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Structure of 108052-76-2 * 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; 2,2'-azobis(isobutyronitrile) In tetrachloromethaneReflux
General procedure: To a solution of substituted toluene in carbon tetrachloride were added N-bromosuccinimide (1.1 equiv) and 2,2'-azobis(isobutyronitrile) (0.15 equiv). The mixture was refluxed, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the target compound.
85%
at 70℃;
0.22 g (1.14 mmol) of compound 2 was placed in a two-neck bottle.0.23 g (1.26 mmol) of N-bromosuccinimide and10 mL of dimethyl carbonate.After removing the air, (0.14 g, 0.57 mmol) of azobisisobutyronitrile was added to the reaction system.The reaction was carried out at 70 ° C overnight, and the initial product was separated through a silica gel column to obtain Compound 3.The yield was 85percent.
84.5%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 4 h;
General procedure: To a solution of 8a-d (1 equiv) in CCl4 was added N-bromobutanimide (0.9 equiv) and benzoyl peroxide (0.1 equiv), then the mixture was refluxed at 75°C for 4h. The mixture was washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=20:1) to yield intermediate 9a-d.
77%
With N-Bromosuccinimide; sodium chloride; dibenzoyl peroxide In tetrachloromethane; ethyl acetate
2). tert-butyl (4-bromomethyl)benzoate A mixture of tert-butyl 4-methylbenzoate (12.00 g, 62.4 mmol), N-bromosuccinimide (12.00 g, 67.4 mmol) and dibenzoyl peroxide (0.82 g, 3.4 mmol) in CCl4 is refluxed for 3 hours. The solid is filtered and the solvent evaporated. The residue is then taken up in ethyl acetate (200 ml) and washed with H2O (2*50 ml) and a saturated solution of NaCl (1*50 ml). The organic phase is dried over Na2SO4, the solvent is evaporated and the oil obtained is purified by column chromatography on silica (eluant: AcOEt/c-Hexane 1/15). 13.0 g of product 2 are obtained, in the form of a transparent oil (Yield 77percent). Rf=0.42 (AcOEt/c-Hexane 1/15). NMR 1H (DMSO-d6) (δppm/HMDS): 1.47 (s, 9H, tBu), 4.65 (s, 2H, CH2Br), 7.50 and 7.85 (dd, 4H, Ar-H).
62%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 20 h; Reflux
Preparation of ferf-Butyl 3-(bromomethyl)benzoate Br; [0340] feri-butyl 4-methylbenzoate (31 g, 0.161 mol), N-bromosuccinimide (31.5 g, 0.177 mol), and benzoyl peroxide (0.39 g, 0.00161 mol) in carbon tetrachloride (200 mL) were heated at reflux for 20 hours. The mixture was allowed to cool to room temperature and succinimide filtered. The filtrate was evaporated and the residue purified by Biotage flash chromatography (gradient to 5percent ethyl acetate/hexanes) to give product as an oil (27 g, 62percent); NMR (DMSO-i 6); .sect.1.55 (s, 9H); 4.78 (s, 2H); 7.47-7.51 (m, 1H); 7.68-7.71 (m, 1H); 7.82-7.85 (m, 1H); 7.97 (t, J = 1.6 Hz, 1H).
40%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane; ethyl acetate
EXAMPLE 7 Preparation of benzyl bromide derivatives N-Bromosuccinimide (NBS) (35.8 g, 0.20 mol) was added in several portions to a solution of 1,1-dimethylethyl 4-methylbenzoate (prepared by the reaction of the respective acid chloride with t-butanol.) (38.0 g, 0.20 mol) and benzoyl peroxide (0.36 g, 1.5 mmol) in carbon tetrachloride (1200 mL) at vigorous reflux. Another portion of benzoyl peroxide (0.36 g, 1.5 mmol) was added just before the final addition of NBS. After the foaming subsided, the reaction mixture was cooled to room temperature, washed with water (2*60 mL) and dried over magnesium sulfate. Filtration and concentration provided an oil that was purified by HPLC on silica gel eluding with a mixture of hexanes and ethyl acetate to give 1,1-dimethylethyl 4-bromomethylbenzoate (21.4 g) in 40percent yield.
90%.
With bromine; sodium carbonate; dibenzoyl peroxide In tetrachloromethane
STR478 13.2 Grams (0.006 mole) of tert-butyl 4-methylbenzoate, 0.3 g (0.0012 mole) of benzoyl peroxide and 6 g (0.006 mole) of sodium carbonate were suspended in 100 ml of carbon tetrachloride, and 9.6 g (0.06 mole) of bromine was added dropwise at 50° C. over 30 minutes with stirring. After completion of the addition, reaction was continued for further 30 minutes. The reaction solution was then cooled and filtered to remove carbon tetrachloride-insoluble matters. Carbon tetrachloride was then removed by evaporation under reduced pressure to obtain 16.2 g of tert-butyl 4-bromomethylbenzoate as crystals. Yield 90percent. m.p. 53.4° C.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 10, p. 3156 - 3172
[2] Angewandte Chemie - International Edition, 2007, vol. 46, # 46, p. 8869 - 8871
[3] Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 709 - 715
[4] Patent: CN108329259, 2018, A, . Location in patent: Paragraph 0047; 0052
[5] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 175 - 194
[6] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3737 - 3741
[7] Patent: US2002/55463, 2002, A1,
[8] Monatshefte fur Chemie, 2003, vol. 134, # 7, p. 991 - 1014
[9] Patent: WO2011/160084, 2011, A1, . Location in patent: Page/Page column 121-122
[10] Patent: US5182263, 1993, A,
[11] Tetrahedron Letters, 1996, vol. 37, # 37, p. 6661 - 6664
[12] Organic letters, 2003, vol. 5, # 9, p. 1407 - 1410
[13] Patent: US4843068, 1989, A,
2
[ 6232-88-8 ]
[ 115-11-7 ]
[ 108052-76-2 ]
[ 118507-45-2 ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrabutyl ammonium fluoride In sulfuric acid; acetonitrile
Preparation of α-fluorotoluic acid. 4-Bromomethylbenzoic acid was converted to t-butyl 4-bromomethylbenzoate using isobutylene in sulfuric acid [16], in 50percent yield. The product, an oil, had the following NMR spectrum in CDCl3: 6 7.96 and 7.43 (each d, 2H, J=8Hz), 4.50 (s, 2H), 1.59 (s, 9H, t-Bu). The chemical ionization mass spectrum (NH3) showed peaks at 211 (m+1), 228. The bromomethyl compound was fluorinated as above using tetrabutylammonium fluoride in acetonitrile, in 90percent yield. NMR spectrum in CDCl3: 6 8.01 and 7.41 (each d, 2H, J-8Hz), 5.44 (d, 2H, J=47Hz), 1.60 (s, 9H, t-Bu). The t-butyl ester was removed quantitatively upon 10 min exposure to neat trifluoroacetic acid. The product, α-fluorotoluic acid, was obtained as a white solid, melting at 178°-181°. The chemical ionization mass spectrum (NH3) showed a peak at 172=m+1+17). NMR spectrum in CDCl3: δ 8.12 and 7.47 (each d, 2H, J=8Hz), 5.47 (d, 2H, J=47Hz).
Reference：
[1] Patent: US5098996, 1992, A,
3
[ 52780-16-2 ]
[ 865-47-4 ]
[ 108052-76-2 ]
Reference：
[1] Journal of the American Chemical Society, 2000, vol. 122, # 31, p. 7518 - 7527
4
[ 98946-18-0 ]
[ 6232-88-8 ]
[ 108052-76-2 ]
Reference：
[1] Patent: US2002/49316, 2002, A1,
[2] Organic Process Research and Development, 2017, vol. 21, # 12, p. 1972 - 1979
5
[ 6232-88-8 ]
[ 75-65-0 ]
[ 108052-76-2 ]
Yield
Reaction Conditions
Operation in experiment
39%
With sulfuric acid; magnesium sulfate In dichloromethane for 336 h;
This compound was prepared from 4-(bromomethyl)benzoic acid (2.15 g; 10.0 mmol), t-butyl alcohol (4.8 mL; 50 mmol), anhydrous MgS04 (4.8 g; 40 mmol), and concentrated sulphuric acid in dichloromethane (40 mL) as described in Example 6a. After 14 days, the mixture was worked up as described in Example 6a. 1.07 g (39percent) product was obtained (white solid). The product was used in 7b without further purification. H NMR: (200 MHz; CDCI3): δ 1.59 (9H, s), 4.49 (2H, s), 7.42 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz). 3C NMR: (50 MHz; CDCI3): δ 28.1 , 32.3, 81.2, 128.7, 129.8, 130.6, 141.9, 165.0.
Reference：
[1] Journal of the American Chemical Society, 2000, vol. 122, # 31, p. 7518 - 7527
11
[ 876-07-3 ]
[ 865-47-4 ]
[ 108052-76-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2011, # 22, p. 4121 - 4132
12
[ 874-60-2 ]
[ 108052-76-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 709 - 715
[2] Patent: WO2011/160084, 2011, A1,
13
[ 13756-42-8 ]
[ 108052-76-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 3, p. 1125 - 1136
[2] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11357 - 11360
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane Reflux;
4.2.2. General procedure B (GP-B)
General procedure: To a solution of substituted toluene in carbon tetrachloride were added N-bromosuccinimide (1.1 equiv) and 2,2'-azobis(isobutyronitrile) (0.15 equiv). The mixture was refluxed, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the target compound.
93%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In benzene for 5h; Heating;
92%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Heating;
85%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); carbonic acid dimethyl ester at 70℃;
1.c Step c:
0.22 g (1.14 mmol) of compound 2 was placed in a two-neck bottle.0.23 g (1.26 mmol) of N-bromosuccinimide and10 mL of dimethyl carbonate.After removing the air, (0.14 g, 0.57 mmol) of azobisisobutyronitrile was added to the reaction system.The reaction was carried out at 70 ° C overnight, and the initial product was separated through a silica gel column to obtain Compound 3.The yield was 85%.
84.5%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 75℃; for 4h;
4 General procedure B for preparation of intermediates 9a-d
General procedure: To a solution of 8a-d (1 equiv) in CCl4 was added N-bromobutanimide (0.9 equiv) and benzoyl peroxide (0.1 equiv), then the mixture was refluxed at 75°C for 4h. The mixture was washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=20:1) to yield intermediate 9a-d.
84%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane at 20℃; for 10h;
77%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane
77%
With N-Bromosuccinimide; sodium chloride; dibenzoyl peroxide In tetrachloromethane; ethyl acetate
2 2).
2). tert-butyl (4-bromomethyl)benzoate A mixture of tert-butyl 4-methylbenzoate (12.00 g, 62.4 mmol), N-bromosuccinimide (12.00 g, 67.4 mmol) and dibenzoyl peroxide (0.82 g, 3.4 mmol) in CCl4 is refluxed for 3 hours. The solid is filtered and the solvent evaporated. The residue is then taken up in ethyl acetate (200 ml) and washed with H2O (2*50 ml) and a saturated solution of NaCl (1*50 ml). The organic phase is dried over Na2SO4, the solvent is evaporated and the oil obtained is purified by column chromatography on silica (eluant: AcOEt/c-Hexane 1/15). 13.0 g of product 2 are obtained, in the form of a transparent oil (Yield 77%). Rf=0.42 (AcOEt/c-Hexane 1/15). NMR 1H (DMSO-d6) (δppm/HMDS): 1.47 (s, 9H, tBu), 4.65 (s, 2H, CH2Br), 7.50 and 7.85 (dd, 4H, Ar-H).
73%
With N-Bromosuccinimide; dibenzoyl peroxide for 2h; Heating;
62%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 20h; Reflux;
96
Preparation of ferf-Butyl 3-(bromomethyl)benzoate Br; [0340] feri-butyl 4-methylbenzoate (31 g, 0.161 mol), N-bromosuccinimide (31.5 g, 0.177 mol), and benzoyl peroxide (0.39 g, 0.00161 mol) in carbon tetrachloride (200 mL) were heated at reflux for 20 hours. The mixture was allowed to cool to room temperature and succinimide filtered. The filtrate was evaporated and the residue purified by Biotage flash chromatography (gradient to 5% ethyl acetate/hexanes) to give product as an oil (27 g, 62%); NMR (DMSO-i 6); §1.55 (s, 9H); 4.78 (s, 2H); 7.47-7.51 (m, 1H); 7.68-7.71 (m, 1H); 7.82-7.85 (m, 1H); 7.97 (t, J = 1.6 Hz, 1H).
52%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 60℃; for 8h;
47.2 Step 2. tert-butyl 4-(bromomethyl)benzoate (47c)
To a solution of 47b (3 g, 15.60 mmol) in carbon tetrachloride (30 mL) was added NBS (2.77 g, 15.60 mmol) followed by AIBN (260 mg, 1.56 mmol) and the resulting mixture was stirred at 60° C. for 8 h. Upon complete consumption of the starting material, the reaction mixture was cooled to rt, filtered through a small pad of Celite filter aid, and washed with DCM. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 2% EtOAc in hexane. The pure fractions were collected and evaporated under reduced pressure to afford 47c as a pale brown oil (2.2 g, 8.11 mmol, 52% yield). 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 4.94 (s, 2H), 1.59 (s, 9H)
40%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane; ethyl acetate
7 Preparation of benzyl bromide derivatives
EXAMPLE 7 Preparation of benzyl bromide derivatives N-Bromosuccinimide (NBS) (35.8 g, 0.20 mol) was added in several portions to a solution of 1,1-dimethylethyl 4-methylbenzoate (prepared by the reaction of the respective acid chloride with t-butanol.) (38.0 g, 0.20 mol) and benzoyl peroxide (0.36 g, 1.5 mmol) in carbon tetrachloride (1200 mL) at vigorous reflux. Another portion of benzoyl peroxide (0.36 g, 1.5 mmol) was added just before the final addition of NBS. After the foaming subsided, the reaction mixture was cooled to room temperature, washed with water (2*60 mL) and dried over magnesium sulfate. Filtration and concentration provided an oil that was purified by HPLC on silica gel eluding with a mixture of hexanes and ethyl acetate to give 1,1-dimethylethyl 4-bromomethylbenzoate (21.4 g) in 40% yield.
With N-Bromosuccinimide
3.65 g
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 15h; Irradiation;
90%.
With bromine; sodium carbonate; dibenzoyl peroxide In tetrachloromethane
S.1 Synthetic Example 1
STR478 13.2 Grams (0.006 mole) of tert-butyl 4-methylbenzoate, 0.3 g (0.0012 mole) of benzoyl peroxide and 6 g (0.006 mole) of sodium carbonate were suspended in 100 ml of carbon tetrachloride, and 9.6 g (0.06 mole) of bromine was added dropwise at 50° C. over 30 minutes with stirring. After completion of the addition, reaction was continued for further 30 minutes. The reaction solution was then cooled and filtered to remove carbon tetrachloride-insoluble matters. Carbon tetrachloride was then removed by evaporation under reduced pressure to obtain 16.2 g of tert-butyl 4-bromomethylbenzoate as crystals. Yield 90%. m.p. 53.4° C.
4-{4-[(1S,2S,3S,4R,6R)-6-((S)-1-Carbamoyl-ethylcarbamoyl)-2,3,4-trihydroxy-cyclohexylsulfanyl]-2,3-dihydroxy-butylsulfanylmethyl}-benzoic acid tert-butyl ester[ No CAS ]
4-{4-[(1S,2S,3S,4R,6R)-6-((S)-1-Carbamoyl-2-carboxy-ethylcarbamoyl)-2,3,4-trihydroxy-cyclohexylsulfanyl]-2,3-dihydroxy-butylsulfanylmethyl}-benzoic acid tert-butyl ester[ No CAS ]
4-{4-[(1S,2S,3S,4R,6R)-6-((S)-1-Carbamoyl-3-carboxy-propylcarbamoyl)-2,3,4-trihydroxy-cyclohexylsulfanyl]-2,3-dihydroxy-butylsulfanylmethyl}-benzoic acid tert-butyl ester[ No CAS ]
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
0.9 g (3.31 mmol) of the compound obtained in the preceding step was dissolved in 50 ml of DMF. 1.18 g (3.64 mmol) of cesium carbonate and 0.986 g (3.64 mmol) of t-butyl 4-bromomethyl-benzoate were then added. The reaction mixture was stirred at room temperature for 24 hours. 200 ml of EtOAc were then added, and the organic layer was washed with 3 x 100 ml of water, dried over [MGS04] and concentrated. The residue was purified on a silica gel column using 4: 1 dichloromethane : hexane increasing gradually to a 1: 1 ratio, to yield 0.97 g (62%) of white powder as the desired product. N. M. R [(CDCL3) 1H A] (ppm) 5.21 (s, 2H), 7.36 (d, [J=] 8. 5Hz, 2H), 7.43 (d, [J=] 8.5 Hz, [1H),] 7.96 (dd, Jl = 6. 6Hz, [J2] = 3. 1Hz, 2H), 8.01 (dd, Jl = 6. [5HZ,] [J2] = 2. 1Hz, [1H),] 8.07 (s, 1H), 8.64 (d, [J=] [1.] 8Hz, [1EI)] ; MS (APCI), M/z 270.9 [(M-1).]
62%
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
0.9 g (3.31 mmol) of compound obtained in the preceding Step 2 is dissolved in 50 ml of DMF. 1.18 g (3.64 mmol) of cesium carbonate and 0.986 g (3.64 mmol) of ter-butyl 4-bromomethyl-benzoate is added. The reaction is stirred at room temperature for 24 hours. 200 ml of EtOAc is then added, and then washed with 3×100 ml of water. The organic layer is dried over MgSO4 and concentrated. The residue is purified on a silica gel column using 4:1 dichloromethane:hexane increasing gradually to a 1:1 ratio, to yield 0.97 g (62%) of white powder as the desired product. [00378] MS(APCI), M/z 270.9 (M-1) [00379] N.M.R (CDCl3) 1H delta(ppm) 5.21 (s, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 1H), 7.96 (dd, J1=6.6 Hz, J2=3.1 Hz, 2H), 8.01 (dd, J1=6.5 Hz, J2=2.1 Hz, 1H), 8.07 (s, 1H), 8.64 (d, J=1.8 Hz, 1H)
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h;
<strong>[1627-28-7]5-Methyl-6-chloropyrimidine-2,4-dione</strong> (1.00 g, 6.22 mmol) was dissolved in dimethylformamide (15 mL).To the solution was added cesium carbonate (2.02 g, 6.22 mmol) and t-butyl 4-bromomethylbenzoate (1.69 g, 6.22 mmol). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under a vacuum at 60 C. The residue was mixed with tetrahydrofuran (50 mL) and methanol (10 mL) and filtered. The filtrate was evaporated in a vacuum to an amber oil. The oil was purified by flash chromatography on silica gel eluding first with dichloromethane then with dichloromethane:methanol (19:1) to give the desired product (0.88 g, 40% yield). 1H-NMR (DMSO-d6) delta11.8 (s, 1H), 7.85 (d, 2H), 7.34 (d, 2H), 5.22 (s,2H), 1.88 (s, 3H), 1.51 (s, 9H).
40%
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h;
[5-METHYL-6-CHLOROPYRIMIDINE-2,] 4-dione (1.00 g, 6.22 mmol) was dissolved in dimethylformamide (15 mL). To the solution was added cesium carbonate (2.02 g, 6.22 mmol) and t-butyl 4-bromomethylbenzoate (1.69 g, 6.22 mmol). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under a vacuum at [60 C.] The residue was mixed with tetrahydrofuran (50 mL) and methanol (10 mL) and filtered. The filtrate was evaporated in a vacuum to an amber oil. The oil was purified by flash chromatography on silica gel eluting first with dichloromethane then with dichloromethane: methanol (19: 1) to give the desired product (0.88 g, 40% [YIELD). LH-NMR (DMSO-D6) o 11.] 8 (s, [1H),] 7.85 (d, [2H),] 7.34 (d, 2H), 5.22 (s, 2H), 1.88 (s, 3H), 1.51 (s, 9H).
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
A suspension [OF 7-BROMO-1-HYDROXYISOQUINOLINE] (7.02g, 28. [2MMOL)] in dimethylformamide [(75ML)] was treated with 4-bromomethylbenzoic acid tert- butyl ester (12.5g, 36.7mmol) and cesium carbonate [(11.] 94g, 36.7mmol), then stirred overnight at room temperature. The dimethylformamide was evaporated in vacuo, the residue diluted with ethyl acetate, washed with IN HC1, the organic portion washed with brine, dried over [MGS04] and evaporated to dryness. The residue was triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid collected by filtration and dried to give 8.77g of the product as white crystals (75.7% yield). [1H-NMR] [(CDC13)] ; d 8.58 (d, 1H), 7.95-7. 93 (d, 2H), 7.73-7. 71 (dd, 1H), 7.39- 7.32 (m, [3H),] 7.07-7. 05 (d, [1H),] 6.46-6. 44 (d, 1H), 5.24 (s, [2H),] 1.57 (s, 9H). MS: [M+ +1] = 414.0/416. 0 Da
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;
1A.1 EXAMPLE 1A;4-[3-Oxo-7-(3-phenyl-prop-l-ynyl)-2H-isoquinolin-2-ylmethyl]benzoicacidtert-butyl ester; Step (1): 4-(7-bromo-3-oxo-2H-isoquinolin-2-ylmethyl)benzoic acid tert-butyl ester
A suspension of 7-bromo-3-hydroxy-isoquinoline (7.02g, [28.] [2MMOL)] in dimethylformamide (75mL) is treated with 4-bromomethylbenzoic acid tert-butyl ester (12.5g, 36. [7MMOL)] and cesium carbonate [(11.] 94g, 36. [7MMOL),] then stirred overnight at room temperature. The dimethylformamide is evaporated in vacuo, the residue is diluted with ethyl acetate, washed with 1N [HCI,] the organic portion washed with brine, dried over [MGS04] and evaporated to dryness. The residue is triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid is collected by filtration and dried to give the desired product.
6
tert-Butyl 4-(bromomethyl)benzoate 4-(Bromomethyl)benzoic acid (6 g, 26 mmol) and isobutene (30 ml) were reacted by the same procedure as described in Example 3 for the preparation of tert-butyl 4-iodobutanoate and afforded the title material (2.4 g) as a pale yellow oil. 1H NMR (CDCl3, δ, ppm); 1.60 (9H, s, -tBu), 4.51 (2H, s, -CH2Br), 7.44 and 7.97 (2*2H, d, J=8.2 Hz, aromatic H).
6
tert-Butyl 4-(bromomethyl)benzoate 4-(Bromomethyl)benzoic acid (6 g, 26 mmol) and isobutene (30 ml) were reacted by the same procedure as described in Example 3 for the preparation of tert-butyl 4-iodobutanoate and afforded the title material (2.4 g) as a pale yellow oil. 1H NMR (CDCl3, δ, ppm): 1.60 (9H, s, -tBu), 4.51 (2H, s, -CH2Br), 7.44 and 7.97 (2*2H, d, J=8.2 Hz, aromatic H).
Step B: Tert-butyl 4-[2-(dimethylamino)-1-ethoxy-1-oxopropyl]benzoate. Ethyl (dimethylamino)acetate (0.16 mL, 1.11 mmol) was dissolved in THF (10 mL) and cooled to -78 C. LiHMDS (1.2 mL, 1M solution in THF) was added. The reaction was allowed to stir about 30 minutes. Tert-butyl 4-(bromomethyl)benzoate (0.3063 g, 1.13 mmol) in THF (3 mL) was slowly added to the reaction. The reaction was allowed to stir overnight under nitrogen, slowly warming to room temperature. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The resulting mixture was separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography. 1H NMR 600 MHz (CDCl3) delta 7.87 (m, 2H), 7.24 (m, 2H), 4.08 (m, 1H), 4.06 (m, 1H), 3.41 (dd, 1H, J=9.2, 6.0), 3.07 (dd, 1H, J=13.5, 9.3), 2.97 (dd, 1H, J=13.4, 5.8), 2.39 (s, 6H), 1.56 (s, 9H), 1.16 (m, 3H). MS: cal'd 322 (MH+), exp 322 (MH+).
With potassium tert-butylate; In N,N-dimethyl-formamide;
Reference Example 24; Ethyl 4-bromo-1-[4-(tert-butoxycarbonyl)benzyl]-5-methyl-1H-pyrazole-3-carboxylate <strong>[6076-14-8]Ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate</strong> (25.5 g) was dissolved in DMF (500 mL), ice-cooled, and potassium tert-butoxide (14.7 g) was added. The reaction mixture was stirred for 10 min, and a solution (14.7 g/50 mL) of tert-butyl 4-(bromomethyl)benzoate in DMF was added dropwise slowly. The reaction mixture was stirred at 0 C. for 1.5 hr, poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (hexane-ethyl acetate) to give two kinds of positional isomers. A high polar compound was washed with diisopropyl ether-hexane to give the title compound (11.6 g) as colorless crystals.1H-NMR (CDCl3) delta: 1.43 (3H, t), 1.58 (9H, s), 2.16 (3H, s), 4.45 (2H, q), 5.45 (2H, s), 7.13 (2H, d), 7.95 (2H, d).
Step (F) : 4- (6-CHLORO-4-OXO-4H-PYRIDO [3, 4-D] PYRIMIDIN-3-YLMETHYL)-BENZOIC acid tert-butyl ester A 2 L round bottomed flask was charged with 6-chloro-3H-pyrido [3,4- D] PYRIMIDIN-4-ONE (61.9 g, 0.34 moles), CS2CO3 (155 g, 0. 48 moles, 1.4 mole equivalents), and 900 mL of DMF. The slurry was stirred for 5 minutes, then t- butyl-4-bromomethylbenzoate (129 g, 0.48 moles, 1.4 mole equivalents) was added, and stirring of the resulting thick slurry was continued. After 15 minutes HPLC (C18,4 : 1/CH3CN : 0. 1% TFA, 254 nm, 1 ML/MIN) showed less than 3% of 6-chloro-3H-pyrido [3,4-d] PYRIMIDIN-4-ONE remained. After 30 minutes the reaction was complete. Added 450 mL of H20 to the slurry, and collected the resulting solid by filtration. The solid was washed twice with 2: 1/DMF: H20, once with H2O, and dried overnight in the vacuum oven at 45C. The reaction yielded 124 g (98% total) OF 4- (6-CHLORO-4-OXO-4H-PYRIDO [3,4-d] pyrimidin-3- ylmethyl) -benzoic acid tert-butyl ester as a white solid that was 99% pure by HPLC. OH (DMSO) 8.94 (1 H, d), 8. 71 (1 H, s), 7.99 (1 H, d), 7. 83 (2 H, d), 7.45 (2 H, d), 5.26 (2 H, s), 1.49 (9 H, s) MS [M+H] + 372 HPLC 99.02%, RT 2. 90 min ; YMC Pack Pro C18 4. 6X150 mm, 3F ; A: 0.05% TFA in H2O, B: 0. 05% TFA in CH3CN ; 10% B to 95% B over 15 minutes, hold for 5 minutes; X 240 nm, 1 ml/min
Tributyl-[[4-[(2-methylpropan-2-yl)oxycarbonyl]phenyl]-methyl]phosphanium Bromide (3)
oxycarbonyl]phenyl]-methyl]phosphanium Bromide (3) To a solution of tert-butyl 4-(bromomethyl) benzoate (22.1 g, 81.6 mmol) in toluene (440 mL) was added tri-n-butyl phosphine (30.5 mL, 121 mmol), and the mixture was stirred at 60°C for 70 min. The reaction mixture was evaporated and the residue was added n-hexane. The mixture was stirred and the resulting precipitate was collected by filtration, and dried to yield 3 (36.0 g, 93%) as a colorless powder:
In toluene at 60℃; for 1.16667h;
153.1
[Example 153] [1-(4-[2-(4-chlorophenyl)ethyl]carbamoyl} benzyl)isoquinolin-4-yl]acetic acid (1) To a solution of 4-(bromomethyl)benzoic acid tert-butyl ester (22. 1. g) in toluene (440 ml), tri-n-butylphosphine (30.5 ml) was added, and the mixed solution was stirred at 60°C for 70 min. The reaction solution was removed by evaporation under reduced pressure, and to the resulting crude product, n-hexane was added and stirred. The resulting solid was filtered out to give [4-(tert-butoxycarbonyl)benzyl](tributyl)phosphonium bromide (36.0 g) as a colorless solid. 1H NMR (600 MHz, CHLOROFORM-d) d ppm 0.93 - 0.98 (m, 9 H), 1.44-1.52 (m, 12 H), 1.60 (s, 9 H), 2.37 - 2.46 (m, 6 H), 4.34 - 4.40 (m, 2 H), 7.50 - 8.02 (m, 4 H)
36.0 g
In toluene at 60℃; for 1.16667h;
1.1 (1)
To a solution of 4-(bromomethyl)benzoic acid tert-butyl ester (22.1 g) in toluene (440 ml), tri-n-butylphosphine (30.5 ml) was added, and the mixed solution was stirred at 60° C. for 70 min. The reaction solution was removed by evaporation under reduced pressure, and to the resulting crude product, n-hexane was added and stirred. The resulting solid was filtered out to give [4-(tert-butoxycarbonyl)benzyl](tributyl)phosphonium bromide (36.0 g) as a colorless solid. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.93-0.98 (m, 9H), 1.44-1.52 (m, 12H), 1.60 (s, 9H), 2.37-2.46 (m, 6H), 4.34-4.40 (m, 2H), 7.50-8.02 (m, 4H)
Preparation of benzyl 3-(4-(fer?-butoxycarbonyl)benzyl)-4-oxo-l -phenyl-1.3.8- triazaspiror4.51decane-8-carboxylate; [0339] Sodium hydride (60%> dispersion in oil, 0.46 g, 0.0114 mol) was added portionwise at 0 C to benzyl 4-oxo-l -phenyl-l,3,8-triazaspiro[4.5]decane-8-carboxylate (4.00 g, 0.0109 mol) in N,N- dimethylformamide (40 mL) and the mixture stirred at 0 C for 10 minutes. tert-Butyl 4- (bromomethyl)benzoate (3.27 g, 0.0120 mol) was added dropwise at 0 C, the mixture then allowed to warm to room temperature, and stirred for 2 hours. The reaction was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgS04), and evaporated. The residue was purified by Biotage flash column chromatography (gradient 0 to 30%> ethyl acetate/hexanes) to give product as an oil (4.97 g, 82%>);'H NMR (DMSO-i/6); 51.53 (s, 9H); 1.72 (d, J = 13.6 Hz, 2H); 2.34-2.42 (m, 2H); 3.57 (m, 2H); 3.99-4.03 (m, 2H); 4.61 (s, 2H); 4.63 (s, 2H); 6.69 (d, J = 8Hz, 2H); 6.78 (t, J = 7.2 Hz, 1H); 7.18 (dd, J = 7.2 Hz and 8.8 Hz, 2H); 7.32-7.39 (m, 5H); 7.42 (d, J = 8.4 Hz, 2H); 7.90 (d, J = 8.4 Hz, 2H);
tert-butyl 4-((3-(2-methoxy-2-oxoethyl)azetidin-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
120 mg
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25℃; for 5.0h;
To a mixture of methyl 2-(azetidin-3-yl)acetate;hydrochloride (112 mg, 676.25 umol, 1.00 eq), diisopropylethylamine (437 mg, 3.38 mmol, 590.53 uL, 5.00 eq) in acetonitrile (3 mL) was added tert-butyl 4-(bromomethyl)benzoate (183 mg, 676.25 umol, 1.00 eq). The mixture was stirred at 25 C for 5 h. To the mixture was added H20 (5 mL). The mixture was extracted with ethyl acetate (5 mL*2). The organic phase was dried with Na2S04 and concentrated under vacuum. The crude residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l to 8: 1) to afford tert-butyl 4-((3- (2-methoxy-2-oxoethyl)azetidin-l-yl)methyl)benzoate (120 mg, 360.69 umol). LCMS (M+ H+) m/z: calcd 320.18; found 319.9.
tert-butyl 4-((4-formyl-1H-pyrazol-1-yl)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.5%
Intermediate 7 (0.829 g, 8.63 mmol) was dissolved in DMF (0.43 mL), and the solution was cooled to 0 °C. NaH, 60percent dispersion in mineral oil (380 mg, 9.49 mmol) was added portionwise under argon. The reaction mixture was stirred for 15 minutes at 0°C, then a solution of tert-butyl 4-(bromomethyl)benzoate (2.57 g, 9.49 mmol) in 10 mLof DMF was added. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was cooled to 0 °C and carefully quenched with water, then diluted with EtOAc, washed with 10percent LiC1 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to provide 46A (0.85 g, 34.5percent). MS(ESI) m/z 287.1 (M+H)t
tert-butyl 4-((4-(1-methoxy-1-oxohex-4-yn-3-yl)phenoxy)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.5%
General procedure: To a solution of 16-20 (1 equiv) in DMF was added K2CO3 (2 equiv), stirred for 5min then add the intermediates 9a-d (1.1 equiv), then the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate, then washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was purified with column chromatography (petroleum ether/ethyl acetate=8:1) to yield intermediate 10a-i.
With sodium iodide; In tetrahydrofuran; at 20℃;Reflux;
General procedure: The alkaloid (12.3 mmol, 1 eq.) and the appropriate substituted benzylic halide derivative(12.3 mmol, 1 eq.) were dissolved in THF (40 mL) with addition of a trace of NaI. The mixture washeated to reflux overnight and then cooled and stirred at ambient temperature for 1 h. In most cases theproduct precipitated as an off-white solid, but where this was not the case and the mixture containedonly a small amount of solid or no solid at all, then diethyl ether (20 mL) was added dropwise.The solid was removed via filtration and washed with THF (50 mL) or ether:THF, (1:1, v/v, 50 mL)and was dried under reduced pressure at 40 C. Where the solid formed was not a fine powder it was then taken up in DCM and this solution was then added dropwise to rapidly stirring ether (100 mL).This usually gives a finely divided solid that could be filtered and dried. (Note: The cinchonine derivedPTCs are usually very insoluble. The quinidine derived PTCs are often completely soluble at the endof the reaction.) The di(t-butyl)benzyl PTC was prepared according to the standard procedure aboveand was filtered directly from the reaction mixture.
tert-butyl 4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)thio)methyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: 4-(bromomethyl)benzoic acid 1,1-dimethylethyl ester With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h;
Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃;
methyl 1-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: methyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate With potassium carbonate In acetonitrile at 20℃; for 0.0833333h;
Stage #2: 4-(bromomethyl)benzoic acid 1,1-dimethylethyl ester In acetonitrile at 80℃; for 16h;
32.3 (Step 3)
Methyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (1.0 g, 5.18 mmol) obtained in step 2 was dissolved in acetonitrile (10 mL), then potassium carbonate (1.43 g, 10.36 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. tert-Butyl 4-(bromomethyl)benzoate (1.4 g, 5.18 mmol) was added to the reaction mixture, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, then water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate/petroleum ether =1/4) to give methyl 1-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (1.45 g, 73%). ESIMS, (M+H)+, m/z: 384.21.
73%
Stage #1: methyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate With potassium carbonate In acetonitrile at 20℃; for 0.0833333h;
Stage #2: 4-(bromomethyl)benzoic acid 1,1-dimethylethyl ester In acetonitrile at 80℃; for 16h;
32.3 Step 3
Methyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (1.0 g, 5.18 mmol) obtained in step 2 was dissolvedin acetonitrile (10 mL), then potassium carbonate (1.43 g, 10.36 mmol) was added to the solution, and the mixture wasstirred at room temperature for 5 minutes. tert-Butyl 4-(bromomethyl)benzoate (1.4 g, 5.18 mmol) was added to thereaction mixture, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reducedpressure, then water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by columnchromatography (ethyl acetate/petroleum ether = 1/4) to give methyl 1-(4-(tert-butoxycarbonyl)benzyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (1.45 g, 73%).ESIMS, (M+H)+, m/z: 384.21.
(2S)-2-[(tert-butoxycarbonyl)amino]-3-[[4-(tert-butoxycarbonyl)phenyl]methoxy]propanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.27%
Stage #1: (S)-N-(tert-butoxycarbonyl)serine With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: 4-(bromomethyl)benzoic acid 1,1-dimethylethyl ester In N,N-dimethyl-formamide at 20℃; for 16h;
1.1 Step 1: Preparation of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[[4-(tert-butoxycarbonyl)phenyl]methoxy] propanoic acid (intermediate 3)
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid (1.00 g, 4.873 mmol, 1.00 equiv) in DMF (40.00 ml_) was added NaH (233.88 mg, 9.746 mmol, 2.00 equiv). The solution was stirred at room temperature for 1 h. Then tert-butyl 4-(bromomethyl)benzoate (1321.35 mg, 4.873 mmol, 1.00 equiv) was added and the solution was stirred for 16 h at room temperature. The reaction was quenched with 40 ml_ water at 0 degrees C. The aqueous layer was washed by EtOAc (30 ml_ x 3) and then acidifed to PH ~ 3 at 0 degrees C. The aqueous phase was then extracted into EtOAc (30 ml_ x 3). The combined organic layers wer dried by sodium sulfate. After removing the organic solvent, the residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 100% gradient in 10 min; detector, UV 210 nm. This resulted in intermediate 3 (1 .2 g, 62.27%) as a white solid. LCMS (ESI) m/z: [M+H]+ = 396.
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