidinopyrazole hydrochloride (217 mg, 1.46 mmol). After stirring at room temperature overnight, the mixture was purified by reversed-phase HPLC (0.05% (v/v)-containing TFA, water/acetonitrile) to give the title compound (408 mg, yield quantitative). 1H-NMR (400 MHz, Deuterium Oxide) delta3.10 (t, J=7.0 Hz, 2H), 2.99 (t, J=6.7 Hz, 2H), 1.56-1.47 (m, 2H), 1.46-1.37 (m, 2H), 1.35 (s, 9H), 1.32-1.23 (m, 2H). MS (ESI)m/z: 245 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
103 mg | (Example 4) 5-methoxy-1'-(4-oxo-3,5,7,8-tetrahydro-4H-thiopyrano[4,3-d] pyrimidin-2-yl)-3H-spiro[isobenzofuran-1,4'-piperidin]-3-on e (Test Target Compound 98) Triethylamine (0.25 mL) and 1-amidinopyrazole hydrochloride (99 mg) were added to a suspension of 5-methoxy-3H-spiro[isobenzofuran-1,4'-piperidin]-3-one hydrochloride (121 mg) in acetonitrile (4.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (4 mL), then methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate ester (0.082 mL) and a 20%sodium ethoxide ethanol solution (0.47 mL) were added thereto, and the obtained mixture was refluxed for 5 hours . The reaction mixture was cooled to 0ºC, and the precipitate generated was collected by filtration to obtain the title compound (103 mg) . 1H-NMR(400MHz, CDCl3) delta: 1.79(d, J=13.8Hz, 2H), 2.16(td, J=13.4, 4.6Hz, 2H), 2.77-2.87(m, 4H ), 3.42-3.52(m, 4H), 3.89(s, 3H), 4.55-4.64(m, 2H), 4.24-7.30(m, 2H ), 7.32-3.39(m, 1H), 11.77(br.m, 1H). MS(ESI)m/z:400[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: C40H47N7O4*(x)ClH; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With hydrogenchloride In methanol at 0℃; for 1h; | 4.10.1. Synthesis of ADG-2a 1H-Pyrazole-1-carboxamidine hydrochloride (38 mg,0.26 mmol)was added to a solution of ADL-3a (60 mg, 0.087 mmol)and DIPEA (0.09 mL, 0.52 mmol) in dimethylformamide (1 mL), andstirred for overnight. The reaction mixture was concentrated under vacuum, dissolved in 1.25M HCl in MeOH (8 mL), and stirred for1 h at 0 C. After that cold ethyl acetate (20 mL) was added. Thewhite precipitate was filtered off and purified by RP-HPLC to givethe final compound ADG-2a as a white solid (67.3 mg, 67%). 1H NMR(900 MHz, DMSO-d6) d 8.78 (d, J 7.2 Hz, 1H), 8.43 (t, J 5.8 Hz, 1H),8.39 (brs, 2H), 8.07 (d, J 8.3 Hz, 1H), 8.01 (d, J 8.4 Hz, 1H), 7.92 (d,J 7.9 Hz, 1H), 7.87 (d, J 8.0 Hz, 1H), 7.82 (d, J 7.8 Hz, 1H), 7.79 (d,J 7.8 Hz, 1H), 7.54e7.48 (m, 3H), 7.46e7.37 (m, 8H), 7.29 (brs, 5H),6.24 (t, J 6.7 Hz, 1H), 4.25e4.22 (m, 1H), 3.94e3.86 (m, 5H),3.50e3.41 (m, 5H), 3.40e3.36 (m, 1H), 3.16e3.07 (m, 4H), 2.23e2.14(m, 2H), 1.87 (s, 3H), 1.85e1.76 (m, 4H). 13C NMR (225 MHz,DMSO-d6) d 170.4,170.2,162.9,158.4,156.9,154.4,141.7,133.3,133.2,132.7, 132.5, 131.9, 131.9, 128.3, 128.2, 127.8, 127.7, 127.1, 127.0, 126.0,125.7, 125.6, 125.5, 125.5, 125.4, 124.3, 124.1, 116.5, 102.9, 84.8, 83.0,50.9, 46.9, 41.5, 39.9, 39.8, 38.9, 36.7, 27.5, 17.1. MS (MALDI-TOF):calcd for C42H51N11O4: 773.4, found 774.5 (M H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: C36H51N7O4*(x)ClH; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With hydrogenchloride In methanol at 0℃; for 1h; | 4.10.1. Synthesis of ADG-2a General procedure: 1H-Pyrazole-1-carboxamidine hydrochloride (38 mg,0.26 mmol)was added to a solution of ADL-3a (60 mg, 0.087 mmol)and DIPEA (0.09 mL, 0.52 mmol) in dimethylformamide (1 mL), andstirred for overnight. The reaction mixture was concentrated under vacuum, dissolved in 1.25M HCl in MeOH (8 mL), and stirred for1 h at 0 C. After that cold ethyl acetate (20 mL) was added. Thewhite precipitate was filtered off and purified by RP-HPLC to givethe final compound ADG-2a as a white solid (67.3 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: C30H51N7O4*(x)ClH; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With hydrogenchloride In methanol at 0℃; for 1h; | 4.10.1. Synthesis of ADG-2a General procedure: 1H-Pyrazole-1-carboxamidine hydrochloride (38 mg,0.26 mmol)was added to a solution of ADL-3a (60 mg, 0.087 mmol)and DIPEA (0.09 mL, 0.52 mmol) in dimethylformamide (1 mL), andstirred for overnight. The reaction mixture was concentrated under vacuum, dissolved in 1.25M HCl in MeOH (8 mL), and stirred for1 h at 0 C. After that cold ethyl acetate (20 mL) was added. Thewhite precipitate was filtered off and purified by RP-HPLC to givethe final compound ADG-2a as a white solid (67.3 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: C28H51N7O4*(x)ClH; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With hydrogenchloride In methanol at 0℃; for 1h; | 4.10.1. Synthesis of ADG-2a General procedure: 1H-Pyrazole-1-carboxamidine hydrochloride (38 mg,0.26 mmol)was added to a solution of ADL-3a (60 mg, 0.087 mmol)and DIPEA (0.09 mL, 0.52 mmol) in dimethylformamide (1 mL), andstirred for overnight. The reaction mixture was concentrated under vacuum, dissolved in 1.25M HCl in MeOH (8 mL), and stirred for1 h at 0 C. After that cold ethyl acetate (20 mL) was added. Thewhite precipitate was filtered off and purified by RP-HPLC to givethe final compound ADG-2a as a white solid (67.3 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: C40H63N7O4*(x)ClH; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With hydrogenchloride In methanol at 0℃; for 1h; | 4.10.1. Synthesis of ADG-2a General procedure: 1H-Pyrazole-1-carboxamidine hydrochloride (38 mg,0.26 mmol)was added to a solution of ADL-3a (60 mg, 0.087 mmol)and DIPEA (0.09 mL, 0.52 mmol) in dimethylformamide (1 mL), andstirred for overnight. The reaction mixture was concentrated under vacuum, dissolved in 1.25M HCl in MeOH (8 mL), and stirred for1 h at 0 C. After that cold ethyl acetate (20 mL) was added. Thewhite precipitate was filtered off and purified by RP-HPLC to givethe final compound ADG-2a as a white solid (67.3 mg, 67%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-(3-aminopropoxy)-N-(2-phenoxyphenyl)benzamide; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 44h; Inert atmosphere; Stage #2: trifluoroacetic acid In water; acetonitrile | 6.1.6 General Procedure 4 for the synthesis of 4-(3-guanidinopropoxy)benzamide derivatives (6b, 6d) General procedure: Adapted from Bernatowicz et al.35 The amine 5 (0.41mmol), DIPEA (0.51mmol) and 1H-pyrazole-1-carboximidine hydrochloride (0.51mmol) were dissolved in dry DMF (4mL) and the mixture was left stirring under nitrogen atmosphere at RT for 44h. The solvent was removed in vacuo, then methanol (3mL) was added and evaporated to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: (10H-phenoxazin-10-yl)(4-(3-aminopropoxy))phenylmethanone; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 44h; Inert atmosphere; Stage #2: trifluoroacetic acid In water; acetonitrile | 6.1.6 General Procedure 4 for the synthesis of 4-(3-guanidinopropoxy)benzamide derivatives (6b, 6d) General procedure: Adapted from Bernatowicz et al.35 The amine 5 (0.41mmol), DIPEA (0.51mmol) and 1H-pyrazole-1-carboximidine hydrochloride (0.51mmol) were dissolved in dry DMF (4mL) and the mixture was left stirring under nitrogen atmosphere at RT for 44h. The solvent was removed in vacuo, then methanol (3mL) was added and evaporated to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydrogencarbonate In 1,4-dioxane at 60℃; | Synthesis of 2,6-Disubstituted 4-Fluoropyrimidines 3a-m and 4a-o; General Procedure General procedure: To a round-bottom flask (10 mL) with a magnetic stirrer bar, 1,4-dioxane(3.0 mL), -CF3-aryl ketone (0.30 mmol, 1.0 equiv), amidine hydrochloride(0.33 mmol, 1.1 equiv) and KHCO3 (0.9 mmol, 3.0 equiv)were added. The resulting mixture was stirred at 60 °C for 12-48 hand the progress of the reaction was monitored by TLC. After the consumptionof -CF3-aryl ketone, the reaction was quenched with H2O(10 mL), and the mixture was extracted with EtOAc (3 × 10 mL). Theorganic layer was then dried over anhydrous Na2SO4 and concentratedunder vacuum by rotary evaporation. The residue was purified bychromatography on silica gel (PE/EtOAc) to afford the desired compound. |
Tags: 4023-02-3 synthesis path| 4023-02-3 SDS| 4023-02-3 COA| 4023-02-3 purity| 4023-02-3 application| 4023-02-3 NMR| 4023-02-3 COA| 4023-02-3 structure
[ 105675-84-1 ]
4-Chloro-1-methyl-1H-pyrazol-5-amine
Similarity: 0.61
[ 152120-62-2 ]
Benzyl (imino(1H-pyrazol-1-yl)methyl)carbamate
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[ 883230-94-2 ]
5-Bromo-2-pyrazol-1-yl-pyrimidine
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[ 857641-46-4 ]
2-(4-Bromo-1H-pyrazol-1-yl)pyrimidine
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H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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