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 874-98-6 * 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.
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 5, p. 1383 - 1400
2
[ 874-98-6 ]
[ 5071-96-5 ]
Reference：
[1] Patent: CN105218382, 2016, A,
3
[ 874-98-6 ]
[ 10516-71-9 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 12, p. 4516 - 4520
4
[ 874-98-6 ]
[ 37116-80-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7444 - 7447
5
[ 874-98-6 ]
[ 49617-80-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4239 - 4251
6
[ 874-98-6 ]
[ 19614-12-1 ]
Yield
Reaction Conditions
Operation in experiment
55%
With bromine In hexane; chloroform
1-Bromo-2-(bromomethyl)-4-methoxybenzene To a solution of above-described crude 1-(bromomethyl)-3-methoxybenzene (152.5 g) in 1 L of chloroform a solution of 134 g (0.841 mol) of bromine in 200 ml of chloroform was added dropwise by vigorous stirring at room temperature. The reaction mixture was stirred overnight at ambient temperature and then evaporated to dryness. The residue was triturated with 1000 ml of n-hexane, and the precipitate was filtered off, washed with 100 ml of n-hexane, and then dried in vacuum. An additional amount of the product was obtained by evaporation of mother liquor followed by treatment of the residue with 200 ml of n-hexane. In total, this procedure gave 153 g (55percent overall yield for two stages) of 1-bromo-2-(bromomethyl)-4-methoxybenzene. (average of two runs) Anal. calc. for C8H8Br2O : C, 34.32; H, 2.88. Found: C, 34.30; H, 3.01. 1H NMR (CDCl3): δ 4.48 (d, J = 8.8 Hz, 1H, 6-H), 7.02 (d, J = 3.0 Hz, 1H, 3-H), 6.76 (dd, J = 8.8 Hz, J = 3.0 Hz, 1H, 5-H), 4.58 (s, 2H, CH2Br), 3.83 (s, 3H, OMe).
55%
With bromine In hexane; chloroform
1-Bromo-2-(bromomethyl)-4-methoxybenzene To a solution of above-described crude 1-(bromomethyl)-3-methoxybenzene (152.5 g) in 1 L of chloroform a solution of 134 g (0.841 mol) of bromine in 200 ml of chloroform was added dropwise by vigorous stirring at room temperature. The reaction mixture was stirred overnight at ambient temperature and then evaporated to dryness. The residue was triturated with 1000 ml of n-hexane, and the precipitate was filtered off, washed with 100 ml of n-hexane, and then dried in vacuum. An additional amount of the product was obtained by evaporation of mother liquor followed by treatment of the residue with 200 ml of n-hexane. In total, this procedure gave 153 g (55percent overall yield for two stages) of 1-bromo-2-(bromomethyl)-4-methoxybenzene. (average of two runs) Anal. calc. for C8H8Br2O: C, 34.32; H, 2.88. Found: C, 34.30; H, 3.01. 1H NMR (CDCl3): δ 4.48 (d, J=8.8 Hz, 1H, 6-H), 7.02 (d, J=3.0 Hz, 1H, 3-H), 6.76 (dd, J=8.8 Hz, J=3.0 Hz, 1H, 5-H), 4.58 (s, 2H, CH2Br), 3.83 (s, 3H, OMe).
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 776 - 794
12
[ 874-98-6 ]
[ 60760-04-5 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 1904
13
[ 874-98-6 ]
[ 167145-13-3 ]
Reference：
[1] Patent: CN104496769, 2016, B,
14
[ 874-98-6 ]
[ 122-52-1 ]
[ 60815-18-1 ]
Yield
Reaction Conditions
Operation in experiment
95.9%
at 90℃; Inert atmosphere
Step 1: diethyl 3-methoxybenzylphosphonate[00246j A mixture of triethyl phosphite (1.45 g, 8.70 mmol) and 1-(bromomethyl)-3-methoxybenzene (1.507.50 mmol) was stirred under N2 at 90 °C overnight. The mixture was cooled to room temperature to give yellow oil (1.84 g, 95.9 percent). The reaction mixture was used directly for the next step without further operation. The compound was characterized by the following spectroscopic data:MS(ESI, pos.ion)m/z: 259.2 (M+1); exact mass of C12H1904P: 258.10.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 7724 - 7730
[2] Patent: WO2015/90232, 2015, A1, . Location in patent: Paragraph 00246
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7444 - 7447
[4] Journal of the American Chemical Society, 1976, vol. 98, # 18, p. 5574 - 5581
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 4, p. 1292 - 1295
[6] Journal of Medicinal Chemistry, 2007, vol. 50, # 24, p. 6116 - 6125
[7] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 86, p. 640 - 644
[8] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5871 - 5876
[9] Patent: CN104496769, 2016, B, . Location in patent: Paragraph 0017-0018
15
[ 78-40-0 ]
[ 874-98-6 ]
[ 60815-18-1 ]
Reference：
[1] Chinese Chemical Letters, 2010, vol. 21, # 3, p. 287 - 289
16
[ 874-98-6 ]
[ 74597-04-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 10, p. 4239 - 4251
[2] Patent: WO2004/20408, 2004, A1, . Location in patent: Page 56
Step 1: diethyl 3-methoxybenzylphosphonate[00246j A mixture of triethyl phosphite (1.45 g, 8.70 mmol) and 1-(bromomethyl)-3-methoxybenzene (1.507.50 mmol) was stirred under N2 at 90 C overnight. The mixture was cooled to room temperature to give yellow oil (1.84 g, 95.9 %). The reaction mixture was used directly for the next step without further operation. The compound was characterized by the following spectroscopic data:MS(ESI, pos.ion)m/z: 259.2 (M+1); exact mass of C12H1904P: 258.10.
at 160℃; for 5h;Inert atmosphere;
General procedure: A flask was charged with 1-(bromomethyl)-2,3-dichlorobenzene (1.0 g, 4.17 mmol) and triethyl phosphite (1.39 g, 8.34 mmol). The flask was fitted with a reflux condensor and heated to 160 C under a gentle stream of nitrogen (to aid in the removal of ethyl bromide) for 5 h. The reaction was cooled to room temperature, and concentrated by rotary evaporation under high vaccuum (bath temp 70 C) to give 1.317 g (quant.) as a colorless oil which was used without purification.
at 140℃;
(1), first m-methoxyphenyl bromide 241.2g and 228g triethyl phosphite was added to the reaction vessel, stirred and incubated at 140 C 7-8 hours, after the completion of the reaction by distillation under reduced pressure, To give 3-methoxyphenyl phosphate diethyl ester;
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78℃;
To a solution of 4.44 g of diisopropylamine in 20 ml of tetrahydrofuran were sequentially added 26 ml of 1.6 M solution of n-butyllithium in hexane, 5.30 g of methyl tetrahydro-2-furancarboxylate in 20 ml of tetrahydrofuran and 8.85 g of 1-bromomethyl-3-methoxybenzene in 25 ml of tetrahydrofuran at -70C under an atmosphere of nitrogen gas. After warming to room temperature, 100 ml of 1N hydrochloric acid and 200 ml of ethyl acetate were added. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 6.01 g of the title compound from the 4:1 hexane-ethyl acetate fraction.1H-NMR(CDCl3): 1.71-1.76 (m, 1H), 1.75-1.86 (m, 1H), 1.88-1.96 (td, J=8.3, 13.1Hz, 1H), 2.23-2.39 (ddd, J=5.6, 7.8, 13.1Hz, 1H), 2.96 (d, J=13.7Hz, 1H) 3.19 (d, J=13.7Hz, 1H), 3.70 (s, 3H), 3.78 (s, 3H), 3.85-3.95 (m, 2H), 6.74-6.82 (m,3H), 7.16 (t, J=7.8Hz,1H)
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 potassium tert-butylate; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 20℃; for 1.6h;
Example 1; 5-[ 4-(2-{ 3-bromo-5-chloro-2-[ (3-methoxybenzyl)oxy ]phenyl }ethyl)phenyl]-IH -tetrazole; Step 1; 3-bromo-5-chloro-2-[(3-methoxybenzyl)oxy]benzaldehyde; To a solution of <strong>[19652-32-5]3-bromo-5-chloro-2-hydroxybenzaldehyde</strong> (2.004 g, 8.51 mmol) in DMF (20 ml), a solution of potassium tert-butoxide 1 M in THF (9.5 ml) was added slowly and the mixture was stirred at r. t. for 10 min. Then, 3-methoxybenzyl bromide (1.43 ml, 1.2 equiv. ) was added and the mixture was stirred at r. t. for 1.5 h. The reaction was quenched by addition of a saturated solution of NH4Cl and the product was extracted in EtOAc, washed with dilute HCl and brine, dried over Na2S04 and concentrated. The residue was triturated in cold hexane to yield 2.507 g of the title material as a slightly yellow solid. 'H NMR (acetone-d6) No. 10.08 (lH, s), 8.05 (lH, d), 7.70 (1H, d), 7.35 (1H, dd), 7.10 (2H, m), 6.96 (1H, dd), 5.22 (2H, s), 3.84 (3H, s).
3-ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1.5h;
Example 4; 4-r3-Ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-phenyll-2-methyl-5-oxo-7-propyl- 1,4,5, 6,7,8-hexahvdro-quinoline-3-carbonitrile(a). 3-Ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehvdeA mixture of <strong>[178686-24-3]5-nitro-3-ethoxy-4-hydroxybenzaldehyde</strong> (100 mg), 3-methoxybenzyl bromide (73 mul), potassium carbonate (144 mg) and tetrabutylammonium iodide (10 mg) in DMF (5 ml) was stirred at 60 0C for 90 min. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 2/1 (v/v) as eluent.Yield: 43 mg.
Exemplary Procedure for the Synthesis of Spiro-piperidine Hydantoin Scaffold for R1 Analogs. As depicted in Scheme 7 above, N-benzyl-4-piperidone (20 g, 106 mmol), NaCN (7.9 g, 160.4 mmol), and (NH4)2CO3 (52 g, 542 mmol) in EtOH (50 mL) and H2O (50 mL) was heated at 60 C. overnight. Upon cooling to ambient temperature, the white solid was filtered, washed with warm H2O, and dried in vacuo to provide 27.4 g. The solid (3.0 g, 11.6 mmol) was dissolved in DMF (30 mL), NaH (0.51 g of 60% dispersion in mineral oil, 12.8 mmol) was added, stirred at ambient temperature 2 hours, then 3-methoxybenzyl bromide (11.6 mmol) was added and the reaction was stirred overnight. Typical aqueous work-up provided 5.5 g ER-811159 as a solid which could be recrystallized from MeOH.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.0166667h;Microwave irradiation;Product distribution / selectivity;
Alternative Procedure for the Synthesis of Spiro-piperidine Hydantoin Scaffold for R1 Analogs. As depicted in Scheme 8 above, N-benzyl-4-piperidone (20 g, 106 mmol), NaCN (7.9 g, 160.4 mmol), and (NH4)2CO3 (52 g, 542 mmol) in EtOH (50 mL) and H2O (50 mL) was heated at 60 C. overnight. Upon cooling to ambient temperature, the white solid was filtered, washed with warm H2O, and dried in vacuo to provide 27.4 g. The solid (3.5 g, 13.3 mmol), 3-methoxybenzyl bromide (13.3 mmol), and DBU (20 mmol) were dissolved in NMP (30 mL), separated into 5 vials and each vial was microwave heated at 180 C. for 60 s. The batches were combined, subjected to typical aqueous work-up, then recrystallized from MeOH/MTBE/hexanes to provided 2.2 g ER-811159.
With potassium carbonate; In acetone; for 3h;Heating / reflux;
Example 12 2-(2,6-Dioxo-piperidin-3-yl)-4-(3-methoxy-benzyloxy)-isoindole-l,3-dioneStep 1:[196] To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol) was added 1- bromomethyl-3-methoxy-benzene (0.77 mL, 5.5 mmol) and refluxed for three hours. The solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL) and washed with water (2 x 50 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.1 g, 118% crude yield). The product was used in the next step without further purification.
With potassium carbonate; In acetone; for 3h;Heating / reflux;
2-Chloro-6-hydroxy-quinoline (CAS RN 577967-89-6, 0.6 g, 3 mMol) and 3-methoxybenzylbromid (0.56 mL, 0.004 Mol) were dissolved in a slurry of potassium carbonate (0.55 g, 4 mMol) in 15 mL acetone and heated to reflux for 3 hr. Then water was added and the mixture extracted with ethyl acetate (3*20 mL). The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel (heptane/ethyl acetate 10:0?9:1?4:1 gradient) to yield 2-chloro-6-(3-methoxy-benzyloxy)-quinoline (0.40 g, 40%) as a colorless solid; MS: m/e=300.3 (M+H+).
40%
With potassium carbonate; In acetone; at 20℃; for 3h;Reflux;
To a stirred solution of <strong>[577967-89-6]2-chloro-6-hydroxy-quinoline</strong> (0.6 g, 3.0 mmol) in aceton (15 ml) potassium carbonate (0.55 g, 4.0 mmol) and 3-methoxybenzylbromide (0.8 g, 4.0 mmol) were added at ambient temperature. Then the reaction mixture was heated to reflux for 3 h. Upon cooling to ambient temperature water was added and the whole mixture extracted twice with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane, ethyl acetate 1:0=>1:4) yielded 2-chloro-6-(3-methoxy-benzyloxy)-quinoline as a white solid (0.4 g, 40%), MS 300.8 [(M+H)+].
With caesium carbonate; In N,N-dimethyl-formamide; at 25.0℃; for 15.0h;
A solution of <strong>[4121-22-6]5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde</strong> (75mg, 0.51mmol), Cs2CO3 (3eq, 500mg), and 3-methoxybenzyl bromide (1.2eq, 0.087mL) in DMF (6mL) was stirred at 25C for 15h. The reaction was diluted with EtOAc and washed with peta7 buffer (2x). The organic layer was dried over Na2SO4 and concentrated. The residue was purified via flash chromatography eluding with a gradient of 0 - 100% EtOAc/hexanes. 5-(3- methoxybenzyl)-<strong>[4121-22-6]5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde</strong> was isolated as a yellow solid. 1H NMR (500 MHz, CDCl3): delta 10.25 (s, IH), 8.65 (d, IH), 8.40 (d. IH), 8.12 (s, IH), 7.29 (t, IH), 6.80 (d, IH), 6.83 (m, IH), 5.48 (d, 2H), 3.78 (s, 3H).
Exemplary Procedure for the Synthesis of Spiro-piperidine Hydantoin Scaffold for R3 Analogs. As depicted in Scheme I above, N-Boc-4-piperidone (100 g, 502 mmol), NaCN (37 g, 755 mmol), and (NH4)2CO3 (243 g, 253 mmol) in EtOH (250 mL) and H2O (250 mL) was heated at 60 C. overnight. Upon cooling to ambient temperature, the white solid was filtered, washed with warm H2O, and dried in vacuo to provide 134 g. The solid (30 g, 112 mmol) was dissolved in DMF (300 mL), NaH (5.4 g of 60% dispersion in mineral oil, 135 mmol) was added, stirred at ambient temperature 2 hours, then 3-methoxybenzyl bromide (112 mmol) was added and the reaction was stirred overnight. Typical aqueous work-up provided ER-811161-00 as an oil. ER-811161-00 was dissolved in DMF (300 mL), NaH (5.4 g of 60% dispersion in mineral oil, 135 mmol) was added, stirred at ambient temperature 15 minutes, then 2-methoxyethyl bromide was added and the reaction was stirred overnight. Typical aqueous work-up provided the Boc protected intermediate, which was dissolved in 4 M HCl in dioxane (100 mL). After stirring 2 hours, the reaction was concentrated to give 20.7 g of ER-811163-01 as a foam.
General procedure: A mixture of 44 (300 mg, 1.56 mmol), K2CO3 (372 mg, 2.34 mmol), and halogenated compound (1 equiv) in acetone (10 mL) was stirred for 0.5-3.5 h at rt. After filtering the mixture and removing the solvent in vacuo, the residue was purified by column chromatography (eluent: hexane/EtOAc 85:15) to obtain the target compounds (11-23) as white solids.
With FeCl(THF)L1; In diethyl ether; at 20℃; for 0.5h;Schlenk technique; Inert atmosphere;Catalytic behavior;
General procedure: [00283] Catalyst 20 (0.10 mmol) in CH2C12 (3 mL) was added to a 30 mL Schlenk flask and the solvent removed in vacuo. Et20 (5 mL) and the alkyl halide (2.0 mmol) were added to the catalyst under dry nitrogen. A solution of Grignard reagent (4.0 mmol) was added dropwise under vigorous stirring. The resulting mixture was stirred at roomtemperature for 30 min and the reaction was quenched with HC1 (2.0 M, 5 mL). The organic phase was extracted with Et20 (5 mL) and dried over MgSC>4. The organic phase was then passed through a plug of silica and the diethyl ether was removed in vacuo. The resulting products were then analyzed by GC-MS (using dodecane as internal standard) and NMR spectroscopy (using acetophenone as internal standard).
General procedure: Benzyl bromide 1 (0.17mmol), [(bpy)Cu(SCF3)] (80mg, 0.25mmol, 1.5equiv), and CH3CN (1.0mL) were added to a reaction tube equipped with a stir bar. The mixture was stirred at room temperature for 8-24h until the reaction was judged complete by TLC analysis. The reaction mixture was filtered through a pad of Celite. The filtrate was added water (3×10mL) at 0C. The resulting mixture was extracted with Et2O (3×15mL), and the combined organic layers was washed with water, and then dried over MgSO4. The solvent was removed to give the desired product 3 without further purification.
1-(3-methoxybenzyl)-1H-pyrazole-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
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).
ethyl 1-(3-methoxybenzyl)quinolinium-3-carboxylate bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 80 - 100℃; for 0.5h;
General procedure: One equivalent of <strong>[50741-46-3]ethyl quinoline-3-carboxylate</strong> 1 (1 g,4.96 mmol) was melted in a flask on an oil bath at a temperature of 80-100 C. Then one and a half equivalent of the respective benzylhalogenide 2 (7.44 mmol) was added dropwise under stirring at the maintained temperature and for additional 30 min. Stirring continued until the mixture reached rt and then after the addition 30 mL of diethyl ether for additional 20 min. The organic phase was removed by decanting and washing of the reaction product was repeated for two times. After a final filtration the yielded solid product was crushed and kept dried over phosphorus pentoxide.4.1.1.2 Ethyl 1-(3-methoxybenzyl)quinolinium-3-carboxylate bromide (4) Yield 73%, brownish powder; 1H NMR (methanol-d4) delta = 1.46 (t, J = 7.0 Hz, 3H, CH3), 3.78 (s, 3H, 3'-OCH3), 4.54 (q, J = 7.0 Hz, 2H, CH2CH3), 6.82 (s, 2H, NCH2), 6.96 (dd, J = 8.2, 2.7 Hz, 1H, 6'-H), 7.07 (d, J = 7.0 Hz, 1H, 4'-H), 7.29-7.31 (m, 2H, 2'-, 5'-H), 8.17 (dt, J = 8.2, 1.2 Hz, 1H, 6-H), 8.39 (dt, J = 8.2 Hz, 1.6 Hz, 1H, 7-H), 8.76 (dd, J = 8.2 Hz, 1.6 Hz, 1H, 5-H), 8.87 (dd, J = 8.2, 1.2 Hz, 1H, 8-H), 9.93 (d, J = 1.6 Hz, 1H, 2-H), 10.48 (d, J = 1.6 Hz, 1H, 4-H); IR nu = 1735, 1596, 1382, 1261, 1233, 1171 cm-1; m/z 322 (M+-cation); Anal. Calcd for C20H20BrNO3: C, 59.71; H, 5.01; N, 3.48. Found: C, 59.31; H, 4.89; N, 3.27%.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation;
To a solution of 1 -(bromomethyl)-3-methoxybenzene (0.362 g, 1 .8 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3-dioxolan-2-yl)pyridin-2-amine (0.480 g, 2.16 mmol) and potassium carbonate (0.498 g, 3.6 mmol) in 1 ,4-dioxane (9 ml_) and water (3 ml_) was added [1 ,1 '-b/'s(diphenylphosphino)ferrocene]dichloropalladium(ll) (132 mg, 0.18 mmol) under nitrogen. The reaction mixture was stirred in the microwave at 100 C for 30 minutes. After the reaction was completed, water (50 ml_) was added, the mixture was extracted with ethyl acetate (80 ml_ x 3). The organic layers were dried with sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column (petroleum ether/ethyl acetate from 1 /1 to 0/1 ) to give 5-(3-methoxybenzyl)pyridin-2-amine (0.285 g, 1 .33 mmol, 74%) as a brown solid. LCMS (ESI) m/z: 215.1 [M+H]+.
4-(3-(3-Methoxyphenyl)oxiran-2-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
(101) Dissolve 1.1 mmol of trifluoroacetic anhydride in a nitrogen environment at -60 C.In 1 mL of anhydrous dichloromethane, 2.2 mmol was slowly added dropwise to the reaction system.Anhydrous dimethyl sulfoxide, stirred for 10 min to obtain A10;(102) dissolving 1.1 mmol of 4-cyanobenzyl alcohol in 0.5 mL of anhydrous dichloromethane,Slowly add to A10, stir for 1 h, and slowly add 5.5 mmol of pyridine to the reaction system.Stir for 2h to get B10;(103) TLC (thin layer chromatography) detection, the raw materials disappeared, the reaction was moved to room temperature,Add 1.1 mmol of 3-methylbenzyl bromide, 5.5 mmol of sodium carbonate to B10 at room temperature,0.2mL water and 0.5mL methanol, reacted at 25 for 24h, TLC (thin layer chromatography) detection,The starting point disappears, and the reaction is stopped to obtain C10;(104) Add saturated aqueous sodium bicarbonate solution to C10 to quench the reactionAdd 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.216.2mg of product was separated by column chromatography,This compound was 10 with a yield of 92%.
6-bromo-2-(3-methoxybenzyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
To a stirred solution of commercially available 2a (100mg, 0.444 mmol) in DMF was added NaH (32 mg, 1.333 mmol) at 0 oC. After stirring for 20 min, 3-methoxybenzyl bromide (62 muL, 0.444 mmol) was added into the cooled solution. Then the reaction was transferred to RT and kept stirring for 12h. The reaction mixture was concentrated to dryness under vacuum and then partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The organic phase was concentrated to dryness under vacuum and puried via a ash chromatography silica gel plate (20 × 20 cm) to afford intermediate 3a (petroleum ether/ethyl acetate, 2/1) in 45% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO) delta 8.42 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.03 (dd, J = 8.5, 1.9 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.87 (s, 2H), 6.85 (dd, J = 7.7, 2.9 Hz, 1H), 5.28 (s, 2H), 3.72 (s, 3H).
6-bromo-2-(3-methoxybenzyl)isoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
General procedure: To a stirred solution of commercially available 2a (100mg, 0.444 mmol) in DMF was added NaH (32 mg, 1.333 mmol) at 0 oC. After stirring for 20 min, 3-methoxybenzyl bromide (62 muL, 0.444 mmol) was added into the cooled solution. Then the reaction was transferred to RT and kept stirring for 12h. The reaction mixture was concentrated to dryness under vacuum and then partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The organic phase was concentrated to dryness under vacuum and puried via a ash chromatography silica gel plate (20 × 20 cm) to afford intermediate 3a (petroleum ether/ethyl acetate, 2/1) in 45% yield as a pale yellow solid.
6-bromo-3-(3-methoxybenzyl)thieno[2,3-d]pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12.0h;
To a stirred solution of intermediate 6 (100 mg, 0.433 mmol) in DMF was added K2CO3 (179 mg, 1.299 mmol) and 3-methoxybenzyl bromide (61 muL, 0.433 mmol) at RT. After stirring for 12 h, the solvent was removed under reduced pressure and the residue was extracted with CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. Then the organic phase was concentrated to dryness and puried via a ash chromatography silica gel plate (petroleum ether/ethyl acetate, 3/1) to afford the desired compound as a white solid in 47% yield. 1H NMR (400 MHz, DMSO) delta 8.65 (s, 1H), 7.59 (s, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.94 (s, 1H), 6.87 (dd, J = 10.8, 5.0 Hz, 2H), 5.16 (s, 2H), 3.73 (s, 3H).
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