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CAS No. : | 195314-59-1 | MDL No. : | MFCD01076211 |
Formula : | C11H22N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FEYLUKDSKVSMSZ-UHFFFAOYSA-N |
M.W : | 214.30 | Pubchem ID : | 2756050 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.91 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 60.1 |
TPSA : | 64.35 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.67 cm/s |
Log Po/w (iLOGP) : | 2.48 |
Log Po/w (XLOGP3) : | 1.32 |
Log Po/w (WLOGP) : | 1.78 |
Log Po/w (MLOGP) : | 1.15 |
Log Po/w (SILICOS-IT) : | 0.64 |
Consensus Log Po/w : | 1.47 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.74 |
Solubility : | 3.93 mg/ml ; 0.0184 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.27 |
Solubility : | 1.14 mg/ml ; 0.00534 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.69 |
Solubility : | 4.42 mg/ml ; 0.0206 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.99 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P273-P280-P301+P312+P330-P305+P351+P338+P310 | UN#: | 3077 |
Hazard Statements: | H302-H318-H410 | Packing Group: | Ⅲ |
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 |
---|---|---|
6.3% | at 0 - 20℃; for 1 h; | To a solution of 1.17g (10.24mmol) of trans-1,4-diaminocyclohexane in 60 ml water/THF (1:1) 2.25g (10.31 mmol) of di-t-butyldicarbonate at 0 °C was added. The mixture was stirred for 1 h at room temperature. After evaporation of the organic solvent, the aqueous phase was extracted with ethyl acetate twice. Combined organic phase was extracted with 0.5N hydrochloric acid. Then the aqueous phase was adjusted to pH 10 with 1 N NaOH solution and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 138 mg (6.3percent) of the title compound. MS 299.4 (M+H+DMSOd6)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h; | To a cooled (0C) solution of cyanuric chloride (1 eq.) in THF and DIPEA is added dropwise, <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (2 eq.) in THF. After stirring at RT for 1 hour, the solvent is removed in vacuo and the product is partitioned between DCM <n="66"/>and 2 M HCl. The organic portion is separated, washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield Intermediate IAl which is used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 0 - 20℃; for 1h; | Intermediate E; [4-((R)-3-Pyrrolidin-3-ylureido)-cyclohexyl]-carbamic acid tert-butyl ester; Step E1: (4-tert-Butoxycarbonylamino-cyclohexyl)-carbamic acid phenyl ester; Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine/DCM. The reaction mixture is cooled to 0C and a solution of <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. | |
With pyridine; In dichloromethane; at 0 - 20℃; for 1h; | Phenyl chloro formate (1 eq.) is added dropwise to a solution of pyridine in DCM. The reaction mixture is cooled to 0C and a solution of (4-amino-cyclohexyl)-carbamic acid tert- butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at RT for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water (x2), (sat)NaHCO3(aq) and brine. The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 120℃; for 1h;Microwave; | (4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (2 eq.) and 3,4-dimethoxy-3- cyclobutene-l,2-dione (1 eq.) are dissolved in EtOH and heated at 120C for 1 hour in the microwave. The solvent is removed in vacuo. The resulting material is dissolved in DCM. TFA is added and the reaction mixture is stirred at RT for 2 hours. The solvent is removed in vacuo the material is then dissolved in minimal volume of ethanol/saturated aqueous sodium carbonate solution until the pH of the solution is adjusted to pH 9 (ensuring the compound remains in solution). The solution is loaded onto an Isolute C 18 column and washed through firstly with water and then MeOH. The fractions are combined and concentrated in vacuo to yield the title product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate I; {4-[4-(Pyrrolidin-3-ylamino)-[1,3,5]triazin -2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester; Step/1: (R)-3-[4-(4-tert-Butoxycarbonylamino-cyclohexylamino)-[1,3,5]triazin-2-ylamino]-pyrrolidine-1 -carboxylic acid allyl ester; (R)-3-Amino-pyrrolidine-1-carboxylic acid allyl ester(1 eq.) is dissolved in DCM. The reaction mixture is cooled to 0C and a solution of 2,4-dichloro-[1,3,5]triazine (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is re-cooled to 0C and a solution of <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated NaHCO3(aq) and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo, to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20 - 50℃; for 2h; | To a solution of the <strong>[61700-61-6]1H-<strong>[61700-61-6]indazole-5-carboxylic acid</strong></strong> (200 mg, 1.23 mmol) obtained in Reference Example 1 in N,N-dimethylformamide (15 ml) were added trans-tert-butyl 4-aminocyclohexylcarbamate (317 mg, 1.48 mmol), triethylamine (0.172 ml, 1.23 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (355 mg, 1.85 mmol) and hydroxybenzotriazole (200 mg, 1.48 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction solution was heated at 50C for 1 hour, water was added thereto at 0C. The resulting solid was filtered and then dried under reduced pressure to obtain trans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate (435 mg, 98%).1H-NMR (DMSO-d6) delta; 1.18-1.44 (6H, m), 1.36 (9H, s), 1.82 (4H, m), 7.54 (1H, d, J=8.6Hz), 7.81 (1H, d, J=8.6Hz), 8.17 (1H, s), 8.19 (1H, d, J=7.6Hz), 8.29 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.3% | In tetrahydrofuran; water; at 0 - 20℃; for 1h; | To a solution of 1.17g (10.24mmol) of trans-1,4-diaminocyclohexane in 60 ml water/THF (1:1) 2.25g (10.31 mmol) of di-t-butyldicarbonate at 0 C was added. The mixture was stirred for 1 h at room temperature. After evaporation of the organic solvent, the aqueous phase was extracted with ethyl acetate twice. Combined organic phase was extracted with 0.5N hydrochloric acid. Then the aqueous phase was adjusted to pH 10 with 1 N NaOH solution and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 138 mg (6.3%) of the title compound. MS 299.4 (M+H+DMSOd6)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20℃; | To a solution of 1.10 [G] of [(4-AMINO-CYCLOHEXYL)-CARBAMIC] acid tert-butyl ester in 25 [ML] of EtAc 0.58 ml of [ETHOXYCARBONYL-ISOTHIOCYANAT] are added and the mixture obtained is stirred at RT. The precipitate formed is filtered and washed with diethylether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | Preparation 27; {cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexyl}-carbamic acid tert- butyl ester; (4-AMINO-CYCLOHEXYL)-CARBAMIC acid ter-butyl ester (80: 20 syn : anti, 4.49g, 20. 9MMOL) was dissolved in dimethylformamide (100MOI) and triethylamine (8. 34ml, 59. 8mmol) was added followed by 5-fluoro-2-chloronicotinic acid (3.5g, 19. 9MMOL), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2g, 21. 9MMOL) and 1- HYDROXYBENZOTRIAZOLE (2. 96g, 21. 9MMOL). The reaction was stirred under nitrogen at room temperature for 18h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (50ML) and ethyl acetate (100ml) and the aqueous phase was extracted with DICHLOROMETHANE (2X50ML). The combined organic extracts were concentrated under reduced pressure, re-dissolved in DICHLOROMETHANE (100ml), washed with water (50ml), dried over MGS04 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate: pentane (2: 3 changing to 1: 1, by volume) to give {CIS-4-[(2- CHLORO-5-FLUORO-PYRIDINE-3-CARBONYL)-AMINO]-CYCLOHEXYL}-CARBAMIC acid ter-butyl ester (5.44g) as a white foam. 1H NMR (400MHZ, CDC13) : 6 = 8.33-8. 38 (1H, d), 7.92-7. 97 (1 H, dd), 6.60-6. 69 (1H, brs), 4. 66-4. 74 (1H, brs), 4.10-4. 20 (1H, brs), 3.56-3. 68 (1H, brs), 1.79-1. 90 (4H, m), 1.48-1. 60 (2H, m, partially masked by solvent), 1.43 (9H, s) ppm. LRMS (thermospray): m/z [M-BOC+H] + 272, [M+H] + 372, [M+NH4] + 389. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | Preparation 45; TEFF-BUTYL 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate (mixture of cis (major) and trans (minor)); tert-Butyl 4-aminocyclohexylcarbamate (4: 1 cis: trans mix of isomers, 1. 00g, 4. 67mmol), 3-HYDROXY-2, 2-DIMETHYLPROPANOIC acid (0.60g, 5. 13MMOL) and triethylamine (1. 30ml, 9. 33MMOL) were dissolved in DIMETHYLFORMAMIDE (20MUT) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (984mg, 5. 13mmol) and 1-HYDROXYBENZOTRIAZOLE (694mg, 5. 13MMOL) were added. The reaction was stirred under nitrogen at room temperature for 18h then partitioned between water and ethyl acetate. The organic phase was washed with water, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane : methanol : 0. 880AMMONIA (95: 5: 0.5) as eluant to give TERT-BUTYL 4- [ (3- HYDROXY-2, 2-DIMETHYLPROPANOYL) AMINO] CYCLOHEXYLCARBAMATE (840mg) as a white foam as a ca. 4: 1 mixture of diastereoisomers. 1H NMR (400MHZ, CDC13) : (peaks relating to major diastereoisomer) 9 = 6. 08-6.18 (1H, m), 4.48-4. 59 (1 H, m), 3.84-3. 94 (1H, m), 3.56 (3H, s), 1.46-1. 82 (8H, m), 1.44 (9H, s), 1.16 (6H, S) ppm. LRMS (electrospray) : m/z [M+Na] + 337 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In tetrahydrofuran; at 20℃; | A mixture of 4-chloro-l- (4-methanesulfonyl-phenyl)-IH-pyrazolo [3, 4-d] pyrimidine (308 mg, 1 mmol), (4-amino-cyclohexyl)-carbamic acid TERT-BUTYL ester (257 mg, 1. 2 mmol) and potassium carbonate (166 mg, 1. 2 mmol) in THF (10 mL) was stirred at rt overnight. The mixture was purified by column chromatography to provide Compound A35 as a solid (76%). 1H NMR (CDC13, 400 MHz) 8 1. 46 (s, 9H), 1. 74-2. 04 (m, 8H), 3. 09 (s, 3H), 3. 73 (s, 1H), 4. 62 (s, 1H), 8. 07-8. 09 (m, 3H), 8. 49 (s, 1H), 8. 57-8. 59 (m, 2H). Exact mass calculated for C23H3ON604S 486. 2, found 487. 2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; | 1-(3,5-Bis-trifluoromethyl-phenyl)-4-chloro-1H-pyrazolo [3, 4-d] pyrimidine (147 mg, 0. 4 mmol), <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (0. 44 mmole, 1. 1 EQ) and diisopropylethyl amine (0. 44 mmol, 1. 1 EQ) were dissolved in THF (3 mL) and then stirred at room temperature over night. THF was removed in vacuo and the solid residue was re-dissolved in 30/70 mixture of water and ACN gave yellow solid. The solid was washed with water and dried in vacuo provided compound A44 as creamy green solid (179 mg, 82%). 1H NMR (CDC13, 400 MHZ) B 1. 43 (s, 9H), 1. 75 (m, 2H), 1. 98-1. 97 (m, 2H), 2. 04 (m, 2H), 2. 95 (sb, 2H), 4. 12 (q, 1H), 4. 62 (m, 1H), 7. 80 (s, 1H), 8. 09 (s, 1H), 8. 50 (s, 1H), 8. 94 (s, 2H). Exact mass calculated for C24H26F6N602 544. 2, Found 545. 5 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In tetrahydrofuran; tert-butylmethyl ether; water; | (4-Amino-cyclohexyl)-carbamic acid t-butyl ester (1) A solution of di-t-butyl-dicarbonate (12.0 g, 54.7 mmol) and tetrahydrofuran (250 mL) was added slowly under nitrogen over 3 h to a suspension of 1,4-diaminocyclohexane (50.0 g, 0.44 mol) in tetrahydrofuran (250 mL) while maintaining the temperature below 10 C. The mixture was allowed to warm to room temperature and subsequently stirred for 16 hours, then filtered. The filtrate was concentrated in vacuo to give a residue. Water (500 mL) was added to the residue, followed by stirring for approximately 15 min, after which the mixture was filtered and the aqueous layer was extracted with dichloromethane (3*200 mL). The organic extracts were combined and concentrated to give a residue which was dissolved in t-butylmethyl ether (350 mL) and washed with water (3*50 mL). The t-butylmethyl ether was removed in vacuo to give the title compound 1 (8.1 g, 69%) as a solid: deltaH (360 MHz: CDCl3) 1.06-1.24 (m, 4H), 1.43 (s, 9H), 1.83 (d, 2H), 1.98 (d, 2H), 2.56-2.66 (m, 1H), 3.30-3.35 (m, 1H) and 4.31-4.38 (m, 1H). |
69% | In tetrahydrofuran; tert-butylmethyl ether; water; | (4-Amino-cyclohexyl)-carbamic Acid t-butyl Ester (1) A solution of di-t-butyl-dicarbonate (12.0 g, 54.7 mmol) and tetrahydrofuran (250 mL) was added slowly under nitrogen over 3 h to a suspension of 1,4-diaminocyclohexane (50.0 g, 0.44 mol) in tetrahydrofuran (250 mL) while maintaining the temperature below 10 C. The mixture was allowed to warm to room temperature and subsequently stirred for 16 hours, then filtered. The filtrate was concentrated in vacuo to give a residue. Water (500 mL) was added to the residue, followed by stirring for approximately 15 min, after which the mixture was filtered and the aqueous layer was extracted with dichloromethane (3*200 mL). The organic extracts were combined and concentrated to give a residue which was dissolved in t-butylmethyl ether (350 mL) and washed with water (3*50 mL). The t-butylmethyl ether was removed in vacuo to give the title compound 1 (8.1 g, 69%) as a solid: deltaH (360 MHz: CDCl3) 1.06-1.24 (m, 4H), 1.43 (s, 9H), 1.83 (d, 2H), 1.98 (d, 2H), 2.56-2.66 (m, 1H), 3.30-3.35 (m, 1H) and 4.31-4.38 (m, 1H). |
69% | In tetrahydrofuran; tert-butylmethyl ether; water; | (4-Amino-cyclohexyl)-carbamic Acid t-butyl Ester (1) A solution of di-t-butyl-dicarbonate (12.0 g, 54.7 mmol) and tetrahydrofuran (250 mL) was added slowly under nitrogen over 3 h to a suspension of 1,4-diaminocyclohexane (50.0 g, 0.44 mol) in tetrahydrofuran (250 mL) while maintaining the temperature below 10 C. The mixture was allowed to warm to room temperature and subsequently stirred for 16 hours, then filtered. The filtrate was concentrated in vacuo to give a residue. Water (500 mL) was added to the residue, followed by stirring for approximately 15 min, after which the mixture was filtered and the aqueous layer was extracted with dichloromethane (3*200 mL). The organic extracts were combined and concentrated to give a residue which was dissolved in t-butylmethyl ether (350 mL) and washed with water (3*50 mL). The t-butylmethyl ether was removed in vacuo to give the title compound 1 (8.1 g, 69%) as a solid: 8H (360 MHz: CDCl3) 1.06-1.24 (m, 4H), 1.43 (s, 9H), 1.83 (d, 2H), 1.98 (d, 2H), 2.56-2.66 (m, 1H), 3.30-3.35 (m, 1H) and 4.31-4.38 (m, 1H). |
50% | In tetrahydrofuran; | Reference Example 49 Under ice-cooling, to 30 ml of a THF solution containing 13.7 g of 1,4-diaminocyclohexane was added dropwise 30 ml of a THF solution containing 8.73 g of di-tert-butyl dicarbonate. The mixture was stirred at the same temperature for 30 minutes and further at room temperature overnight. Then, THF was removed under reduced pressure and a saturated saline solution was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed to give 4.3 g cf 1-tert-butoxycarbonylamino-4-aminocyclohexane (yield: 50%, oily product, IR (KBr): 3343, 1683, 1525 cm-1). |
In chloroform; for 21h; | Synthesis of tert-butyl 4-aminocyclohexylcarbamate (1.2) To a stirred solution of compound 1.1 (10 g, 1 equiv.) in chloroform (100 mL) under an Ar atmosphere, was added over a period of 6 h a solution of di-tert-butyl dicarbonate (9.5 g, 0.5 equiv.) in chloroform (150 mL). The reaction mixture was stirred for an additional 15 h. The chloroform was removed in vacuo, and the white residue was treated with dichloromethane and sat. Na2CO3 solution. The layers were separated, and the organic layer was washed with sat. Na2CO3 solution. The dichloromethane layer was then dried (Na2SO4) and concentrated to give a white solid. The solid was purified by silica gel column chromatography to give amine 1.2 as a white powder. | |
In tetrahydrofuran; | (3) Synthesis of compound 7 (compound 7 shown in Figure 2); Compound 5 (compound 5 shown in Figure 2) was protected with Boc according to the method described in the publication of Komatsu et al. (T. Komatsu et al., (2006), J. Am. Chem. Soc., 128, 15946-15947), so as to obtain compound 6 (compound 6 shown in Figure 2). Compound 6 (0.166 g; 0.78 mmol; 1.2 eq) was dissolved in CH2Cl2 (30 ml). Thereafter, p-Methyl Red (0.177 g; 0.66 mmol), WSC (0.253 g; 1.32 mmol; 2 eq), and TEA (2 drops) were added to the solution, and the obtained mixture was then stirred overnight in an Ar atmosphere. After the disappearance of compound 6 had been confirmed using TLC (CHCl3 : MeOH = 20 : 1), the residue was dissolved in CH2Cl2, and it was then separated with 2 N HCl and H2O once each. The organic layer was dried over anhydrous NaSO4, and the residue was then purified with a silica gel column, so as to obtain compound 7 (80.9 mg; 0.17 mmol; 26%). [Show Image] 1H-NMR (400MHz, CDCl3): delta 7.91-7.83 (6H, m), 6.77 (2H, d, J= 9.0 Hz), 6.12-5.98 (1H, m), 4.60-4.44 (1H, m), 4.12-3.98, 3.69-3.48 (each 1H, m), 3.11 (6H, s), 2.13-1.25 (8H, m), 1.46 (9H, s). 13C-NMR (99.5 MHz, CDCl3): delta166.13, 154.87, 152.65, 143.49, 134.66, 127.60, 125.29, 122,16, 111.37, 48.29, 46.56, 40.35, 32.16, 31.94, 28.94, 28.52. QSTAR (Applied Biosystems/MDS SCIEX) (ESI): [MH+] C26H36N5O4: 466.2818, found: 466.2805. | |
In dichloromethane; at 0 - 20℃; for 22h; | Preparation 26; (4-AMINO-CVCLOHEXVL)-CARBAMIC acid ter-butyl ester; 1, 4-DIAMINOCYCLOHEXANE (80: 20 cis : trans, 25.7g, 0. 229MOL) was dissolved in dichloromethane (300ml) under nitrogen and cooled to 0C. A solution of DITERTBUTYL dicarbonate (10g, 45. 8MMOL) in DICHLOROMETHANE 100ml) was then added dropwise over 4h and the reaction was allowed to warm to room temperature and stirred for 18h. The solvent was removed under reduced pressure and the residue was partitioned between 10% citric acid 200ml) and diethylether (100MOI). The aqueous phase was extracted with diethylether (100ML) and basified to pH 10 with concentrated aqueous ammonia. It was then extracted with DICHLOROMETHANE (300ML + 4x100ml) and the combined dichloromethane extracts were washed with brine (100MOI), dried over MGS04 and the solvent was removed under reduced pressure to give (4-Amino-cyclohexyl)-carbamic acid ter-butyl ester (9.29g) as a crystalline solid. 'H NMR (400MHZ, CDCI3) : DZ 4.53-4. 68 (0.8H, brs), 4.25-4. 37 (0.2H, brs), 3.53-3. 71 (0.8H, brs), 3.32-3. 42 (0.2H, brs), 2.81-2. 90 (0.8H, m), 2.57-2. 66 (0.2H, m), 1.96-2. 02 (0.4H, d), 1.83-1. 89 (0.4H, d), 1.55-1. 73 (3.2H, m), 1.10-1. 55 (13H, 2XM + S) ppm. LRMS (thermospray): M/Z [M+H] + 215. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In acetonitrile; at 90℃; for 72h; | Step 1; To a solution of 1.28 g (6 mmol) of (4-amino-cyclohexyl)-carbamic acid tert butyl ester (prepared as described by Anslyn, et al., J. Org. Chem., 1996,8811) in 40 mL of acetonitrile was added TEA (0.87 mL, 6 mmol) and 2-chloro-6-methoxy-3- nitropyridine (1.13 g, 6 mmol). The mixture was heated at 90 C for 3 days. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was digested with 50 mL of hot ethyl acetate, filtered, and concentrated to afford 1.80 g (82%) of [4- (6-methoxy-3-nitro-pyridin-2-ylamino)-cyclohexyl]-carbamic acid tert butyl ester. NMR (CD30D) : 8.55 (br d, 1 H); 8.28 (d, 1 H); 6.61 (br d, 1 H); 6.08 (d, 1 H); 4.14 (m, 1 H); 3.95 (s, 3 H); 3.31 (m, 1 H); 2.15 (m, 2 H) ; 1.94 (m, 2 H) ; 1.55- 1.20 (m, 4 H); 1.42 (s, 9 H). APCI MS: 367 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (4-amino-cyclohexyl)-carbamic acid ter-butyl ester (6.72 g) in CHC13 (67 mL) were added 4-bromo-2-trifluoromethoxy-benzaldehyde (8.44 g), acetic acid (1.88 g), and NaBH (OAc) 3 (9.97 g). The mixture was stirred at ambient temperature for 4 hr and poured into saturated aqueous NaHC03. The aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgS04, filtrated, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 33% EtOAc in hexane) to give [cis-4- (4-bromo-2-trifluoromethoxy-benzylamino)- cyclohexyl]-carbamic acid tert-butyl ester. To a solution of the above material (3.00 g) in EtOAc (30 mL) was added 4 M hydrogen chloride in EtOAc (60 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated under reduced pressure. The residue was alkalized with saturated aqueous NaHC03 and the aqueous layer was extracted with CHCl3 (seven times). The combined organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to give N-(cis-4-bromo-2-trifluoromethoxy- benzyl)-cyclohexane-1, 4-diamine (2.39 g). ESI MS m/e 367, M+ ; 1H NMR (300 MHz, CDCl3) 5 1.22-1. 96 (m, 8 H), 2.51-2. 71 (m, 1 H), 2.87-3. 13 (m, 1 H), 3.74 (brs, 2 H), 7.28-7. 50 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In dichloromethane; N,N-dimethyl-formamide; | Preparation 20 {4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)amino]-cyclohexyl}-carbamic Acid tert-Butyl Ester 2-Chloro-5-fluoro nicotinic acid (3.00 g, 0.017 mol) (see Preparation 41), was dissolved in dichloromethane (100 ml) and N,N-dimethylformamide (1 drop) was added, followed by oxalyl chloride (3.0 ml, 0.034 mol). The reaction mixture was held at room temperature for 4 hours, after which time the solvent was removed in vacuo. The residue was suspended in dichloromethane (100 ml) and triethylamine (5 ml) added followed by addition of <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (5.40 g, 0.026 mol) (Preparation 42a). The reaction mixture was then held under an atmosphere of nitrogen at room temperature for a further 18 hours. The reaction mixture was then washed with water (100 ml) and the organic phase dried over anhydrous magnesium sulphate. The solvent was removed in vacuo, and the residue triturated with ethyl acetate/pentane (1:1, by volume, 10 ml) giving {4-[(2-chloro-5-fluoro-pyridine-3-carbonyl)amino]-cyclohexyl}-carbamic acid tert-butyl ester (2.5 g, 80:20 syn:anti) as a white solid. 1H NMR (300 MHz, CDCl3): delta=8.32-8.38 (1H, d), 7.95-8.00 (0.8H, m), 7.81-7.88 (0.2H, d), 6.58-6.75 0.8H, m), 6.29-6.37 (0.2H, m), 4.38-4.62 (1H, m), 4.12-4.25 (0.8H, m), 3.95-4.03 (0.2H, m), 3.58-3.73 (0.8H, m), 3.38-3.56 (0.2H, m), 2.03-2.2 (0.8H, m), 1.66-1.95 (6.4H, m), 3.87-4.02 (1H, m), 1.58 (9H, s), 1.23-1.44 (0.8H, m, partially masked by solvent) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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With ammonia; citric acid; In dichloromethane; | Preparation 40 Anti-(4-Amino-cyclohexyl)-carbamic Acid tert-Butyl Ester Anti 1,4-Diamino cyclohexane (18.27 g, 0.16 mol) was dissolved in dichloromethane (80 ml) and the solution cooled at 0 C. under an atmosphere of nitrogen. The reaction mixture was maintained at 0 C. and a solution of di-tert-butyl dicarbonate (6.98 g, 0.032 mol) in dichloromethane (70 ml) added dropwise over a period of 5 hours. The reaction mixture was stirred at room temperature for a further 16 hours and then washed with water (200 ml). The organic layer was separated, extracted with a 10% aqueous solution of citric acid (200 ml) and the organic phase disgarded. The pH of the aqueous phase was then increased to pH>8 by the addition of 0.88 ammonia and extracted with dichloromethane (3-fold 150 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate and the solvent removed in vacuo to give anti (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (4.83 g) as a solid. 1H NMR (400 MHz, CDCl3): delta=4.35 (br s, 1H), 4.55 (br s, 1H), 3.40 (br S, 1H), 2.60-2.65 (m, 1H), 1.80-2.00 (m, 4H), 1.10-1.50 (m, ~14H) ppm. LRMS (electrospray): m/z [M+H]+ 215. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
palladium on charcoal; In methanol; hexane; ethyl acetate; toluene; | Preparation 42b Syn-(4-Amino-cyclohexyl)-carbamic Acid tert-Butyl Ester 5% Palladium on charcoal (5 g) was mixed with toluene (10 ml) and was added to (4-azido-cyclohexyl)-carbamic acid tert-butyl ester (170 g, 0.71 mol, see WO 99/54284) in methanol (400 ml). The mixture was hydrogenated (80 atmospheres) at room temperature for 18 hours and then filtered. The solvent was evaporated in-vacuo and the residue was triturated with ethyl acetate (50 ml) and then with hexane (200 ml). The solid obtained was isolated by filtration, dissolved in ethyl acetate (600 ml) and filtered through Celite. The filtrate was concentrated in-vacuo to give a slush that was diluted with hexane (300 ml). The solid obtained was isolated by filtration and was washed with ethyl acetate in hexane (20:80). The mother liquors were combined and evaporated in-vacuo, the residue was purified by chromatography on silica gel using ethyl acetate and then methanol as eluant. The material obtained was crystallized from ethyl acetate and hexane and combined with the first crop to give syn-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester as a white solid (76 g). Mp 88-90 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Synthesis of 3-Chloro-benzo[b]thiophene-2-carboxylic acid (4'-cyano-6-methoxy-biphenyl-3-ylmethyl)-(4-methylaminocyclohexyl)-amide hydrochloride (7) (4-Amino-cyclohexyl)-carbamic acid t-butyl Ester (1) A solution of di-t-butyl-dicarbonate (12.0 g, 54.7 mmol) and tetrahydrofuran (250 mL) was added slowly under nitrogen over 3 h to a suspension of 1,4-diaminocyclohexane (50.0 g, 0.44 mol) in tetrahydrofuran (250 mL) while maintaining the temperature below 10 C. The mixture was allowed to warm to room temperature and subsequently stirred for 16 hours, then filtered. The filtrate was concentrated in vacuo to give a residue. Water (500 mL) was added to the residue, followed by stirring for approximately 15 min, after which the mixture was filtered and the aqueous layer was extracted with dichloromethane (3*200 mL). The organic extracts were combined and concentrated to give a residue which was dissolved in t-butylmethyl ether (350 mL) and washed with water (3*50 mL). The t-butylmethyl ether was removed in vacuo to give the title compound 1 (8.1 g, 69%) as a solid: deltaH (360 MHz: CDCl3) 1.06-1.24 (m, 4H), 1.43 (s, 9H), 1.83 (d, 2H), 1.98 (d, 2H), 2.56-2.66 (m, 1H), 3.30-3.35 (m, 1H) and 4.31-4.38 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide; In tetrahydrofuran; water; | N-Methyl-cyclohexane-1,4-diamine (2) Amine 1 (15.0 g, 0.7 mol) was added slowly over 45 min to a 1N solution of lithium aluminium hydride in THF (450 mL, 0.36 mol) under nitrogen. The mixture was stirred for 30 min at room temperature, then heated at reflux for 5-6 hours under nitrogen. Water (13.2 mL) was added to the mixture followed by 15% aqueous sodium hydroxide (13.2 mL), and water (39.7 mL). The mixture was then stirred for 15-30 min. The solid was filtered off and washed with t-butylmethyl ether (200 mL), dichloromethane (200 mL), and t-butylmethyl ether (200 mL). The organic extracts were collected, dried (MgSO4), and filtered. The drying agent was then washed with dichloromethane and the organic extracts combined and concentrated in vacuo to give the title compound 2 (7.52 g, 84%) as a pale yellow solid: deltaH (360 MHz: CDCl3) 1.04-1.20 (q, 4H), 1.51 (br s, 3H), 1.80-1.96 (m, 4H), 2.25-2.35 (m, 1H), 2.41 (s, 3H), 2.61-2.72 (m, 1H). |
84% | With sodium hydroxide; In tetrahydrofuran; water; | N-Methyl-cyclohexane-1,4-diamine (2) Amine 1 (15.0 g, 0.7 mol) was added slowly over 45 min to a 1N solution of lithium aluminium hydride in THF (450 mL, 0.36 mol) under nitrogen. The mixture was stirred for 30 min at room temperature, then heated at reflux for 5-6 hours under nitrogen. Water (13.2 mL) was added to the mixture followed by 15% aqueous sodium hydroxide (13.2 mL), and water (39.7 mL). The mixture was then stirred for 15-30 min. The solid was filtered off and washed with t-butylmethyl ether (200 mL), dichloromethane (200 mL), and t-butylmethyl ether (200 mL). The organic extracts were collected, dried (MgSO4), and filtered. The drying agent was then washed with dichloromethane and the organic extracts combined and concentrated in vacuo to give the title compound 2 (7.52 g, 84%) as a pale yellow solid: deltaH (360 MHz: CDCl3) 1.04-1.20 (q, 4H), 1.51 (br s, 3H), 1.80-1.96 (m, 4H), 2.25-2.35 (m, 1H), 2.41 (s, 3H), 2.61-2.72 (m, 1H). |
84% | With sodium hydroxide; In tetrahydrofuran; water; | N-Methyl-cyclohexane-1,4-diamine (2) Amine 1 (15.0 g, 0.7 mol) was added slowly over 45 min to a 1N solution of lithium aluminium hydride in THF (450 mL, 0.36 mol) under nitrogen. The mixture was stirred for 30 min at room temperature, then heated at reflux for 5-6 hours under nitrogen. Water (13.2 mL) was added to the mixture followed by 15% aqueous sodium hydroxide (13.2 mL), and water (39.7 mL). The mixture was then stirred for 15-30 min. The solid was filtered off and washed with t-butylmethyl ether (200 mL), dichloromethane (200 mL), and t-butylmethyl ether (200 mL). The organic extracts were collected, dried (MgSO4), and filtered. The drying agent was then washed with dichloromethane and the organic extracts combined and concentrated in vacuo to give the title compound 2 (7.52 g, 84%) as a pale yellow solid: deltaH (360 MHz: CDCl3) 1.04-1.20 (q, 4H), 1.51 (br s, 3H), 1.80-1.96 (m, 4H), 2.25-2.35 (m, 1H), 2.41 (s, 3H), 2.61-2.72 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 77(2) cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamine (77 mg) was obtained as an oil from cis-4-(N-tert-butoxycarbonylamino)cyclohexylazide (252 mg) in a manner similar to Preparation 61(3). NMR (CDCl3, delta): 1.44 (9H, s), 1.5-1.8 (4H, m), 1.8-2.2 (4H, m), 2.91 (1H, br), 3.65 (1H, br), 4.66 (1H, br); Mass (ESI+): 215(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 77(1) 2-[cis-4-(N-tert-Butoxycarbonylamino)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (282 mg) was obtained as amorphous powders from N-(3,4-dimethoxybenzyl)-2-fluoro-5-nitrobenzamide (200 mg) and cis-4-(N-tert-butoxycarbonylamino)cyclohexylamine (256 mg) in a manner similar to Example 1(1). NMR (CDCl3, delta): 1.45 (9H, s), 1.51-1.70 (2H, m), 1.75-1.94 (6H, m), 3.55-3.80 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.54 (2H, d, J=5 Hz), 4.59 (1H, m), 6.49 (1H, m), 6.66 (1H, d, J=9 Hz), 6.82-6.95 (3H, m), 8.15 (1H, d, J=9 Hz), 8.33 (1H, d, J=2 Hz), 9.17 (1H, d, J=7 Hz); Mass (ESI-): 527(M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In tetrahydrofuran; | b. Trans-4-[3-(3-methyl-4-pyrrolidinocarbonyl-phenyl)-propargylamino]-cyclohexylamine 0.53 g (4.09 mmol) of N-ethyl-diisopropylamine is added to a solution of 0.50 g (1.63 mmol) of 3-(3-methyl4-pyrrolidinocarbonyl-phenyl)-propargyl bromide at 0 C. and 0.88 g (4.10 mmol) of trans-4-tert-butoxycarbonyl-aminocyclohexylamine in 50 ml of THF and then stirred for 2 hours at 0 C., 2 hours at 50 C. and 15 hours at ambient temperature. The mixture is then washed twice with 50 ml of saturated sodium hydrogen carbonate solution and with 50 ml of sodium chloride solution. The aqueous phases are then extracted with 50 ml of ethyl acetate and the combined organic phases are dried with sodium sulphate and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; | a) [4-[[[4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl]amino]cyclohexyl]-carbamic acid, 1,1-dimethylethyl ester Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), (4-aminocyclohexyl)-carbamic acid, 1,1-dimethylethyl ester (0.194 g, Journal of Organic Chemistry, 1996, 61(25), 8811-8818), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluding with ethyl acetate: iso-hexane (1:1) then ethyl acetate: ethanol (95:5) to give the subtitle compound as a colourless oil (0.24 g). MS (APCI+ve) 530 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; benzaldehyde; | Preparation 26 tert-Butyl trans-4-(benzylamino)cyclohexylcarbamate The title compound was prepared by a similar method to example 5 from tert-butyl trans-4-aminocyclohexylcarbamate (1.0 g, 4.7 mmol) (J. Org. Chem. 8811, 61, 1996), benzaldehyde (530 mg, 5 mmol) and sodium triacetoxyborohydride (2.0 g, 9.4 mmol). The product was purified by column chromatography on silica gel eluding with a solvent system of dichloromethane:methanol:ammonia (95:5:0.5) to give the title compound (0.73 g) as a solid. 1H NMR (CDCl3) delta=7.35-7.20 (5H, m), 4.35 (1H, br s), 3.80 (2H, s), 3.40 (1H, br s), 2.50-2.40 (1H, m), 2.05-1.90 (4H, m), 1.45 (9H, s), 1.30-1.05 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate; In dichloromethane; | Preparation 32 tert-Butyl trans-4-[(methylsulfonyl)amino]cyclohexylcarbamate Methanesulfonyl chloride (0.56 g, 4.7 mmol) was added to a stirred solution of tert-butyl trans-4-aminocyclohexylcarbamate (J. Org. Chem. 8811, 61, 1996) (1.0 g, 4.7 mmol) and N-ethyl-N-isopropyl-2-propanamine (0.67 g, 0.52 mmol) in dichloromethane (30 ml). The reaction mixture was stirred for 30 min at room temperature and then partitioned between ethyl acetate (300 ml) and water (100 ml). The organic layer was washed twice with 1 molar aqueous citric acid solution and then with a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous sodium sulfate and the solvent removed under reduced pressure to give a residue that was triturated with diethyl ether to give the title compound (0.99 g) as a white solid. 1H NMR (CDCl3) delta=4.35 (1H, br s), 4.15-4.10 (1H, m), 3.40 (1H, br s), 3.30-3.20 (1H, m), 2.95 (3H, br s), 2.10-2.00 (4H, m), 1.40 (9H, s), 1.40-1.15 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(114) 4-[(3-Methylphenyl-)amino]-6-[(trans-4-methylsulphonylaminocyclohexyl)amino]pyrimido[5,4-d]pyrimidine Prepared from the compounds of Example 2 by reaction with trans-4-tert-butyloxycarbonylamino-cyclohexylamine and subsequent reaction with ethereal hydrogen chloride solution and methanol, as well as subsequent reaction with methanesulphonyl chloride. Melting point: 192-195 C. Rf value: 0.37 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(113) 4-[(3-Methylphenyl)amino]-6-[(trans-4-aminocyclohexyl)amino]pyrimido[5,4-d]pyrimidine Prepared from the compounds of Example 2 by reaction with trans-4-tert-butyloxy-carbonylamino-cyclohexylamine and subsequent reaction with ethereal hydrogen chloride solution and methanol. Melting point: >260 C. Rf value: 0.28 (reversed phase silica gel; methanol/5% strength sodium chloride solution=10:4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; | (115) 4-[(3-Methylphenyl)amino]-6-[(trans-4-acetylaminocyclohexyl)amino]-pyrimido[5,4-d]pyrimidine Prepared from the compounds of Example 2 by reaction with trans-4-tert-butyloxycarbonylamino-cyclohexylamine and subsequent reaction with ethereal hydrogen chloride solution and methanol, as well as subsequent reaction with acetic anhydride and triethylamine. Melting point: 302-305 C. Rf value: 0.38 (silica gel; petroleum ether/ethyl acetate/methanol=10:8:3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | 13t) In analogy to Example 13m), from ethyl 2-(2-chloro-4-iodo-benzoyl)-3-ethoxy-acrylate and trans-4-tert-butoxycarbonylamino-cyclohexyl-amine there is obtained 1-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylate as a colourless solid. Yield: 35%. M.p. 137-140. |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; | General Procedure A for the Hartwig-Buchwald amination reaction:1.0 eq of the arylbromide, 1.5 eq Cs2CO3 and 1.2 eq of the amine were dissolved in toluene. If the amine was taken as a salt another equivalent of CS2CO3 was used; if additionally the arylbromide was used as a salt (HCI- or TFA-salt of the isoquinolines), again, 1 additional equivalent of CS2CO3 was used. The solution was degassed and flushed with argon. Then, 0.03 eq Pd(OAc)2 and 0.045 eq BINAP were added and the solution was heated at 100 0C until the reaction was complete or no further improvement could be achieved. For product isolation, the solution was cooled to room temperature, filtered and the filtrate was evaporated. The residue was taken up in H2O and extracted ethyl acetate. The organic layer was separated, dried with MgSO4 and the solvent was removed i. vac. The crude product was purified by preparative HPLC. The following compounds were synthesized following General Procedure A (Table 1): |
Yield | Reaction Conditions | Operation in experiment |
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Step (a) tert-butyl {cis-4-[(imidazo[l,2-a]pyridin-2- ylcarbonyl)amino] cyclohexyl} carbamate, O <n="53"/>Imidazo[l,2a]pyridine-2-carboxyli acid (5 g, 30.8 mmol) was dissolved in NMP (200 ml) and DIEA (11.96 g, 16.43 ml) was added, followed by O-(7-Azabezotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (14.07 g, 37 mmol). The reaction was stirred for 5 min. (4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (6.61 g, 30.8 mmol) was then added and the solution stirred at room temperature ovenight. Water was added and the product extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulphate), filtered and concentrated in vacuo to afford the sub-title compound (8.5 g, contains some NMP). This was used without further purification. APCI (+ve) m/z: 359 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With triethylamine; In dichloromethane; at 20℃; for 16h; | A. Synthesis of tert-butyl (4-{r(2-nitrophenyl)carbonyllamino)cvclohexyl)carbamate. To a solution of 2-nitrobenzoyl chloride (0.38 g, 2.05 mmol) in dichloromethane (5 mL) were added slowly tert-butyl 4-aminocyclohexylcarbamate (0.43 g, 2.00 mmol) and triethylamine (0.31 mL, 2.20 mmol) at ambient temperature. The mixture was stirred at ambient temperature for sixteen hours followed by the addition of dichlromethane (100 mL). The mixture was washed with 1 M citric acid solution, saturated sodium carbonate solution and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give tert-butyl (4-[(2- nitrophenyl)carbonyl]amino}cyclohexyl)carbamate (0.30 g, 41%) as a white solid: MS (ES+) m/z 364.2 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol; at 70℃; | Synthesis of tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexylcarbamate (1.4); Isocyanate 1.3 (1 equiv.) was added to the solution of amine 1.2 (1 equiv.) in ethanol. The reaction mass was warmed to 70 C. and stirred at this temperature overnight. The solvent was then removed in vacuo, and the crude product was recrystallised in diethyl ether to give compound 1.4 as a solid. |
Yield | Reaction Conditions | Operation in experiment |
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Synthesis of tert-butyl 4-(4-fluorobenzamido)cyclohexylcarbamate (3.2) To a solution of compound 3.1 (1 equiv.) in dichloromethane, EDC (1.2 equiv.) and DMAP (1.5 equiv.) were added with stirring at 0 C. The resulting solution was stirred at this temperature for 15 min after which compound 1.2 (1.2 equiv.) was added, and the resulting mixture allowed to room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N HCl, sat. NaHCO3 and brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain compound 3.2 as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane;Inert atmosphere; | (3) Synthesis of compound 7 (compound 7 shown in Figure 2); Compound 5 (compound 5 shown in Figure 2) was protected with Boc according to the method described in the publication of Komatsu et al. (T. Komatsu et al., (2006), J. Am. Chem. Soc., 128, 15946-15947), so as to obtain compound 6 (compound 6 shown in Figure 2). Compound 6 (0.166 g; 0.78 mmol; 1.2 eq) was dissolved in CH2Cl2 (30 ml). Thereafter, p-Methyl Red (0.177 g; 0.66 mmol), WSC (0.253 g; 1.32 mmol; 2 eq), and TEA (2 drops) were added to the solution, and the obtained mixture was then stirred overnight in an Ar atmosphere. After the disappearance of compound 6 had been confirmed using TLC (CHCl3 : MeOH = 20 : 1), the residue was dissolved in CH2Cl2, and it was then separated with 2 N HCl and H2O once each. The organic layer was dried over anhydrous NaSO4, and the residue was then purified with a silica gel column, so as to obtain compound 7 (80.9 mg; 0.17 mmol; 26%). [Show Image] 1H-NMR (400MHz, CDCl3): delta 7.91-7.83 (6H, m), 6.77 (2H, d, J= 9.0 Hz), 6.12-5.98 (1H, m), 4.60-4.44 (1H, m), 4.12-3.98, 3.69-3.48 (each 1H, m), 3.11 (6H, s), 2.13-1.25 (8H, m), 1.46 (9H, s). 13C-NMR (99.5 MHz, CDCl3): delta166.13, 154.87, 152.65, 143.49, 134.66, 127.60, 125.29, 122,16, 111.37, 48.29, 46.56, 40.35, 32.16, 31.94, 28.94, 28.52. QSTAR (Applied Biosystems/MDS SCIEX) (ESI): [MH+] C26H36N5O4: 466.2818, found: 466.2805. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 A sample of (4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (available from Albany Molecular Research; 2.00 g, 10.7 mmol, 1 eq.), acetone (1.18 mL, 16.1 mmol, 1.5 eq.), sodium triacetoxyborohydride (3.41 g, 16.1 mmol, 1.5 eq.) and 50 mL of methylene chloride were stirred at RT for 20 hours. Added 20 mL of 1 N NaOH and stirred 10 minutes then extracted 3* with methylene chloride. The organic layers were combined, dried and stripped in vacuo to obtain an oil. Added sodium triacetoxyborohydride (3.41 g, 16.1 mmol, 1.5 eq.) and 37% formaldehyde (aqueous) (2.62 mL, 32.2 mmol, 3 eq). Stirred 4 hours. Added 20 mL of 1 N NaOH and stirred 10 minutes then extracted the aqueous 3* with methylene chloride. The organic layers were combined, dried and stripped in vacuo to give cis-[4-(Isopropyl-methyl-amino)-cyclohexyl]-carbamic acid tert-butyl ester (3.20 g) as a colorless oil. MS found: (M+H)+=271. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; for 18h;Reflux; Inert atmosphere; | Preparation 34 <n="222"/>(4-Pyrrolidin-1 -yl-cyclohexyl)-carbamic acid tert-butyl ester (4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (4.9 g, 23mmol) and sodium hydrogencarbonate (5.8 g) were added to toluene followed by 1 ,4-dibromobutane (5.0 g, 23mmol). The heterogenous mixture was then heated at reflux with a Dean-Stark trap to remove water, under a nitrogen atmosphere, for 18 hours. The mixture was cooled to room temperature, filtered and evaporated. The crude residue was dissolved in ethyl acetate, loaded onto a pad of silica (120 g) and eluted with ethyl acetate (~ 300 ml) and then 90/10/2 ethyl acetate/MeOH/0.880 ammonia (400 ml). The eluate was evaporated to give the title compound as an amorphous solid (5.1 g). LRMS: m/z [M+1] 269. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20 - 50℃; for 76h; | Example 140 terf-Butyl [4-([6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)cyclohexyl]carbamate <n="103"/> 6-(3-Fluorophenyl)nicotinic acid (1.01 g, 4.67 mmol) and te/f-butyl (4-aminocyclohexyl) carbamate (1.0 g, 4.67 mmol) was dissolved in DMF (5 ml_). The solution was stirred and triethylamine (2.36 g, 23.3 mmol) and HBTU (2.21 mg, 5.83 mmol) were added. The reaction mixture was stirred for 16 hours at 5O0C and then left to stand at room temperature for 60 hours. The solvent was then removed under reduced pressure and the residue was partitioned between dichloromethane (30 ml.) and semi-saturated aqueous sodium hydrogen carbonate solution (20 ml_). The organic layer was separated by filtration through a phase separation tube and then evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a mixture of heptane:ethyl acetate 100:0 and 20:80 to give the title compound (680mg) as a brown solid. LRMS (ES): observed 412 (M-1 ), calculated 412.21 [M-1]. 1H NMR (400MHz, DMSOd6) delta ppm 1.31-1.41 (s, 9H), 1.49-1.61 (m, 4H), 1.66-1.81 (m, 4H), 3.36-3.44 (m, 1 H), 3.79-3.87 (m, 1 H), 6.57-6.67 (m, 1 H), 7.26-7.35 (m, 1 H), 7.51-7.59 (m, 1 H), 7.91-8.02 (m, 2H), 8.04-8.14 (m, 1 H), 8.24-8.34 (m, 2H), 9.02-9.08 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In methanol; | A solution of Boc2O (1.0 g, 4.6 mmol) in methanol (25 mL) was slowly added to trans-1,4-diaminocyclohexane (1.0 g, 8.8 mmol) in methanol (100 mL), and the reaction mixture was stirred at room temperature for 1 h. After filtration, the filtrate was concentrated under vacuum to ca. 5 mL, and then cooled to -20 C. The crystallized product was collected. The filtrate was resubmitted to the same reaction condition. After the second cycle the desired product 6 was obtained in 56% yield (1.05 g). IR (cm-1): 3365, 2933, 1686, 1520; 1H NMR (300 MHz, CDCl3): 4.90-5.02 (br, 1H), 3.30-3.42 (br, 1H), 2.58-2.66 (m, 1H), 1.92-2.00 (br, 2H), 1.85-1.97 (m, 4H), 1.43 (s, 9H), 1.10-1.25 (m, 4H); 13C NMR (75 MHz, CDCl3): 154.0, 77.9, 48.7, 48.0, 34.2, 34.1, 31.0, 30.9, 27.3; MS (EI) calcd for C11H22N2O2(M+) 214, found 214. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 12h; | Example 43 {4-[3-(3-Bromo-phenyl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester To a solution of 3-(3-bromo-phenyl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine (from Example 42 supra) (1.10 g, 2.0 mmol) in DMF (20 mL) was add DIPEA (0.39 g, 2.8 mmol) and <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (0.60 g, 2.8 mmol). This mixture was stirred at 120 C. for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration. The obtained yellow solid was purified by chromatography (silica gel, MeOH:dichloromethane, 1:100) to give a light solid which was washed with ether (4 mL) to give {4-[3-(3-bromo-phenyl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid. (Yield 730 mg, 50.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 0.333333h;Microwave irradiation; | Trans (4-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]-cyclohexyl} - carbamic acid tert-butyl ester Trans [4-(3-Nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl esterA mixture of trans <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (394 mg, 1.80 mmol), DIPEA (0.44 mL, 2.50 mmol) and 4-chloro-3-nitro-[l,5]naphthyridine (350 mg, 1.67 mmol) in propan-2-ol (6 mL) was heated to 120 C using microwave irradiation for 20 minutes. After cooling, the resulting precipitate was isolated by filtration and the solid washed (propan-2-ol) and dried to afford 233 mg (36%) of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]- carbamic acid tert-butyl ester as a pale yellow solid. The above filtrate was concentrated in vacuo and the residue taken up in to ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated to provide an additional 238 mg (37%) of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT = 3.87 min, m+H = 388; 1H NMR (400 MHz, DMSO-d6): delta 9.44 (br s, 1 H), 9.18 (s, 1 H), 8.92 (dd, 1 H), 8.29 (dd, 1 H), 7.86 (dd, 1 H), 6.78 (m, 1 H), 5.13 (br s, 1 H), 2.13 (m, 2 H), 1.85 (m, 2 H), 1.54-1.51 (m, 2 H), 1.39 (s, 9 H), 1.33 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 0.416667h;Microwave irradiation; | Trans (R)- 1 - { 1 -[4-(2,2,2-Trifluoro-ethylamino)-cyclohexyl]- lH-imidazo[4,5-c]quinolin-2-yl} - ethanolTrans [4-(3-Nitro-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl esterA suspension of 4-chloro-3-nitro-quinoline (800 mg, 3.80 mmol) in propan-2-ol (10 mL) was treated with <strong>[195314-59-1](4-amino-cyclohexyl)-carbamic acid tert-butyl ester</strong> (903 mg, 4.20 mmol) and DIPEA (1.00 mL, 5.80 mmol) and the reaction mixture was heated at 120 C using microwave irradiation for 25 minutes. After cooling, the resulting precipitate was collected by filtration, washed (propan-2-ol, water and diethyl ether) and dried between 50-70 C under vacuum for 90 minutes. Trans [4-(3-nitro-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.30 g, 88%) was isolated as a yellow solid. LCMS (Method B, ESI): RT = 3.17 min, m+H = 387; 1H NMR (400 MHz, CDC13): delta 9.37 (s, 1 H), 9.34 (d, 1 H), 8.14 (d, 1 H), 8.01 (dd, 1 H), 7.78 (ddd, 1 H), 7.51 (ddd, 1 H), 4.40 (s, 1 H), 4.18-4.05 (m, 1 H), 3.53 (s, 1 H), 2.28 (m, 2 H), 2.16 (m, 2 H), 1.79-1.59 (m, 2 H), 1.46 (s, 9 H), 1.37-1.24 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In isopropyl alcohol; at 100℃; for 1.0h; | A mixture of <strong>[110651-92-8]7-chloro-6-nitrothieno[3,2-b]pyridine</strong> (118 mg, 0.550 mmol), tert-butyl (4-aminocyclohexyl)carbamate (140 mg, 0.66 mmol) and triethylamine (0.23 mL, 1.6 mmol) in isopropyl alcohol (5 mL) was heated at 100 C. for 1 h. The mixture was concentrated to give the desired product as a mixture of cis- & trans-isomer mixtures to be used in the next step directly. LCMS calculated for C18H25N4O4S (M+H)+: m/z=393.2. Found: 393.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium tris(acetoxy)borohydride; In methanol; at 30℃; | To a solution of <strong>[195314-59-1]tert-butyl N-(4-aminocyclohexyl)carbamate</strong> (25 g, 117 mmol, 1.0 eq) and 3- nitrobenzaldehyde (18 g, 117 mmol, 1 .0 eq) in MeOH (500 mL) was added NaBH(OAc)3 (50 g, 234 mmol, 2.0 eq) by portions. Then the resulting mixture was stirred overnight at 30C. LC-MS indicated complete conversion. The solvent was removed under vacuum and the residue was purified by column chromatography (DCM: MeOH = 15:1) to provide tert-butyl N-(4-[(3- nitrobenzyl)amino]cyclohexyl)carbamate (33 g, 83%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In N,N-dimethyl-formamide; at 80℃; | To a solution of the obtained compound (2) (75 mg, 0.107 mmol) in 1 mL anhydrous DMF was added N-Boc-cyclohexane-1,4-diamine (69 mg, 0.322 mmol) and TEA (60 muL, 0.428 mmol), and the reaction mixture was stirred at 80 C. After the reaction completion monitored by TLC, the resulting solution was diluted with distilled water, then extracted with ethyl acetate. The combined organic layer was washed with brine and condensed under reduced pressure. The desired compound (5) was purified by silica-gel flash column chromatography (n-hexane:ethylacetate=1:1?dichloromethane:methanol=10:1) as a yellowish oil (45 mg, 50%) 1H NMR (500 MHz, CDCl3) delta8.10-7.87 (m, 8H), 7.57-7.28 (m, 12H), 6.19 (dd, J=10.0, 10.0 Hz, 1H), 5.69 (dd, J=10.0, 9.5 Hz, 1H), 5.38 (d, J=3.5 Hz, 1H), 5.30 (dd, J=10.0, 3.5 Hz, 1H), 4.61-4.59 (m, 1H), 4.99-4.43 (m, 2H), 3.95-3.93 (m, 1H), 3.62-3.59 (m, 1H), 2.87-2.78 (m, 2H), 2.33-2.31 (m, 1H), 2.03-2.02 (m, 2H), 1.96-1.87 (m, 2H), 1.73-1.68 (m, 2H), 1.44 (s, 9H), 1.30-1.21 (m, 3H), 1.05-0.96 (m, 3H); LC/MS calcd for C47H53N2O12 [M+H]+: 837; found: 837. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 15h;Inert atmosphere; Sealed tube; | As shown in step 4-ii of Scheme 4, a degassed solution of 3-(8- bromoquinoxalin-6-yl)-8-oxa-3-azabicyclo[3.2.l]octane (261 mg, 0.815 mmol), tert- butyl A-(4-aminocyclohexyl (carbarn ate (210 mg, 0.98 mmol), rac-BINAP (102 mg, 0.163 mmol), CS2CO3 (797 mg, 2.45mmol), and Pd2(dba)3 (75 mg, 0.0815 mmol) in toluene (10.5 mL) was heated at l00C (oil bath temp) in a sealed microwave tube for 15 hours. After cooling, the mixture was applied directly to a chromatography column and purified by medium pressure silica gel chromatography (0 to 100% EtO Ac/hexanes gradient) to afford /er/-butyl (4-((7-(8-oxa-3-azabicyclo[3.2. l]octan- 3-yl)quinoxalin-5-yl)amino)cyclohexyl)carbamate (compound 1007, 141 mg, 36% yield) as a white solid: 1H-NMR (400 MHz, CDCl3) d 8.49 (s, 1H), 8.23 (d, J = 1.5 Hz, 1H), 6.48 (s, 1H), 6.18 (d, J = 1.9 Hz, 1H), 6.06 (s, 1H), 4.52 (s, 1H), 4.47 (s, 2H), 3.60 (s, 2H), 3.45 (d, J = 11.6 Hz, 2H), 3.14-3.12 (m, 2H), 1.96-1.84 (m, 4H), 1.79 (s, 5H), 1.54 (s, 3H) and 1.38 (s, 9H) ppm; ESMS (M+H+) = 453.96. |
Tags: 195314-59-1 synthesis path| 195314-59-1 SDS| 195314-59-1 COA| 195314-59-1 purity| 195314-59-1 application| 195314-59-1 NMR| 195314-59-1 COA| 195314-59-1 structure
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