There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 2615-25-0 * Storage: {[proInfo.prStorage]}
* 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.
In a 500 mL autoclave, 100 g of 1,4-diaminocyclohexane (cis / trans form = 80/20, manufactured by Tokyo Chemical Industry Co., Ltd.), 100 g of propylene glycol monomethyl ether (PGME) 7.5 g of Ru catalyst ("AA-4501", 5percent Ru alumina powder, manufactured by N. E-Chemcat Co., Ltd.) and 0.63 g of sodium methoxide (manufactured by Tokyo Chemical Industry Co., Ltd.) were charged, (N 2) gas (10 kgf / cm 3) was repeated three times, and the inside of the system was replaced with nitrogen gas.While stirring at a stirring speed of 300 rpm, a temperature The reaction was carried out for 2 hours under the condition of 200 ° C. and pressure (pressure of N 2 gas) of 12 MPa. After the reaction, the reaction mixture was cooled to room temperature and pressure filtered using a 0.2 μm membrane filter to remove the catalyst to obtain a filtrate. Analysis of the obtained filtrate by gas chromatography mass spectrometry (GC-MS) revealed that the proportion of cis isomer was 63.37 areapercent, the proportion of trans form was 34.7 areapercent, the other components (4-aminocyclo By-product such as hexanol) was 1.93 areapercent, and cis / trans form = 65/35.
Reference:
[1] Patent: JP2015/13833, 2015, A, . Location in patent: Paragraph 0062; 0073
2
[ 106-50-3 ]
[ 2615-25-0 ]
Reference:
[1] Patent: US2175003, 1937, ,
[2] Nippon Kagaku Kaishi, 1941, vol. 62, p. 190,192[3] Chem.Abstr., 1942, p. 5140
[4] Bulletin of the Chemical Society of Japan, 1944, vol. 19, p. 153,154[5] Nippon Kagaku Kaishi, 1941, vol. 62, p. 190,192[6] Chem.Abstr., 1942, p. 5140
[7] Patent: US2175003, 1937, ,
[8] Nippon Kagaku Kaishi, 1941, vol. 62, p. 190,192[9] Chem.Abstr., 1942, p. 5140
[10] Bulletin of the Chemical Society of Japan, 1944, vol. 19, p. 153,154[11] Nippon Kagaku Kaishi, 1941, vol. 62, p. 190,192[12] Chem.Abstr., 1942, p. 5140
[13] Patent: US2175003, 1937, ,
[14] Nippon Kagaku Kaishi, 1941, vol. 62, p. 190,192[15] Chem.Abstr., 1942, p. 5140
[16] Bulletin of the Chemical Society of Japan, 1944, vol. 19, p. 153,154[17] Nippon Kagaku Kaishi, 1941, vol. 62, p. 190,192[18] Chem.Abstr., 1942, p. 5140
Example 17. N-(3-(5-((lr,4r)-4-(Dimethylamino)cyclohexylamino)-3-ethylpyrazolo[l,5- ajpyrimidin- 7-ylamino)phenyl)acrylamide (SB1-E-21) tert-Butyl (lr,4r)-4-aminocyclohexylcarbamate (SBl-E-21-1) To a solution of SM-21-1 (2.0 g, 17.5 mmol) in MeOH (100 mL) was added the solution of (Boc)20 (1.1 g, 5.04 mmol) in MeOH (60 mL) dropwise for 30 min, the mixture was stirred at r.t overnight. After completion, concentrated to remove the solvent, the residue was added H20 (50 mL), further stirred at r.t for 20 min, then filtered, the filtrate was extracted with ethyl acetate (120 mL χ 2), the organic phase was washed with brine (50 mL χ 2), dried with Na2S04. Filtered, concentrated to remove the solvent to obtain SBl-E-21-1 (off-white solid, 900 mg, yield 83percent).
66%
at 5 - 20℃;
(a) terf-Butyl ((l,4-frans)-4-aminocyclohexyl)carbamate (compound 15, Scheme 3, wherein Pq is Boc) In a 10 L reactor, a solution of (l,4-trans)-cyclohexane-l,4-diamine (compound 14, Scheme 3) (89 g, 779 mmol, Aldrich Sigma) in Et20 (2 L) was cooled to 5 °C, then a solution of di-tert-butyl dicarbonate (170 g, 779 mmol) in Et20 (1 L) was added dropwise over 2 h. The reaction mixture was stirred at 5 °C for 2 h and at RT overnight. To the reaction mixture, 10percent citric acid solution (3 L) was added and stirred for 30 min. The insoluble solid was filtered off, and the phases were separated. The aqueous layer was washed with Et20 (1 L). The aqueous phase was cooled to 10 °C and basified with solid NaOH (pH 14), then extracted with DCM (2 x 2 L). The combined organic phases were dried over Na2S04 and evaporated under reduced pressure to give a white solid (110 g, 66percent yield). This was combined with another batch (210 g) of this compound (compound 15) then re-purified by flash column chromatography (2-5percent MeOH/ DCM) to afford a white solid (compound 23) (297 g). *H NMR (400 MHz, CDCI3) δ 4.48 - 4.28 (1H, m), 3.48-3.28 (1H, m) , 2.68 - 2.57 (1H, m) , 2.01 - 1.89 (2H, m) , 1.89 - 1.69 (2H, m), 1.35 (9H, s) and 1.28 - 1.05 (4H, m).
43%
at 0 - 20℃; for 16.5 h;
Synthesis of Compound 390; terf-Butyl (4-amino-cyclohexyl)-carbamate (223); A solution of irα"^- 1,4-diaminocyclohexane (1 kg, 8.76 mol) in THF (14 L) at 0°C is treated with a solution dicarbonate (238 g, 1.09 mol) in THF (500 mL) over 30 minutes. The reaction mixture is then warmed to RT, stirred 16 h and filtered. The isolated solids are washed with THF (3 x 2 L) and then the filtrate is reduced in vacuo. The residue thus obtained is suspended in water (8 L) and filtered once more. The filtrate is extracted with DCM (3 x 2 L) and the combined organic phases dried over Na2SO4 and reduced in vacuo. The residue is taken up in TBME (2.4 L), washed with water (3 x 300 mL) then concentrated to -400 mL. Heptane (1 L) is added to induce precipitation of the desired amine; the resulting suspension is stirred 1 h at 0°C, filtered and washed with heptane (2 x 100 mL) to afford the title compound. Yield: 100.5 g (43percent).
27.7%
at -60 - 20℃; for 13.5 h;
To a solution of trans- 1 ,4-diaminocyclohexane (commercially available from Sigma- Aldrich, Milwaukee, WI) (5 g, 43.78mmol) in MeOH (100 mL) was added di-tert-butyl dicarbonate (4.77 g, 21.89 mmol) with MeOH (50 mL) at -60°C over 90 minutes. The temperature was slowly allowed to warm to ambient temperature. The reaction mixture was stirred for 12 hours at ambient temperature. After completion of the reaction, monitored by TLC (TLC eluent: 10percent MeOH in CHC13, Ninhydrin stain active), the reaction mixture was concentrated to remove MeOH. Water was added to form a white precipitate. The resulting mixture was stirred for 10 minutes and then the precipitate was filtered and washed with water. The filtrate (aqueous layer) was extracted with EtOAc (2 x 150mL). The extract was washed with saturated aqueous NaCl solution and separated and further dried on anhydrous Na2S04. Following filtration, the organic layer was concentrated under reduced pressure to afford tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate as a white solid (2.6 g, 27.70 percent). The filtered solid (3 g) product was bisboc protected compound and unreacted starting material remained in the aqueous layer. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-d6): δ 6.67 (d, J= 7.6 Hz, 1H), 3.12 (m, 1H), 2.44 (m, 1H), 1.71 (m, 4H), 1.36 (s, 9H), 1.17 (m, 2H), 1.04 (m, 2H).
Reference:
[1] Chemistry - An Asian Journal, 2010, vol. 5, # 4, p. 877 - 886
[2] Patent: WO2016/160617, 2016, A2, . Location in patent: Paragraph 00401
[3] Journal of Organic Chemistry, 1996, vol. 61, # 25, p. 8811 - 8818
[4] Patent: WO2016/116563, 2016, A1, . Location in patent: Page/Page column 34-35
[5] Patent: WO2008/57468, 2008, A1, . Location in patent: Page/Page column 352
[6] Patent: WO2013/134079, 2013, A1, . Location in patent: Paragraph 0176-0177
[7] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 6, p. 1451 - 1466
[8] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5223 - 5226
[9] Patent: KR2015/83721, 2015, A, . Location in patent: Page/Page column 18
[10] Chemical Communications, 2017, vol. 53, # 6, p. 1064 - 1067
[11] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 865 - 877
[12] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 655 - 666
[13] Patent: EP1323710, 2003, A1,
Barium(2+), (7a,8,9,10,11,11a,21a,22,23,24,25,25a,35a,36,37,38,39,39a-octadecahydro-5,42:14,19:28,33-triethenohexabenzo1><1,4,11,14,21,24>hexaazacyclotriacontine-43,44,45,46,47,48-hexol-O,O',O'',O''',O'''',O''''')-, (OC-6-11)-, salt ...[ No CAS ]
To a stirred solution of (1r,4r)-cyclohexane-1,4-diamine (1) (2 g, 17.54 mmol, 3.6 eq) in MeOH (50 mL) at 0 C. was added (Boc)2O (1.1 mL, 4.91 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 h. After completion of reaction by TLC, volatiles were evaporated and the residue was diluted with water and extracted with ethyl acetate (2*100 mL). The combined organic layer was washed with brine solution (50 mL), dried over sodium sulphate and concentrated to afford tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (Compound 114-01) (900 mg, yield: 86%). TLC system: MeOH/DCM (5:95), Rf value: ?0.3 (Ninhydrin stain); 1H NMR (400 MHz, CDCl3) delta 4.35 (brs, 1H), 3.39 (brs, 1H), 2.67-2.62 (m, 1H).
85%
In dichloromethane; at 20℃; for 2h;
To a solution of 22.8 g of trans 1,4-cyclohexanediamine in 200 mL of DCM was added 10.8 di-tert-butyl dicarbonate (Boc2O), and the mixture was stirred at room temperature for 2 hours. After the reaction, it was concentrated, and purified by column chromatography (200-300 mesh silica gel, eluent: dichloromethane: methanol = 7: 1) to obtain pure intermediate 41.
83%
In methanol; at 20℃;
Example 17. N-(3-(5-((lr,4r)-4-(Dimethylamino)cyclohexylamino)-3-ethylpyrazolo[l,5- ajpyrimidin- 7-ylamino)phenyl)acrylamide (SB1-E-21) tert-Butyl (lr,4r)-4-aminocyclohexylcarbamate (SBl-E-21-1) To a solution of SM-21-1 (2.0 g, 17.5 mmol) in MeOH (100 mL) was added the solution of (Boc)20 (1.1 g, 5.04 mmol) in MeOH (60 mL) dropwise for 30 min, the mixture was stirred at r.t overnight. After completion, concentrated to remove the solvent, the residue was added H20 (50 mL), further stirred at r.t for 20 min, then filtered, the filtrate was extracted with ethyl acetate (120 mL chi 2), the organic phase was washed with brine (50 mL chi 2), dried with Na2S04. Filtered, concentrated to remove the solvent to obtain SBl-E-21-1 (off-white solid, 900 mg, yield 83%).
66%
In diethyl ether; at 5 - 20℃;
(a) terf-Butyl ((l,4-frans)-4-aminocyclohexyl)carbamate (compound 15, Scheme 3, wherein Pq is Boc) In a 10 L reactor, a solution of (l,4-trans)-cyclohexane-l,4-diamine (compound 14, Scheme 3) (89 g, 779 mmol, Aldrich Sigma) in Et20 (2 L) was cooled to 5 C, then a solution of di-tert-butyl dicarbonate (170 g, 779 mmol) in Et20 (1 L) was added dropwise over 2 h. The reaction mixture was stirred at 5 C for 2 h and at RT overnight. To the reaction mixture, 10% citric acid solution (3 L) was added and stirred for 30 min. The insoluble solid was filtered off, and the phases were separated. The aqueous layer was washed with Et20 (1 L). The aqueous phase was cooled to 10 C and basified with solid NaOH (pH 14), then extracted with DCM (2 x 2 L). The combined organic phases were dried over Na2S04 and evaporated under reduced pressure to give a white solid (110 g, 66% yield). This was combined with another batch (210 g) of this compound (compound 15) then re-purified by flash column chromatography (2-5% MeOH/ DCM) to afford a white solid (compound 23) (297 g). *H NMR (400 MHz, CDCI3) delta 4.48 - 4.28 (1H, m), 3.48-3.28 (1H, m) , 2.68 - 2.57 (1H, m) , 2.01 - 1.89 (2H, m) , 1.89 - 1.69 (2H, m), 1.35 (9H, s) and 1.28 - 1.05 (4H, m).
43%
In tetrahydrofuran; at 0 - 20℃; for 16.5h;
Synthesis of Compound 390; terf-Butyl (4-amino-cyclohexyl)-carbamate (223); A solution of iralpha«^- 1,4-diaminocyclohexane (1 kg, 8.76 mol) in THF (14 L) at 0C is treated with a solution dicarbonate (238 g, 1.09 mol) in THF (500 mL) over 30 minutes. The reaction mixture is then warmed to RT, stirred 16 h and filtered. The isolated solids are washed with THF (3 x 2 L) and then the filtrate is reduced in vacuo. The residue thus obtained is suspended in water (8 L) and filtered once more. The filtrate is extracted with DCM (3 x 2 L) and the combined organic phases dried over Na2SO4 and reduced in vacuo. The residue is taken up in TBME (2.4 L), washed with water (3 x 300 mL) then concentrated to -400 mL. Heptane (1 L) is added to induce precipitation of the desired amine; the resulting suspension is stirred 1 h at 0C, filtered and washed with heptane (2 x 100 mL) to afford the title compound. Yield: 100.5 g (43%).
39.1%
In chloroform; at 80℃; for 16h;
A solution of di-tert-butyl dicarbonate (2.86 g, 13.1 mmol) in CHCl3 (70 mL) was slowly added to a solution of trans-1,4-diaminocyclohexane (3 g, 26.3 mmol) in CHCl3 (50 mL). suspension,The reaction was stirred for 16 hours, the reaction temperature was 80 C, and then CHCl 3 was distilled off under reduced pressure.A solution of CH 2 Cl 2 and saturated Na 2 CO 3 was added to the white evaporated residue.The organic layer was washed with a saturated Na 2 CO 3 solution and dried over Na 2 SO 4Then, it was concentrated under vacuum to give 2.2 g of white solid 4-ethylcyclohexylcarbamic acid tert-butyl ester in a yield of 39.1% by mass.
27.7%
In methanol; at -60 - 20℃; for 13.5h;
To a solution of trans- 1 ,4-diaminocyclohexane (commercially available from Sigma- Aldrich, Milwaukee, WI) (5 g, 43.78mmol) in MeOH (100 mL) was added di-tert-butyl dicarbonate (4.77 g, 21.89 mmol) with MeOH (50 mL) at -60C over 90 minutes. The temperature was slowly allowed to warm to ambient temperature. The reaction mixture was stirred for 12 hours at ambient temperature. After completion of the reaction, monitored by TLC (TLC eluent: 10% MeOH in CHC13, Ninhydrin stain active), the reaction mixture was concentrated to remove MeOH. Water was added to form a white precipitate. The resulting mixture was stirred for 10 minutes and then the precipitate was filtered and washed with water. The filtrate (aqueous layer) was extracted with EtOAc (2 x 150mL). The extract was washed with saturated aqueous NaCl solution and separated and further dried on anhydrous Na2S04. Following filtration, the organic layer was concentrated under reduced pressure to afford tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate as a white solid (2.6 g, 27.70 %). The filtered solid (3 g) product was bisboc protected compound and unreacted starting material remained in the aqueous layer. FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-d6): delta 6.67 (d, J= 7.6 Hz, 1H), 3.12 (m, 1H), 2.44 (m, 1H), 1.71 (m, 4H), 1.36 (s, 9H), 1.17 (m, 2H), 1.04 (m, 2H).
18%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;Inert atmosphere;
General procedure: A mixture of piperazine (500mg, 5.8mmol, 1.0eq.), N,N-diisopropylethylamine (DIPEA) (1.5mL, 8.7mmol, 1.5eq.), and di-tert-butyl dicarbonate (Boc2O) (500mg, 2.3mmol, 0.4eq.) in dry dichloromethane (15mL) was stirred at room temperature for 24h under nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The titled compound (4a) as a colorless solid was afforded after purification by column chromatography on silica gel (chloroform/methanol=50/1). The same procedure was performed to obtain compounds 4b and 4c
With hydrogenchloride; In ethanol;
Reference Example 4 To 250 ml of an ethanol solution containing 30.00 g of 1,4-trans-cyclohexane diamine and 131 ml of 2N hydrochloric acid was added dropwise over 4 hours 150 ml of an ethanol solution containing 52.13 g of di-tert-butyl-dicarbonate under ice-cooling. The reaction mixture was stirred for 20 hours, concentrated and diluted with an aqueous citric acid solution. It was then washed with chloroform and made alkaline by an aqueous sodium hydroxide solution. The solution was extracted with chloroform, dried, and concentrated to obtain 22.33 g of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine.
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
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.
Stage #1: 1-[4-(pyridin-2-yl)phenyl]methanamine; 2,6 dichloropurine In ethanol; water for 24h; Reflux;
Stage #2: 2-iodo-propane With potassium carbonate In dimethyl sulfoxide at 20℃; for 24h;
Stage #3: trans-1,4-cyclohexyldiamine In ethanol at 170 - 190℃;
Stage #1: (5-bromothiophen-3-yl)methylamine; 2,6 dichloropurine With N-ethyl-N,N-diisopropylamine In ethanol; water for 24h; Reflux;
Stage #2: 2-iodo-propane With potassium carbonate In dimethyl sulfoxide at 20℃;
Stage #3: trans-1,4-cyclohexyldiamine In ethanol at 120 - 170℃;
Stage #1: [6-(1H-pyrazol-1-yl)pyridin-3-yl]methanamine; 2,6 dichloropurine With N-ethyl-N,N-diisopropylamine In ethanol; water Reflux;
Stage #2: 2-iodo-propane With potassium carbonate In dimethyl sulfoxide at 20℃;
Stage #3: trans-1,4-cyclohexyldiamine In ethanol at 120 - 150℃;
Stage #1: C9H10N2S2; 2,6 dichloropurine With N-ethyl-N,N-diisopropylamine In ethanol; water Reflux;
Stage #2: 2-iodo-propane With potassium carbonate In dimethyl sulfoxide at 20℃;
Stage #3: trans-1,4-cyclohexyldiamine In ethanol at 120 - 150℃;
Stage #1: 2,6 dichloropurine; 5-(aminomethyl)-2,2′-bipyridine With N-ethyl-N,N-diisopropylamine In ethanol; water Reflux;
Stage #2: 2-iodo-propane With potassium carbonate In dimethyl sulfoxide at 20℃;
Stage #3: trans-1,4-cyclohexyldiamine In ethanol at 120 - 150℃;
In ethanol; at 180℃; for 4h;Microwave irradiation;
Example 7A trans N1-(6-chloro-4-iodopyridin-2-yl)cyclohexane-1,4-diamine A mixture of <strong>[98027-84-0]2,6-dichloro-4-iodopyridine</strong> (1 g, 3.65 mmol) and trans-cyclohexane-1,4-diamine (2 g, 18 mmol) in ethanol (2 mL) was heated in a Biotage Initiator microwave reactor at 180 C. for 4 h. After cooling, the mixture was poured into water and the solid collected by filtration and washed with water to give the title compound. Yield: 1.02 g (79%). MS (DCI/NH3) m/z 352 (M+H)+.
With triethylamine In N,N-dimethyl-formamide at 20℃;
103
Example 103. Synthesis of l-N,l-N-dimethyl-4-N-[6-(propan-2-yl)thi1-181Page 190 of 4072009184-0008 [00486] Synthesis of l-N-[6-(propan-2-yl)thieno[2,3-d]pyrimidin-4-yl]cyclohexane-l,4- diamine. To a 100-mL round-bottom flask was added a solution of commercially available 4- chloro-6-(propan-2-yl)thieno[2,3-d]pyrimidine (3 g, 14.10 mmol, 1.00 equiv) in N,N- dimethylformamide (30 mL), TEA (4.3 g, 42.49 mmol, 3.01 equiv), and cyclohexane- 1 ,4- diamine (9.6 g, 84.07 mmol, 5.96 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x 100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.5 g (85%) of l-N-[6-(propan- 2-yl)thieno[2,3-d]pyrimidin-4-yl]cyclohexane- l ,4-diamine as a yellow oil.[00487] Synthesis of Compound 1-181. To a 100-mL round-bottom flask was added l -N-[6- (propan-2-yl)thieno[2>3-d]pyrimidin-4-yl]cyclohexane- l ,4-diamine (3.5 g, 12.05 mmol, 1.00 equiv), formic acid (35 mL) and polyoxymethylene (3.6 g, 1 12.35 mmol, 9.32 equiv). The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 10 with 3N sodium hydroxide at 0-5°C. The solids were collected by filtration. The crude product was purified by re-crystallization from MeCN. This resulted in 3.4 g (89%) of Compound 1-181 as a white solid. NMR: (400 MHz, CDC13) δ 8.45 (I H, s), 6.79 ( I H, s), 4.82-4.84( l H, d), 4.10-4.17 (I H, m), 3.19-3.25 ( I H, m), 2.26-2.36 (9H, m), 2.00-2.03 (2H, d), 1.46- 1.55 (2H,q) , 1.39- 1.41 (6H, d) , 1.26- 1.39 (2H,q). MS: Jz 319 (M+H)+.
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 90℃; for 2.0h;
A mixture of <strong>[110651-92-8]7-chloro-6-nitrothieno[3,2-b]pyridine</strong> (0.21 g, 0.98 mmol) (Example 1, step 2), trans-cyclohexane-1,4-diamine (from Aldrich, 0.13 g, 1.2 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in isopropyl alcohol (3.3 mL) was heated at 90 C. for 2 h. The solvent in the resulting mixture was removed to give the desired product, which was used directly in the next step. LCMS calculated for C13H17N4O2S (M+H)+: m/z=293.1. Found: 293.0.
With potassium carbonate In tetrahydrofuran; water at 20℃; for 0.5h;
trans-ISRIB: 2-(4-Chlorophenoxy)-N-[(lr,4r)-4-[2-(4-chlorophenoxy )acetamido] cyclohexyl] acetamide
trans-ISRIB: 2-(4-Chlorophenoxy)-N-[(lr,4r)-4-[2-(4-chlorophenoxy )acetamido] cyclohexyl] acetamide [0409] To a mixture of (lr,4r)-cyclohexane-l,4-diamine (20 mg, 0.18 mmol) in tetrahydrofuran:water (1 : 1, 1 ml) were sequentially added potassium carbonate (73 mg, 0.53 mmol) and 4-chlorophenoxyacetyl chloride (56 μ, 0.36 mmol). Upon addition of the acid chloride, a white solid immediately formed. The reaction mixture was vigorously stirred at ambient temperature for 30 min. Water (2.5 ml) was added. The mixture was vigorously vortexed then centrifuged, and the water was decanted. This washing protocol was repeated with potassium bisulfate (1% aq, 2.5 ml), water (2.5 ml), and diethyl ether (2 x 2.5 ml). The resulting wet white solid was dried by partially dissolving in dichloromethane/methanol (10/1, 10 ml) and gravity filtering through an Autochem 4.5 mL reaction tube. The residual undissolved product was extracted from the wet filter cake by adding dichloromethane (4 x 4.5 ml) and gravity filtering. The combined filtrate was concentrated using rotary evaporation to afford 51 mg (65%) of the title compound as a white solid. XH NMR (400 MHz, DMSO-d6) δ 7.91 (d, J= 8.1 Hz, 2H), 7.31 (d, J= 9.0 Hz, 4H), 6.94 (d, J= 9.0 Hz, 4H), 4.42 (s, 4H), 3.55 (br. s., 2H), 1.73 (br. d, J= 5.9 Hz, 4H), 1.30 (quin, J= 10.5 Hz, 4H); LC-MS: m/z = 451 [M+H, 35C1 x 2]+, 453 [M+H, 35C1, 37C1]+.
With 1-methoxy-2-propanol; 5% rhodium on activated aluminium oxide; sodium methylate; at 200℃; under 90009.0 Torr; for 2h;Inert atmosphere; Autoclave;
In a 500 mL autoclave, 100 g of 1,4-diaminocyclohexane (cis / trans form = 80/20, manufactured by Tokyo Chemical Industry Co., Ltd.), 100 g of propylene glycol monomethyl ether (PGME) 7.5 g of Ru catalyst ("AA-4501", 5% Ru alumina powder, manufactured by N. E-Chemcat Co., Ltd.) and 0.63 g of sodium methoxide (manufactured by Tokyo Chemical Industry Co., Ltd.) were charged, (N 2) gas (10 kgf / cm 3) was repeated three times, and the inside of the system was replaced with nitrogen gas.While stirring at a stirring speed of 300 rpm, a temperature The reaction was carried out for 2 hours under the condition of 200 C. and pressure (pressure of N 2 gas) of 12 MPa. After the reaction, the reaction mixture was cooled to room temperature and pressure filtered using a 0.2 mum membrane filter to remove the catalyst to obtain a filtrate. Analysis of the obtained filtrate by gas chromatography mass spectrometry (GC-MS) revealed that the proportion of cis isomer was 63.37 area%, the proportion of trans form was 34.7 area%, the other components (4-aminocyclo By-product such as hexanol) was 1.93 area%, and cis / trans form = 65/35.
(1r,4r)-N1-(5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)cyclohexane-1,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 85℃;
Example 20. N-( (lS,4r)-4-( (3-ethyl-5-( (S)-2-(2-hydroxyethyl)piperidin-l-yl)pyrazolo[l, 5- ajpyrimidin- 7-yl)amino)cyclohexyl)acrylamide (MFH-1-175-1) (lr,4r)-Nl-(5-chloro-3-ethylpyrazolo[l,5-a]pyrimidin-7-yl)cyclohexane-l,4-diamine (MFH-1-161-1) The mixture of SM-1-49-1 (300 mg, 1.388 mmol), SM-1-175-1 (250 mg, 2.19 mmol), DIPEA (270 mg) and i-PrOH (8 mL) was stirred at 85 C for 1 h. After completion, the solvent was removed and the residue was purified by silica gel (NH3/MeOH(1.75N)/DCM = 0-20%) to obtain MFH-1-161-1 ( 230 g, yield 56%). LCMS (m/z): 294 [M + H]+.
6-phenyl-3-((1r,4r)-4-(6-phenyl-4-oxo-2-thioxo-2H-1,3-thiazin-3(4H)-yl)cyclohexyl)-2,3-dihydro-2-thioxo-1,3-thiazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In water at 20℃; for 0.166667h; Sonication; Green chemistry;
Ultrasound irradiation method:
General procedure: Ultrasound irradiation method: Amines 2a-d (2 mmol) or diamines 4a-c (1 mmol) was slowly added to a magnetically stirred solution ofcarbon disulfide (2 mmol) and monoacetylenic ester 1a-h (2 mmol) in water (4 mL) (in case of 2b, noneed to add water). After a pre-stirring of 1 min at rt, the vial was subjected to ultrasound irradiation for10 min. The completion of the reaction was monitored by TLC. The crude material formed was filteredand washed with chilled EtOH (3x5 mL) to afford pure title compounds.
2,3-dihydro-6-methyl-3-((1r,4r)-4-(6-methyl-4-oxo-2-thioxo-2H-1,3-thiazin-3(4H)-yl)cyclohexyl)-2-thioxo-1,3-thiazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
In water at 20℃; for 0.166667h; Sonication; Green chemistry;
Ultrasound irradiation method:
General procedure: Ultrasound irradiation method: Amines 2a-d (2 mmol) or diamines 4a-c (1 mmol) was slowly added to a magnetically stirred solution ofcarbon disulfide (2 mmol) and monoacetylenic ester 1a-h (2 mmol) in water (4 mL) (in case of 2b, noneed to add water). After a pre-stirring of 1 min at rt, the vial was subjected to ultrasound irradiation for10 min. The completion of the reaction was monitored by TLC. The crude material formed was filteredand washed with chilled EtOH (3x5 mL) to afford pure title compounds.
(1r,4r)-N<SUP>1</SUP>-(6-bromo-2-chloroquinazolin-4-yl)cyclohexane-1,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 12h;
To a sttired solution of trans-1,4-cyclohexanediamine (4.45 g, 39.0 mmol) and DIPEA (11.34 mL, 64.9 mmol) in THF (100 mL) was added dropwise a solution of 27 (3.61 g, 12.99 mmol) in THF (20 mL) at 0 oC, and the mixture was stirred for 12h at room temperature. The reaction mixture was diluted with AcOEt and H2O. The precipitate was collected and dried (2.4 g, 52%). The filtrate was separated to organic layer and aqueous layer, the organic layer was washed with H2O and sat. NaCl. The organic was dried over MgSO4 and concentrated in vacuo. The mixture was evaporated and the residue was purified by amino silica gel column chromatography (MeOH/AcOEt-hexane (1:1); 0:100 to 1:5) to give the title compound as white solid (1.1 g, 24%). 1H NMR (DMSO-d6) delta = 1.18 (m, 2H), 1.44 (m, 2H), 1.87 (m, 4H), 2.57 (m, 1H), 3.31 (br, 2H), 4.04 (m, 1H), 7.54 (d, 1H, J = 8.8 Hz), 7.91 (dd, 1H, J = 2.1, 8.8 Hz), 8.45 (br, 2H), 8.64 (d, 1H, J = 2.1 Hz). MS:355.0 (M+H)+
(1r,4r)-N<SUP>1</SUP>-(7-bromo-2-chloroquinazolin-4-yl)cyclohexane-1,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃; for 12h;
To a sttired solution of trans-1,4-cyclohexanediamine (99 mg, 0.864 mmol) and DIPEA (0.113 mL, 0.648 mmol) in THF (2 mL) was added dropwise a solution of 28 (120.1 mg, 0.432 mmol) in THF (2 mL) at 0 oC, and the mixture was stirred for 12h at room temperature. The reaction mixture was diluted with AcOEt and H2O. The organic layer was washed with H2O and sat. NaCl, then dried over MgSO4 and filtered. After removal of the solvent in vacuo, the residue was purified by amino silica gel column chromatography (MeOH/AcOEt-hexane (1:1); 0:100 to 1:7) to give the title compound as white solid (96.6 mg, 63%). 1H NMR (DMSO-d6) delta = 1.17 (m, 2H), 1.46 (m, 2H), 1.86 (m, 4H), 2.58 (m, 1H), 4.05 (m, 1H), 7.70 (dd, 1H, J = 2.0, 8.8 Hz), 7.82 (d, 1H, J = 2.0 Hz), 8.29 (d, 1H, J = 2.0 Hz), 8.49 (br, 1H). MS:355.0 (M+H)+
di-tert-butyl ((1S,1'S)-(((1S,4S)-cyclohexane-1,4-diyl)bis(azanediyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46.2%
With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide at -15 - 20℃;
28.1 Step 1: di-tert-butyl ((1S', 4S)-cyclohexane-1,4-diyl)bis(azanediyl))bis(2-oxo-1- phenylethane-2,1-diyl))dicarbamate
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetic acid (600 mg, 2.1 mmol) in N,N-dimethylformamide (20 mL) at- 15oC was added (1r,4r)-cyclohexane-1,4- diamine (136.3 mg, 1.0 mmol), diethyl cyanophosphonate (584 mg, 3.0 mmol) and triethylamine (483 mg, 4.0 mmol) successively. The reaction was stirred at roomtemperature overnight. The mixture was poured into water (300 mL) to give a precipitate which was filtered and dried to give di-tert-butyl ((1S,1'S)-(((1S,4S)-cyclohexane-1,4- diyl)bis(azanediyl))bis(2-oxo-1-phenylethane-2,1-diyl))dicarbamate (640 mg, 1.1 mmol, 46.2 % yield) as white solid. LCMS (2.5 min formic acid): Rt = 1.61 min, m/z: 480.8 (M-Boc+1)+
(1r,4r)-N1,N4-bis(1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-ylidene)cyclohexane-1,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With triethylamine In acetonitrile at 0℃; for 2h; Cooling with ice;
General procedure for the synthesis of bis(2-imino-1,3-dimethylbenzimidazoline) derivatives (4a-i)
General procedure: 2-Chloro-1,3-dimethylbenzimidazolium chloride 3 (0.22 mg, 1 mmol) was dissolved in dry acetonitrile (10 mL) in a 50 mL round bottom flask under an ice bath for 30 minutes. Diamine (0.5 mmol) and triethylamine (1 mmol) were mixed in dry acetonitrile (30 mL), and slowly added to the reaction flask. The reaction mixture was stirred at 0 °C for additional 2 hours, and then warmed to the room temperature. The organic phase was washed with 50 % wt NaOH solution (5 mL X 2), brine solutions (5 mL X 2), and dried over Na2SO4. The organic solution was then concentrated to dryness by rotary evaporator. The crude product was loaded and purified by flash column chromatography with hexanes/ethyl acetate (20/80) as solvent. Monitored by TLC, pure bis(2-imino-1,3-dimethylbenzimidazoline) derivatives were isolated.