[ CAS No. 251085-87-7 ] {[proInfo.proName]}

Name: 251085-87-7|Methyl 5-bromo-2-chlorobenzoate|98%
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Quality Control of [ 251085-87-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 251085-87-7 ]

CAS No. :	251085-87-7	MDL No. :	MFCD00144770
Formula :	C₈H₆BrClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DOVGGQQIXPPXDC-UHFFFAOYSA-N
M.W :	249.49	Pubchem ID :	842098
Synonyms :

Calculated chemistry of [ 251085-87-7 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.43
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.45
Log Po/w (XLOGP3) :	4.12
Log Po/w (WLOGP) :	2.89
Log Po/w (MLOGP) :	3.24
Log Po/w (SILICOS-IT) :	3.01
Consensus Log Po/w :	3.14

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.22
Solubility :	0.015 mg/ml ; 0.0000602 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.38
Solubility :	0.0104 mg/ml ; 0.0000418 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.95
Solubility :	0.0282 mg/ml ; 0.000113 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.72

Safety of [ 251085-87-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 251085-87-7 ]

* 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.

Upstream synthesis route of [ 251085-87-7 ]
Downstream synthetic route of [ 251085-87-7 ]

[ 251085-87-7 ] Synthesis Path-Upstream 1~3

1
[ 251085-87-7 ]
[ 149965-40-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; for 2.5 h;	Preparation 13. (5-bromo-2-chlorophenyl)methanolTo a THF (50 mL) solution of methyl 5-bromo-2-chlorobenzoate (Preparation 12, 10.5 g, 42 mmol) was added sodium borohydride (3.18 g, 84 mmol) followed by the careful dropwise addition of MeOH (7 mL) over 30 minutes. The reaction was stirred for one hour at room temperature. An additional amount of sodium borohydride (0.5 g) was added and the mixture stirred for one more hour at room temperature. The reaction mixture was poured into ethyl acetate (125 mL) and stirred for twenty minutes. Water (50 mL) was added, slowly at first, then all at once. The layers were stirred vigorously together for fifteen minutes. The organic phase was collected, dried over sodium sulfate, and concentrated at low pressure to give (5-bromo-2-chlorophenyl)methanol as a white solid (7.85 g, 84percent). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.77 (s, 2H) 7.23 (d, J=8.34 Hz, 1H) 7.37 (dd, J=8.34, 2.53 Hz, 1H) 7.68 (d, J=2.53 Hz, 1H)

Reference： [1] Patent: US2011/251247, 2011, A1, . Location in patent: Page/Page column 19

2
[ 251085-87-7 ]
[ 149965-40-2 ]

Reference： [1] Patent: US6313071, 2001, B1,

3
[ 251085-87-7 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: With pyrrolidine; sodium bis(2-methoxyethoxy)aluminium dihydride In tert-butyl methyl ether; toluene at -20 - 25℃; for 1.33333 h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran; tert-butyl methyl ether; toluene Stage #3: at 10℃; for 0.25 h;	5-Bromo-2-chlorobenzaldehyde (74c). A solution of pyrrolidine (4.00 g, 56.0 mmol) in MTBE (12 mL) was added dropwise over 20 min to a solution of Red-Al.(R). (3.4 M solution in toluene, 16 ml, 54.4 mmol) in MTBE (33 mL) maintained at -20 °C. The mixture was stirred for 1 h at 25 °C. A solution of potassium tert-butoxide (0.60 g, 5.36 mmol) in THF (3 mL) was added. The resulting solution was added dropwise to a solution of 2-chloro-5-bromobenzoic acid methyl ester (72, 6.80 g, 27.3 mmol) in MTBE (15 mL) at 10 °C. After 15 min the mixture was quenched with 2 N HCl (300 mL). Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54percent, mp 43-46 °C), which was used without further purification in the next step.; The synthesis of benzaldehyde chlorooxime synthons 52 is depicted in Scheme 4, below. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d were commercially available. The preparation of aldehyde 44f began with the known three-step transformation of 4-methyl-3-nitrobenzonitrile 63 to methoxy compound 64. See Reiner, J. E., et al., Bioorg. Med. Chem. Lett., 12, 1203-1208 (2002). α-Bromination of 64 using one equivalent of N-bromosuccinimide gave little selectivity between the mono- and dibromo adducts, but the analogous reaction using 2.5 equivalents gave dibromide 65 almost exclusively. Silver nitrate oxidation of dibromide 65 gave aldehyde 44f. See Hill. R. A., et al., J. Chem. Soc., Perkin Trans., 1, 2209-2215 (1987). The reaction of the o-nitrotoluene 63 with N,N-dimethylformamide dimethyl acetal in DMF gave the enamine 66, which underwent oxidative cleavage using sodium periodate in THF, see Riesgo, E. C., et al., J. Org. Chem., 61, 3017-3022 (1996), to give aldehyde 74a via a more facile preparation than previously reported. See Dann, O., et al., Liebigs Ann. Chem., 3, 409-425 (1984). Aldehyde 74b also has been prepared previously. See Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976). A more expedient preparation of 74b began with chlorotoluene 67 undergoing α-bromination to 68, see Gilbert, A. M., et al., J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P., et al., Synthesis, 14, 2078-2080 (2001). The reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. See Mallory, F. M., et al., Tetrahedron, 57, 3715-3724 (2001). Commercially available aldehyde 69 and aldehyde 71, see Hino, K., et al., Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which had been prepared via a Sandmeyer reaction from commercially available 70, were converted to methyl esters 72 and 73, respectively. The esters were converted to aldehydes 74c and 74e, respectively, using Red-Al.(R).(sodium bis(2-methoxyethoxy)aluminium hydride) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, United States of America), pyrrolidine, and potassium tert-butoxide in methyl tert-butyl ether. See Abe, T., et al., Tetrahedron, 57, 2701-2710 (2001). Cyanoaldehyde 74f was prepared by debromocyanation of 44d. See Laali, K. K., et al., J. Org. Chem., 58, 1385-1392 (1993). Aldehydes 44e-44f and 74a-74f were converted to oxime derivatives 75a-h (of which 75a,e were known previously), see Quan, M. L., et al., J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in either water/ethanol or pyridine/ethanol. The oximes were treated with N-chlorosuccinimide in DMF to give chlorooximes 52a-h, following the procedure reported for 52e. See Liu. K.-C., et al., J. Org. Chem., 45, 3916-3918 (1980). The chlorooximes 52 were reacted with acetylenes 51 without further purification.; Reagents and conditions: (a) H₂, 10percent Pd/C, EtOH; (b) NaNO₂, aq. H₂SO₄; (c) CH₃l, NaH, DMF; (d) NBS, benzoyl peroxide, CCl₄; (e) AgNO₃, aq. EtOH; (f) DMFDMA, DMF; (g) NalO₄; aq. THF; (h) diethyl phosphite, (i-Pr)₂NEt, THF; (j) 2-nitropropane, NaOEt, EtOH; (k) NaNO₂, aq. HCl, then CuCN, KCN; (I) MeOH, H₂SO₄; (m) DCC, DMAP, MeOH, CH₂Cl₂; (n) Red-Al.(R)., t-BuOK, pyrrolidine, MTBE; (o) NH₂OH HCl, H₂O/EtOH or Py/EtOH (p) NCS, DMF.

Reference： [1] Patent: EP1719767, 2006, A1, . Location in patent: Page/Page column 24-28; 41-42
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485

[ 251085-87-7 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 21739-92-4 ]
[ 251085-87-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; for 72h;Heating / reflux;	2-Chloro-5-bromobenzoic acid methyl ester (72). A solution of benzoic acid 69 (30.0 g, 127 mmol) and H2SO4 (2 mL) in MeOH (2 L) was stirred at reflux for 3 d. The reaction mixture was concentrated to give white crystals (31.2 g, 98%): mp 43-44 C; 1H NMR delta 7.99 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.6 and 2.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 3.87 (s, 3H); HPLC (Method B) tR 6.34 min (100 area % at 230 nm).; Reagents and conditions: (a) H2, 10% Pd/C, EtOH; (b) NaNO2, aq. H2SO4; (c) CH3l, NaH, DMF; (d) NBS, benzoyl peroxide, CCl4; (e) AgNO3, aq. EtOH; (f) DMFDMA, DMF; (g) NalO4; aq. THF; (h) diethyl phosphite, (i-Pr)2NEt, THF; (j) 2-nitropropane, NaOEt, EtOH; (k) NaNO2, aq. HCl, then CuCN, KCN; (I) MeOH, H2SO4; (m) DCC, DMAP, MeOH, CH2Cl2; (n) Red-Al, t-BuOK, pyrrolidine, MTBE; (o) NH2OH HCl, H2O/EtOH or Py/EtOH (p) NCS, DMF.; The synthesis of benzaldehyde chlorooxime synthons 52 is depicted in Scheme 4, below. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d were commercially available. The preparation of aldehyde 44f began with the known three-step transformation of 4-methyl-3-nitrobenzonitrile 63 to methoxy compound 64. See Reiner, J. E., et al., Bioorg. Med. Chem. Lett., 12, 1203-1208 (2002). alpha-Bromination of 64 using one equivalent of N-bromosuccinimide gave little selectivity between the mono- and dibromo adducts, but the analogous reaction using 2.5 equivalents gave dibromide 65 almost exclusively. Silver nitrate oxidation of dibromide 65 gave aldehyde 44f. See Hill. R. A., et al., J. Chem. Soc., Perkin Trans., 1, 2209-2215 (1987). The reaction of the o-nitrotoluene 63 with N,N-dimethylformamide dimethyl acetal in DMF gave the enamine 66, which underwent oxidative cleavage using sodium periodate in THF, see Riesgo, E. C., et al., J. Org. Chem., 61, 3017-3022 (1996), to give aldehyde 74a via a more facile preparation than previously reported. See Dann, O., et al., Liebigs Ann. Chem., 3, 409-425 (1984). Aldehyde 74b also has been prepared previously. See Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976). A more expedient preparation of 74b began with chlorotoluene 67 undergoing alpha-bromination to 68, see Gilbert, A. M., et al., J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P., et al., Synthesis, 14, 2078-2080 (2001). The reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. See Mallory, F. M., et al., Tetrahedron, 57, 3715-3724 (2001). Commercially available aldehyde 69 and aldehyde 71, see Hino, K., et al., Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which had been prepared via a Sandmeyer reaction from commercially available 70, were converted to methyl esters 72 and 73, respectively. The esters were converted to aldehydes 74c and 74e, respectively, using Red-Al(sodium bis(2-methoxyethoxy)aluminium hydride) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, United States of America), pyrrolidine, and potassium tert-butoxide in methyl tert-butyl ether. See Abe, T., et al., Tetrahedron, 57, 2701-2710 (2001). Cyanoaldehyde 74f was prepared by debromocyanation of 44d. See Laali, K. K., et al., J. Org. Chem., 58, 1385-1392 (1993). Aldehydes 44e-44f and 74a-74f were converted to oxime derivatives 75a-h (of which 75a,e were known previously), see Quan, M. L., et al., J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in either water/ethanol or pyridine/ethanol. The oximes were treated with N-chlorosuccinimide in DMF to give chlorooximes 52a-h, following the procedure reported for 52e. See Liu. K.-C., et al., J. Org. Chem., 45, 3916-3918 (1980). The chlorooximes 52 were reacted with acetylenes 51 without further purification.
94.8%	With sulfuric acid; for 3h;Reflux;	To a solution of 5-bromo-2-chlorobenzoic acid (24.8 g, 105.32 mmol, 1 eq) in MeOH (100 mL) was added H2S04 (10.33 g, 105.32 mmol, 5.61 mL, 1 eq), and the mixture was refluxed for 3 h. It was concentrated under reduced pressure to remove most of methanol. The residue was added to cold water (300 mL) and stirred for 10 min. The mixture was filtered, and the white cake was washed with cold water (100 mL), and then dried to give methyl 5-bromo-2-chloro-benzoate (24.9 g, 99.80 mmol, 94.8% yield) as white solid. 1H NMR (CDCL, 400 MHz): 5 7.96 (d, 7 = 2.8 Hz, 1H), 7.78 (dd, 7 = 8.8,2.8 Hz, 1H), 7.54 (d, 7 = 8.8 Hz, 1H), 3.86 (s, 3H) ppm. To a mixture of methyl 5-bromo- 2-chlorobenzoate (5 g, 20.04 mmol, 1 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (7.46 g, 40.08 mmol, 8.18 mL, 2 eq) in THF (100 mL) was added LDA (2 M, 30.06 mL, 3 eq) in one portion at -60C under N2. The mixture was stirred at -60C for 3 h under N2. After completion, the reaction mixture was quenched by addition of aqueous NH4Cl solution (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate = 1/0 to 50:1). Compound methyl 3- bromo-6-chloro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (3 g, 7.99 mmol, 39.9% yield) was obtained as a yellow solid. 1H NMR (DMSO-ifc, 400 MHz): d 7.75 (d, / = 8.8 Hz, 1H), 7.55 (d, / = 8.8 Hz, 1H), 3.86 (s, 3H), 1.31 (s, 12H) ppm. MS (ESI): m/z = 276.9 [M-99]+. To a mixture of methyl 3-bromo-6-chloro-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (0.3 g, 799.04 umol, 1 eq) in THF (10 mL) and MeOH (2 mL) was added NaBH4 (60.46 mg, 1.60 mmol, 2 eq) in one portion at 0C. The mixture was stirred at 25C for 1 h. The reaction mixture was quenched with HC1 (2N, 3mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18 l00*30mm 5um; mobile phase: [water(0.l%TFA)-ACN];B%: 35%-60%, lOmin). Compound 7-bromo-4-chlorobenzo[c][l,2]oxaborol-l(3H)-ol (64.4 mg, 260.43 umol, 32.6% yield) was obtained as a white solid. 1H NMR (DMSO-ifc, 400 MHz): d 9.36 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H) ppm. MS (ESI): m/z = 244.8 & 246.8 [M-H] HPLC: 99.64% (220 nm), 100.00% (254 nm).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Patent: EP1719767,2006,A1 .Location in patent: Page/Page column 24-28; 41
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5475 - 5479
[4]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6224 - 6229
[5]Journal of Agricultural and Food Chemistry,2016,vol. 64,p. 3533 - 3537
[6]Patent: WO2019/108982,2019,A1 .Location in patent: Paragraph 00281
[7]Journal of Medicinal Chemistry,2019,vol. 62,p. 4350 - 4369

2
[ 251085-87-7 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
54%		5-Bromo-2-chlorobenzaldehyde (74c). A solution of pyrrolidine (4.00 g, 56.0 mmol) in MTBE (12 mL) was added dropwise over 20 min to a solution of Red-Al (3.4 M solution in toluene, 16 ml, 54.4 mmol) in MTBE (33 mL) maintained at -20 C. The mixture was stirred for 1 h at 25 C. A solution of potassium tert-butoxide (0.60 g, 5.36 mmol) in THF (3 mL) was added. The resulting solution was added dropwise to a solution of <strong>[251085-87-7]2-chloro-5-bromobenzoic acid methyl ester</strong> (72, 6.80 g, 27.3 mmol) in MTBE (15 mL) at 10 C. After 15 min the mixture was quenched with 2 N HCl (300 mL). Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54%, mp 43-46 C), which was used without further purification in the next step.; The synthesis of benzaldehyde chlorooxime synthons 52 is depicted in Scheme 4, below. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d were commercially available. The preparation of aldehyde 44f began with the known three-step transformation of 4-methyl-3-nitrobenzonitrile 63 to methoxy compound 64. See Reiner, J. E., et al., Bioorg. Med. Chem. Lett., 12, 1203-1208 (2002). alpha-Bromination of 64 using one equivalent of N-bromosuccinimide gave little selectivity between the mono- and dibromo adducts, but the analogous reaction using 2.5 equivalents gave dibromide 65 almost exclusively. Silver nitrate oxidation of dibromide 65 gave aldehyde 44f. See Hill. R. A., et al., J. Chem. Soc., Perkin Trans., 1, 2209-2215 (1987). The reaction of the o-nitrotoluene 63 with N,N-dimethylformamide dimethyl acetal in DMF gave the enamine 66, which underwent oxidative cleavage using sodium periodate in THF, see Riesgo, E. C., et al., J. Org. Chem., 61, 3017-3022 (1996), to give aldehyde 74a via a more facile preparation than previously reported. See Dann, O., et al., Liebigs Ann. Chem., 3, 409-425 (1984). Aldehyde 74b also has been prepared previously. See Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976). A more expedient preparation of 74b began with chlorotoluene 67 undergoing alpha-bromination to 68, see Gilbert, A. M., et al., J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P., et al., Synthesis, 14, 2078-2080 (2001). The reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. See Mallory, F. M., et al., Tetrahedron, 57, 3715-3724 (2001). Commercially available aldehyde 69 and aldehyde 71, see Hino, K., et al., Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which had been prepared via a Sandmeyer reaction from commercially available 70, were converted to methyl esters 72 and 73, respectively. The esters were converted to aldehydes 74c and 74e, respectively, using Red-Al(sodium bis(2-methoxyethoxy)aluminium hydride) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, United States of America), pyrrolidine, and potassium tert-butoxide in methyl tert-butyl ether. See Abe, T., et al., Tetrahedron, 57, 2701-2710 (2001). Cyanoaldehyde 74f was prepared by debromocyanation of 44d. See Laali, K. K., et al., J. Org. Chem., 58, 1385-1392 (1993). Aldehydes 44e-44f and 74a-74f were converted to oxime derivatives 75a-h (of which 75a,e were known previously), see Quan, M. L., et al., J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in either water/ethanol or pyridine/ethanol. The oximes were treated with N-chlorosuccinimide in DMF to give chlorooximes 52a-h, following the procedure reported for 52e. See Liu. K.-C., et al., J. Org. Chem., 45, 3916-3918 (1980). The chlorooximes 52 were reacted with acetylenes 51 without further purification.; Reagents and conditions: (a) H2, 10% Pd/C, EtOH; (b) NaNO2, aq. H2SO4; (c) CH3l, NaH, DMF; (d) NBS, benzoyl peroxide, CCl4; (e) AgNO3, aq. EtOH; (f) DMFDMA, DMF; (g) NalO4; aq. THF; (h) diethyl phosphite, (i-Pr)2NEt, THF; (j) 2-nitropropane, NaOEt, EtOH; (k) NaNO2, aq. HCl, then CuCN, KCN; (I) MeOH, H2SO4; (m) DCC, DMAP, MeOH, CH2Cl2; (n) Red-Al, t-BuOK, pyrrolidine, MTBE; (o) NH2OH HCl, H2O/EtOH or Py/EtOH (p) NCS, DMF.

Reference： [1]Patent: EP1719767,2006,A1 .Location in patent: Page/Page column 24-28; 41-42
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

3
[ 251085-87-7 ]
[ 914106-40-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

4
[ 251085-87-7 ]
[ 914106-04-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

5
[ 251085-87-7 ]
[ 914106-15-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

6
[ 251085-87-7 ]
[ 914105-96-7 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

7
[ 251085-87-7 ]
C₁₇H₁₄ClN₅O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

8
[ 251085-87-7 ]
[ 272130-89-9 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1508 - 1518

9
[ 251085-87-7 ]
[ 272130-86-6 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1508 - 1518
[2]MedChemComm,2014,vol. 5,p. 1533 - 1539

10
[ 251085-87-7 ]
[ 1027229-46-4 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1508 - 1518

11
[ 251085-87-7 ]
[ 1027550-08-8 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1508 - 1518

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[ 251085-87-7 ]
2-chloro-5-[2-(8-hydroxy-7,8-dihydro-6<i>H</i>-imidazo[4,5-<i>d</i>][1,3]diazepin-3-yl)-ethyl]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1508 - 1518

13
[ 251085-87-7 ]
[ 478374-63-9 ]

Reference： [1]Patent: EP1394147,2004,A1 .Location in patent: Page 48

14
[ 79-37-8 ]
[ 21739-92-4 ]
[ 251085-87-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	In methanol; dichloromethane; N,N-dimethyl-formamide;	Example 45 6-(5-BROMO-2-CHLORO-PHENYL)-N-(4-CHLORO-PHENYL)-[1,3,5]TRIAZINE-2,4-DIAMINE To a suspension of 5-bromo-2-chloro-benzoic acid (2.5 g, 10.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6 ml, 12 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (10 ml) was added and the mixture was stirred for 20 hours. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate (150 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 5-bromo-2-chloro-benzoate (2.4 g, 91% yield).

Reference： [1]Patent: US2003/153570,2003,A1

15
DIBAL (diisobutylalminium hydride) hexane [ No CAS ]
[ 251085-87-7 ]
[ 149965-40-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In dichloromethane;	Reference Example 2 Preparation of 5-bromo-2-chlorobenzyl alcohol (Compound XII) 25.0 g of <strong>[251085-87-7]methyl 5-bromo-2-chlorobenzoate</strong> was dissolved in 130 ml of dichloromethane. To this solution, 230 ml of a 0.96 M DIBAL (diisobutylalminium hydride) hexane solution was added at -40 C. in a nitrogen atmosphere, followed by stirring at room temperature for 4 hours. To this reaction solution, 10% hydrochloric acid was carefully added while cooling, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with hexane to obtain 20.8 g of 5-bromo-2-chlorobenzyl alcohol as white crystals. 1H-NMR: (CDCl3/TMS, delta(ppm))2.18(t,1H), 4.74(d,2H), 7.19-7.65(m,3H)

Reference： [1]Patent: US6313071,2001,B1

16
[ 75-16-1 ]
[ 251085-87-7 ]
[ 885069-29-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	In tetrahydrofuran; at -78 - 20℃;	To a solution of <strong>[251085-87-7]5-bromo-2-chlorobenzoic acid methyl ester</strong> (1 g, 4 mmol, 1 eq) in THF (20 ml) at -78 C. was added a 3M solution of methyl magnesium bromide (4 ml, 12 mmol, 3 eq) in THF dropwise. The reaction mixture was then warmed to RT and stirred overnight. The mixture was poured into sat. ammonium chloride solution and extracted with ether. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (0 to 20% ether in pentane) to give the desired product as a colorless oil (980 mg, 98%).
33 g	In tetrahydrofuran; at -78℃; for 2h;Inert atmosphere;	To a solution of <strong>[251085-87-7]methyl 5-bromo-2-chloro-benzoate</strong> (31 g, 0.125 mol) in THF (350 mL) was added (CH3)MgBr (91 .6 mL, 0.275 mol) at -78C under an inert atmosphere. It was stirred at-78C for 2 hours. The mixture was quenched with aqueous NH4CI, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to obtain 2-(5-bromo-2-chloro-phenyl)propan-2-ol (33 g) which was used withour further purification.

Reference： [1]Patent: US2007/185058,2007,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2014/207071,2014,A1 .Location in patent: Page/Page column 112

17
[ 109-01-3 ]
[ 14593-46-5 ]
[ 251085-87-7 ]
[ 1059705-49-5 ]
C₁₇H₂₅ClN₂O₂ [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2007,vol. 349,p. 2286 - 2300

18
[ 73183-34-3 ]
[ 251085-87-7 ]
[ 625470-33-9 ]