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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+
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Structure of 18880-00-7 * 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.
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane; hexane
Referential Example 19 Production of N-(4-tert-Butylbenzyl)methylamine (Alternative Method) p-tert-butyltoluene (14.8 g; 0.10 mol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (17.8 g; 0.10 mol) and benzoyl peroxide (200 mg) were added thereto. The mixture was refluxed for 2 hours, and then cooled. Insoluble matter was filtered off, followed by washing with carbon tetrachloride. The filtrate was concentrated under reduced pressure, and the residue was dissolved in n-hexane, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 22.7 g of p-tert-butylbenzyl bromide (yield: 100percent).
89%
With sodium chlorite; hydrogen bromide In dichloromethane; water at 20 - 30℃; Reflux; Irradiation
comprising the steps of: S11. Add 1 lmol of 40percent hydrobromic acid to 300 ml of water to form a dilute acid solution; S12. 1000 ml of reaction flask was charged with 300 ml of dichloromethane and 1 mol of p-methyl-tert-butylbenzene, stirred at 30 ° C Adding to said dilute acid solution; S13. In the case of incandescent light, in the range of 0.5 to 1 hour, add 1 to 15 equivalents of sodium chlorite relative to HBr; S14. Under light conditions, the reaction was stirred at room temperature for 1-2 hours and then heated to reflux for 3-4 hours. The 4-tert-butylbenzyl bromide product obtained in the examples of the present invention had a yield of 89percent or more and a content of 97.8percent.
79%
With bromine In chloroform for 0.0208333 h; Flow reactor; Irradiation; Green chemistry
General procedure: A CHCl3 solution of alkylbenzene (0.5 M) was placed in a syringe, and a CHCl3 solution of Br2 (0.6 M) was placed in another syringe wrapped with aluminium foil. The reaction streams were introduced to each of the inlets of the capillary microreactor through a 25 cm FEP tubing segment. The injection rates for toluene and Br2 varied but were equal for both solutions. Sunlight was focussed with a Fresnel lens, and solar tracking was conducted manually every 15 min. The results ofthe reaction were collected into a brown vial containing an aqueous solution of Na2S2O3. After extraction with additional CHCl3, the organic layer was analysed. The crude yield and selectivity were calculated through GC/MS or 1H NMR analysis. The mixtures were purified via column chromatography.
Reference：
[1] Patent: US6586633, 2003, B1,
[2] Patent: CN105315127, 2016, A, . Location in patent: Paragraph 0044-0050
[3] Tetrahedron Letters, 2009, vol. 50, # 16, p. 1861 - 1865
[4] Synthesis, 2009, # 11, p. 1807 - 1810
[5] Synthetic Communications, 2010, vol. 40, # 7, p. 998 - 1003
[6] Tetrahedron, 2009, vol. 65, # 22, p. 4429 - 4439
[7] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 4, p. 403 - 407
[8] Australian Journal of Chemistry, 2015, vol. 68, # 11, p. 1653 - 1656
[9] Synlett, 2003, # 5, p. 702 - 704
[10] Journal of Organic Chemistry, 1998, vol. 63, # 17, p. 6023 - 6026
[11] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1993, # 1, p. 53 - 57
[12] Chemical Science, 2018, vol. 9, # 40, p. 7843 - 7858
[13] Journal of the Chemical Society, 1936, p. 300
[14] Roczniki Chemii, 1934, vol. 14, p. 1249,1252[15] Chem. Zentralbl., 1935, vol. 106, # I, p. 2807
[16] Recueil des Travaux Chimiques des Pays-Bas, 1954, vol. 73, p. 269,270, 275
[17] Phosphorus, Sulfur and Silicon and the Related Elements, 1990, vol. 53, # 1-4, p. 43 - 67
[18] Journal of the Indian Chemical Society, 1990, vol. 67, # 11, p. 909 - 911
[19] Journal of Medicinal Chemistry, 1989, vol. 32, # 5, p. 1098 - 1108
[20] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 21, p. 2735 - 2740
[21] Journal of the American Chemical Society, 1999, vol. 121, # 45, p. 10538 - 10544
[22] Tetrahedron Letters, 2007, vol. 48, # 18, p. 3247 - 3250
[23] Helvetica Chimica Acta, 2009, vol. 92, # 3, p. 555 - 566
[24] Organic Letters, 2013, vol. 15, # 16, p. 4194 - 4197
[25] European Journal of Organic Chemistry, 2014, vol. 2014, # 16, p. 3402 - 3410
2
[ 877-65-6 ]
[ 18880-00-7 ]
Reference：
[1] Organic Letters, 2013, vol. 15, # 9, p. 2210 - 2213
[2] Tetrahedron Letters, 2017, vol. 58, # 12, p. 1190 - 1193
[3] Organic Letters, 2018, vol. 20, # 10, p. 2980 - 2983
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1991, # 12, p. 2067 - 2080
3
[ 50-00-0 ]
[ 253185-03-4 ]
[ 18880-00-7 ]
Yield
Reaction Conditions
Operation in experiment
86.3%
at 120℃; for 8 h;
50 grams (0.37 mol) of tert-butylbenzene, 12.3 grams (0.40 mol) of paraformaldehyde and 100 mL of acetic acid were mixed in a flask. 109.6 grams of hydrogen bromide (HBr) in 33percent (w/w) acetic acid solution was slowly added into the flask dropwise within 30 minutes and then heated to 120° C. and stirred for 7.5 hours. Samples were obtained and extracted with water and dichloromethane. Organic phase was obtained and subjected to thin-layer chromatography (TLC) for tracing reaction. Until reactants were consumed, 200 mL of water was added into the reaction mixture and then extracted with 200 mL dichloromethane for three times. Organic phases were collected, concentrated and distilled under a condition of a temperature of 165170° C. and a pressure of 4.85.5.x.10-1 torr to obtain distilled fractions. 73.02 grams of compound 1 was obtained with a yield of 86.3percent.
Reference：
[1] Patent: US2012/264981, 2012, A1, . Location in patent: Page/Page column 3
[2] Journal of the Chemical Society, 1962, p. 3915 - 3926
With sodium hydroxide In tetrahydrofuran; water; toluene at 70 - 75℃; for 5 h;
2.3 grams (57.7 mmol) of sodium hydroxide, 0.33 grams (0.88 mmol) of 4-tertbutylbenzyl triethyl ammonium iodide, 7.5 mL of water, 4.2 mL of toluene, 1 mL of THF were added into a flask and heated to 70 to 75° C. Mixture of 10 grams (44.0 mmol) of 4-tertbutylbenzyl bromide and 3.55 grams (61.2 mmol) of propanal was added dropwise and slowly into the flask within 2 hours while the mixed solution in the flask was vigorously stirred, followed by stirring at 70 to 75° C. for another 3 hours when addition was finished. Reaction was traced by gas chromatography. The reaction mixture was extracted with 30 mL of water to obtain an organic layer when reaction was completed. The organic layer was dehydrated with anhydrous sodium sulfate, filtered off salt to isolate mother liquid, and stripped off solvent by vacuum distillation. 7.49 grams of lysmeral was obtained with a yield of 83.3percent.
82.6%
With sodium hydroxide In tetrahydrofuran; water; toluene at 70 - 75℃; for 5 h;
2.3 grams (57.7 mmol) of sodium hydroxide, 0.26 grams (0.88 mmol) of PTC 1, 7.5 mL of water, 4.2 mL of toluene, 1 mL of THF were mixed in a flask and then heated to 70-75° C. Mixture of 10 grams (44.0 mmol) of compound 1 and 3.55 grams (61.2 mmol) of propanal was added into the flask dropwise within 2 hours while the reaction mixture was vigorously stirred. While addition was finished, the reaction mixture was stirred at 70-75° C. for 3 hours and traced by GC. When the reaction stopped, 30 mL water was added for extraction to obtain an organic phase. The organic phase was dehydrated with anhydrous sodium sulfate, filtered and concentrated by vacuum distillation. 7.43 grams of lysmeral was obtained with a yield of 82.6percent and verified to have a purity of 97.27percent by GC analysis.Results of analysis by NMR are shown as follows:1H NMR (CDCl3) δ 9.73 (t, 1H, J=6.851), 7.34 (ddd, 1H, J=8.032, J=3.716, J=0.000), 7.13 (ddd, 1H, J=8.032, J=3.732, J=0.000), 7.11 (ddd, 1H, J=8.032, J=3.716, J=0.000), 7.32 (ddd, 1H, J=8.032, J=3.732, J=0.000), 2.6 (dd, 2H, J=6.945, J=6.851), 3.0 (tq, 1H, J=6.945, J=6.911), 1.32 (m, 9H), 1.1 (d, 3H, J=6.911).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 18, p. 4143 - 4150
[2] Journal of the Chemical Society, 1937, p. 1774,1777
[3] Roczniki Chemii, 1934, vol. 14, p. 1249,1252[4] Chem. Zentralbl., 1935, vol. 106, # I, p. 2807
[5] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7289 - 7298
27
[ 124-38-9 ]
[ 18880-00-7 ]
[ 32857-63-9 ]
Reference：
[1] Chemical Research in Toxicology, 1996, vol. 9, # 2, p. 445 - 450
28
[ 18880-00-7 ]
[ 5406-86-0 ]
Reference：
[1] Chemical Research in Toxicology, 1996, vol. 9, # 2, p. 445 - 450
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7289 - 7298
Part 1. Preparation of (4-tert-Butyl-phenyl)-acetonitrile.; To a solution of potassium cyanide (5.3 g, 81.6 mmol) in 1: 6 water/ethanol (420 mL) was added 4- (tert-butyl) benzyl bromide (18. 5g, 81.6 mmol) and the mixture stirred at reflux for 17 h. After cooling to room temperature the resulting white precipitate was removed by filtration. The filtrate was concentrated in vacuo, the residue taken up in ethyl acetate/water and extracted with ethyl acetate. The organics were dried and concentrated in vacuo to give a colorless oil. Purification by chromatography (Si02, 5% ethyl acetate in n-hexane) gave (4-tert-Butyl-phenyl)- acetonitrile (14.0 g, 80.8 mmol) as a colorless oil.
EXAMPLE 1 This Example illustrates the preparation of 4-[3-(p- t -butylphenyl)- cis -cyclobutylmethyl]-2,6- cis -dimethylmorpholine (Compound No.3.1 in Table 1). A mixture of p- t -butylbenzyl bromide (20.44 g, 0.09 mol) and potassium cyanide (11.72 g, 0.18 ml) in a saturated solution of 18-crown-6 (50 ml) was refluxed at 80C for 5 hours. After cooling to room temperature the solution was poured into water, extracted with dichloromethane and dried over anhydrous sodium sulphate. Removal of the solvent gave a yellow liquid which was purified by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) to give p- t -butylbenzyl cyanide (15.4 g, 99%).
A cooled solution of tert-butyl-N- (tert-butoxycarbonyloxy) carbamate [(5] g, 21.4 mmol) in DMF (20 [MQ)] at [0 C] was treated with sodium hydride (60%, 12. [8] g, 21.4 mmol) portionwisely and stirred for 30 min at room temperature. The reaction mixture was added to 4-tert-butylbenzyl bromide (7.3g, 32.1 mmol) and stirred for [18] hrs at room temperature. The mixture was diluted with H20 and extracted with EtOAc several times. The combined organic layers were washed with [HA0] and brine, dried over [MGS04] and concentrated in vacuo. The residue was purified by column chromatography on Silica gel with [ETOAC/HEXANES] (10: 1) solvent mixture as an eluant to give 7.72 g of colorless [TERT-BUTYL-N-[(TERT-BUTOXYCARBONYL) OXY]-N-(4-TERT-] butylbenzyl) carbamate 2 (yield: 95%). ['H-NMR] [(CDC13)] 8 : 7. [35] (dt, 2 H, [J=] 2.2, 8.5 Hz, Ar), 7.26 (d, 2 H, [J=] 8.5 Hz, Ar), 4.72 (s, 2 H, [CH2),] 1.49 (s, 9 H, C (CH3) 3), 1.44 (s, 9 H, C (CH3) 3), 1.30 (s, 9 H, C (CH3) [3).]
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...
With sodium carbonate; In water; N,N-dimethyl-formamide;
Example 58 Production of N-(4-tert-Butylbenzyl)-N-methyl-(3-bromobenzyl)amine (Compound 78) <strong>[67344-77-8]N-<strong>[67344-77-8](3-bromobenzyl)methylamine</strong></strong> (2.00 g; 10.0 mmol) and sodium carbonate (2.02 g; 19.0 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred at room temperature, 4-tert-butylbenzyl bromide (2.16 g; 9.52 mmol) in N,N-dimethylformamide (15 ml) was added dropwise. The mixture was stirred for 30 minutes at room temperature, and the reaction was stopped by pouring the mixture into ice/water, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate), to thereby yield 2.26 g of the target compound (yield: 68.5percent). 1H-NMR (CDCl3, ppm); 1.32 (9H, s), 2.18 (3H, s), 3.47 (2H, s), 3.57 (2H, s), 7.17 (1H, t, J=7.56 Hz), 7.26~7.38 (6H, m), 7.53 (1H, s).
3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride[ No CAS ]
[ 72011-24-6 ]
[ 3288-99-1 ]
[ 18880-00-7 ]
2-(4-tert-butylphenyl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In tetrahydrofuran; 1,4-dioxane; water; dimethyl sulfoxide;
Synthesis Example 6 Synthesis of 2-(4-tert-butylphenyl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile (Compound No. IV-18) 0.22 g of dibenzo-18-crown-6-ether and 1.57 g of sodium cyanide were suspended in 20 ml of DMSO, and 5.00 g of 4-tert-butylbenzyl bromide was dropwise added thereto with cooling with water. After having been stirred overnight at room temperature, the resulting mixture was further stirred at 50 C. for 5 hours. After this was left to be at room temperature, water was added thereto and extracted with ether. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 1.19 g of 4-tert-butylphenylacetonitrile was obtained from the fraction eluted with n-hexane:ethyl acetate 5:1. 1.00 g of 4-tert-butylphenylacetonitrile and 1.23 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride were dissolved in 20 ml of THF, and 1.01 g of potassium t-butoxide was added thereto with cooling with ice. After the resulting mixture was stirred overnight at room temperature, water was added thereto, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was dissolved in a mixed solvent of 10 ml of water and 10 ml of dioxane, and 0.38 g of potassium hydroxide was added thereto and heated under reflux for 4 hours. After having been left to be at room temperature, this was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 0.64 g of 2-(4-tert-butylphenyl)-3-(l-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile from the fraction eluted with n-hexane:ethyl acetate=2:1.
EXAMPLE 4a 4-t-Butylphenylacetonitrile Sodium cyanide (1.07 g, 22 mmol) was added to a stirred solution of 4-t-butylbenzylbromide (5 g, 22 mmol) in a mixture of EtOH-H2 O (6:1) (70 mL). The reaction mixture was allowed to stir under reflux conditions for 4 hours. After cooling the mixture to room temperature, the solvent was evaporated under reduced pressure to afford a yellow oil. The oil was suspended in water (20 mL) and extracted with ether (3*25 mL). The solvent was removed under reduced pressure to give a yellow oil which was purified by distillation (Kugelrohr, bp 120-125 C., 0.2 mm Hg) to afford 3.37 g (89%) of the title compound as a colorless oil.
N-methyl-N-(4'-t-butylbenzyl)-9-anthrylmethylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; toluene;
Production of N-methyl-N-(4'-t-butylbenzyl)-9-anthrylmethylamine 2.2 g (0.01 mole) of N-methyl-9-anthrylmethylamine was dissolved in 40 ml of toluene, and 1.7 g (0.012 mole) of anhydrous potassium carbonate was added. With continued stirring at room temperature, 2.49 g (0.011 mole) of p-t-butylbenzylbromide was added, and the mixture was reacted at 40 to 50 C. for 4 hours. The reaction mixture was mixed with ice water, and distributed. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 4% ethyl acetate/n-hexane. The elude was concentrated to give 3.3 g (yield 91%) of an oily substance.
With sodium carbonate; In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;
Production of N-methyl-N-(4'-t-butylbenzyl)-1-naphthylmethylamine <strong>[65473-13-4]N-methyl-1-naphthylmethylamine hydrochloride</strong> (2.1 g; 0.01 mole) was dissolved in 50 ml of dry dimethylformamide, and 3.71 g (0.035 mole) of anhydrous sodium carbonate was added. The mixture was stirred at room temperature, and 2.49 g (0.011 mole) of p-t-butylbenzyl bromide was added. The mixture was reacted at 30 to 40 C. for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 5% ethyl acetate/n-hexane. The elude was concentrated to give 2.98 g (yield 94%) of an oily substance.
Part 2. Preparation of 2, 3-Bis- (4-tert-butyl-phenyl)-propionitrilel; To a solution of (4-tert-Butyl-phenyl)-acetonitrile (48.3 g, 279 mmol) in tetrahydrofuran (600 mL) at-78 C was added lithium bis (trimethylsilyl) amide (335 ml, 335 mmol, 1 M solution in tetrahydrofuran) with stirring. After 1 h 4- (tert- butyl) benzyl bromide (63.4 g, 279 mmol) was added dropwise and the mixture stirred for 16 h while warming to room temperature. The mixture was quenched with water, concentrated in vacuo, the residue taken up in ethyl acetate/water and extracted with ethyl acetate. The organics were dried and concentrated in vacuo to give an off-white solid. Crystallization from ethyl acetate/hexanes gave 2, 3-Bis- (4-tert-butyl-phenyl)- propionitrile (57.5 g, 180 mmol) as a white crystalline solid.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 2h;Reflux; Inert atmosphere;
General procedure: N-Methyl-1-(naphthalen-1-yl)ethanamine (8) (0.37g, 2.00mmol), N,N-diisopropylethylamine (0.39g, 3.02mmol), 1-(bromomethyl)-4-tert-butylbenzene (0.50g, 2.20mmol) and acetonitrile (5mL) were mixed and stirred at reflux under an N2-atmosphere for 2h. The solvent was then removed at reduced pressure and CH2Cl2 (5mL) was added. The dichloromethane phase was washed with water (5mL) and the water phase was back extracted with CH2Cl2 (3×5mL). The combined organic fractions were dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica-gel column chromatography. Alternatively, the purification was done by filtration through a short silica-gel column (pentane:EtOAc, 9:1), followed by precipitation as it hydrochloride salt by addition of HCl saturated ether. The solid material was washed with cold pentane. Alternatively, using 8·HCl the reaction was run similarly, but employing a 3-fold excess of N,N-diisopropylethylamine.
4-t-Butylbenzylbroraide (903 mg, 3'.98 mmol ) was reacted wi th NaCN (210 mg, 4.30 mmol ) in ethanol (10 ml ) and H2O (2 ml ) at 80C. The react ion solvent was removed in vacuo . The residue was di luted wi th EtOAc and H2O and the aqueous layer was extracted with EtOAc. The combined organic layer was dried over MgSCU and then concentrated in vacuo. The residue was purified with column chromatography to yield title compound (797 mg)<444> 1H NMR (300MHz, CDCl3): 57.42 (d, 2H, J = 8.4 Hz), 7.27 (d, 2H, J = 8.4 Hz), 3.72 (s, 2H), 1.32 (s, 9H)
Step 1 : 2-(4-t-butyl-benzyl)-2-methyl-malonic acid dimethyl ester; NaH (225mg, 8.9mmol) was suspended to anhydrous THF (20ml) and cooled to EPO <DP n="86"/>0C . Thereto 2-methyl-malonic acid dimethyl ester (Ig, 6.84mmol) dissolved in anhydrous THF (10ml) was added slowly, 4-t Butyl benzyl bromide(l .3ml, 6.84mmol)was added and stirred for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with 300ml of Ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous MgSO4, and filtered, concentrated in vacuo and the residue was purified by columnn chromatography (n-Hexane: Ethyl acetate=2.5:l) to yield title compound (1.85g, 93%) as colorless oil.1H NMR (CDCl3, 300 MHz) delta 7.27 (d, J=8.43Hz, 2H), 7.02 (d, J=8.43), 3.74 (s, 6H), 3.20 (s, 2H), 1.35 (s, 3H), 1.29 (s, 9H)
With sodium hydroxide; In ethanol; water; at 50℃; for 16h;
To a solution of 1-(bromomethyl)-4-tert-butylbenzene (2.00 ml, 9.00 mmol) in 10 mL of EtOH was added a solution of 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2.00 g, 12.0 mmol) in EtOH (35.0 ml, 9.00 mmol), water (4.00 ml, 9.00 mmol), and 3.45 M aqueous NaOH solution (4.00 ml, 13.0 mmol). The whole was heated at 50 C. After 16 h, LCMS showed mainly the product. The reaction was cooled down to rt and concentrated. Water was added until all solids had precipitated out of the solution. The solids were filtered off with an aid of water. White solid was obtained and was purified further by performing a column chromatography using 70:30 DCM:(90:10:1 DCM:MeOH:NH4OH). The product, 2-(4-tert-butylbenzylthio)-6-aminopyrimidin-4(3H)-one was obtained as a white solid (1.8 g, 69% yield). LCMS (ESI) Calcd for C15H19N3OS: [M]+ = 289. Found [M+H]+ = 290. The carbon shift data supported the structure of 6-amino-2-(4-tert-butylbenzylthio)pyrimidin-4(1H)-one. However, line-broadening in the 1D proton and carbon data suggested the double-bond is probably moving between the two nitrogens. Thus, 6-amino-2-(4-tert-butylbenzylthio)pyrimidin-4(1H)-one and 2-(4-tert-butylbenzylthio)-6-aminopyrimidin-4(3H)-one were in equilibrium in DMSO-d6. Proton and carbon chemical shift assignments for 2-(4-tert-butylbenzylthio)-6-aminopyrimidin-4(3H)-one in DMSO-d6 were shown below.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 4h;
General procedure: To a stirred mixture of 2-nitroanilne compound (1.0 eq.) and K2CO3 (1.3 eq.) in dimethylformamide was added dropwise R3CH2Br (1.3 eq.). The reaction mixture was heated to 120 C and stirred for 4 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1a.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 4h;
To a stirred mixture of 2-nitroanilne compound (1.0 eq.) and K2CO3 (1.3 eq.) in dimethylformamide was added dropwise R3CH2Br (1.3 eq.). The reaction mixture was heated to 120 C andstirred for 4 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1a.
N-(4-tert-butylbenzyl)cinchonidium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18.5 g
With tetra-(n-butyl)ammonium iodide; In tetrahydrofuran; at 70℃;
<strong>[485-71-2]Cinchonidin</strong>e (10.6 g) was dissolved in tetrahydrofuran (200 ml), 4-tert-butylbenzylbromide (10.1 g) and tetrabutylammonium iodide (0.66 g) were added, and the mixture was stirred at 70 C. overnight. The reaction mixture was cooled to room temperature, the solid was collected by filtration, and washed with ethyl acetate (50 ml). The obtained solid was dried under reduced pressure overnight to give the title compound (18.5 g). [0185] 1H-NMR (400 MHz, DMSO-D6) delta: 8.99 (1H, d, J=4.4 Hz), 8.27 (1H, d, J=8.2 Hz), 8.11 (1H, dd, J=8.5, 1.0 Hz), 7.89-7.79 (2H, m), 7.78-7.71 (1H, m), 7.63 (2H, d, J=8.4 Hz), 7.59 (2H, t, J=8.4 Hz), 6.72 (1H, d, J=4.2 Hz), 6.57-6.51 (1H, br s), 5.67 (1H, ddd, J=17.0, 10.4, 6.4 Hz), 5.14 (1H, d, J=17.2 Hz), 5.08 (1H, d, J=12.6 Hz), 5.00-4.90 (2H, m), 4.30-4.18 (1H, m), 3.91 (1H, t, J=8.7 Hz), 3.74-3.64 (1H, m), 3.35-3.18 (2H, m), 2.76-2.65 (1H, m), 2.18-1.94 (3H, m), 1.90-1.78 (1H, m), 1.40-1.22 (1H, m), 1.34 (9H, s)
1-(4-(tert-butyl)benzyl)-1H-pyrazole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In acetonitrile; at 20℃;
General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent).
1-(4-tert-butylbenzyl)-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazin-1-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In tetrahydrofuran; at 20℃;
1-(Bromomethyl)-4-tert-butylbenzene (0.150 g, 0.66 mmol) was added to a stirred solution of 1-methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]piperazine (0.2 g, 0.66 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred overnight at room temperature. Additional 1-(bromomethyl)-4-tert-butylbenzene (0.02 g) was addedand the reaction mixture was stirred for further 24 hours at room temperature. The solvent was evaporated and the residue was treated with hexane and filtered. The white solid was washed with diethyl ether to yield the title compound (0.32 g, 86%).LRMS (mlz): 449 (M).
N’’-methyl(4-tert-butylphenyl)-N,N-dimethylimino dicarboanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9.25%
With potassium iodide; sodium hydroxide; In dichloromethane; at 20℃; for 26h;
In a 250 ml round bottom flask, 8 g (48.3 mmol) of <strong>[1115-70-4]metformin hydrochloride</strong> was added, 100 ml of methylene chloride was added, the ice bath was added, 40 ml of 25% sodium hydroxide was added,After stirring, the mixture was further added with 10.97 g (48.3 mmol) of 4-tert-butylbenzyl bromide and 3 small portions of potassium iodide, and the mixture was stirred at room temperature for 26 hours. Reaction flask see solid, filter, dichloromethane 3ml washing, drying, in color 3.2 g. The solid was dissolved in 80 ml of acetone and dissolved, filtered, cooled and crystallized to give 1.23 g of a colorless solid. The yield was 9.25%
7-(4-(tert-butyl)benzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Sealed tube;
General procedure: Synthesis of VU0071063 analogs was carriedabout by alkylation of commercially available theophylline (1)with various benzyl bromides (2)(see Supplemental Table S1). Benzylbromides not commercially available were synthesized by reduction ofthe benzaldehyde to the alcohol then conversion to the bromide viaAppel reaction or by radical bromination of the methylbenzene.Generally, one equivalent of theophylline and benzyl bromide weredissolved in 1 ml of dimethylformamide (DMF) in a 2-dram screw capvial at room temperature. Two equivalents of potassium carbonatewere then added and the reactions were stirred overnight. The productwas precipitated by addition of 2 ml of water and an additional hour ofstirring, then isolated via vacuum filtration. Impure products werepurified by normal-phase column chromatography. Products wereisolated in 5%-85% yield. Guanine-based compounds were synthesizedfrom guanosine using the method above, except dimethylsulfoxide (DMSO) was used in place of DMF. After overnight stirring,the sugar was cleaved by addition of concentrated HCl and an hour ofstirring, then isolated via vacuum filtration. For VU0071063, theophylline(50 mg, 0.278 mmol) and 4-tert-butylbenzyl bromide (63.038 mg,0.278 mmol) were mixed in a 2-g vial. To this mixture was added DMF(1 ml, 0.278 M) and then potassium carbonate (77.831 mg, 0.555mmol). The reaction was stirred overnight, forming a white precipitate,to which 1 ml water was added to induce further precipitation.The white solid was collected via vacuum filtration, washed withwater, and dried under vacuum to yield VU0071063 (60 mg, 66%) asa white solid. Heteronuclear multiple bond coherence analysisconfirmed N7 alkylation. 1H NMR (400 MHz, CDCl3) d (ppm): 7.55(s, 1H), 7.38 (d, J 5 8.4 Hz, 2H), 7.26 (d, J 5 8.4 Hz, 2H), 5.47 (s, 2H),3.58 (s, 3H), 3.41 (s, 3H), 1.29 (s, 9H); 13C NMR (100.6 MHz, CDCl3)d (ppm): 155.4, 151.8, 151.7, 148.9, 140.9, 132.5, 127.9, 126.1, 107.1, 50.1,34.7, 31.3, 29.8, 28.1; high-resolution mass spectrometry (TOF, ES1):calculated for C18H22N4O2, 326.1743; found, 326.1746.
4-(3-(4-(tert-butyl)phenyl)oxiran-2-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
(21) Dissolve 1.1 mmol of acetic anhydride in a nitrogen environment at -70 CIn 1 mL of anhydrous dichloromethane, slowly dropwise into the reaction system.5.5mmol of anhydrous dimethyl sulfoxide, stirred for 50min to obtain A2;(22) 1.1 mmol4-cyanobenzyl alcohol is solubleIn 0.5mL of anhydrous dichloromethane,Slowly add to A2, stir for 1h, slowly add to the reaction system8.8 mmol of triethylamine, stirred for 1 h to obtain B2;(23) TLC (thin layer chromatography) detection.Add 1.1 mmol of 4-tert-butylbenzyl bromide to B2 at room temperature, 7.7 mmolCesium carbonate,0.2mL water and 0.5mL tert-butanol,Reaction at 35 for 15h, TLC (thin layer chromatography)The starting point disappears, and the reaction is stopped to obtain C2;(24) quenching the reaction by adding a saturated aqueous sodium hydrogen carbonate solution to C2,Add 40 mL of dichloromethane and wash the organic phase three times with water.The organic phase was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated.Separated by column chromatography238.2 mg of product, this compound is 2, the yield is 86%.
3-(4-(tert-butyl)benzyl)thiazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium tert-butylate; iodine; In tetrahydrofuran; at 80℃; for 20.0h;
In a reaction tube, p-tert-butylbenzyl bromide (185 muL, 1 mmol), 2- (methylthio) -4,5-dihydrothiazole (56 muL, 0.5 mmol), and potassium tert-butoxide (56 mg, 0.5 mmol) were sequentially added ), Iodine (256 mg, 1.0 mmol) and tetrahydrofuran (1 ml), the reaction was electromagnetically stirred at a reaction temperature of 80 C., and the reaction time was 20 hours.After the reaction was completed, the solvent was removed by rotary evaporation, and the mixture was separated by column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio of 1: 9). After separation, a colorless solid (112 mg, 90%) was obtained.
General procedure: A mixture of 1,2-Diaminobenzene 1 or 2-Mercaptoaniline 4(1 mmol), benzyl bromides (1 mmol) 2 and 4 % Cu:ZnS NPs (10 mol %)in 10 ml of CH3CN were irradiated in visible light (100W OSRAMTungsten Lamp, EFP 64627 HLX) with continuous stirring for the appropriatetime. Catalyst was separated by centrifugation after thecompletion of reaction. Evaporation of the above solution gave thecrude product which was purified using crystallization.
3-(4-tert-butylbenzyl)thiazolidin-2-ylidenecyanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.4%
With sodium hydroxide; In water; acetonitrile; at 20℃; for 8h;
General procedure: Thiazolidin-2-ylidene-cyanamide (0.317 g, 2.50 mmol) inacetonitrile (20 mL) was dropwise added to a stirred solutionof substituted benzyl bromide (2.5 mmol) and 14 mL NaOHaqueous solution (1 M). The mixture is stirred at room temperaturefor 8-10 h. The soild was collected by filtration,washed with n-hexane and dried in vacuo.
2-(bis(4-(tert-butyl)benzyl)amino)ethyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium tert-butylate; at 50℃; for 16h;
General procedure: KOt-Bu (0.5 mmol, 56 mg), 2-oxazoline (0.5 mmol), benzyl bromide (1.0 mmol) and DMC (2 mL) were introduced in a tube, equipped with magnetic stirring bar and the mixture was stirred at 50 C. After 16 h, the progress of the reaction was analyzed by gas chromatography. The solvent was then evaporated under vacuum and the desired product was purified by silica gel chromatography and a mixture of petroleum ether/ethyl acetate as eluent.
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