360576-01-8|Methyl 6-bromobenzo[b]thiophene-2-carboxylate| Ambeed

Structure of 360576-01-8

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Quality Control of [ 360576-01-8 ] Purity: 95% SDS Specification

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Product Details of [ 360576-01-8 ]

CAS No. :	360576-01-8
Formula :	C₁₀H₇BrO₂S
M.W :	271.13
SMILES Code :	COC(=O)C1=CC2=C(S1)C=C(Br)C=C2
MDL No. :	MFCD07371541
InChI Key :	SFDVDNLBYGHFNF-UHFFFAOYSA-N
Pubchem ID :	22474078

Safety of [ 360576-01-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 360576-01-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	9
Fraction Csp3	0.1
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	60.8
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	54.54 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.72
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.45
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.96
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	4.14
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.42

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.27
Solubility	0.0145 mg/ml ; 0.0000535 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.66
Solubility	0.00592 mg/ml ; 0.0000218 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.27
Solubility	0.0145 mg/ml ; 0.0000536 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.24 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.21

Application In Synthesis of [ 360576-01-8 ]

* 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.

Downstream synthetic route of [ 360576-01-8 ]

[ 360576-01-8 ] Synthesis Path-Downstream 1~35

1
[ 67-56-1 ]
[ 19075-58-2 ]
[ 19075-61-7 ]
[ 360576-01-8 ]
[ 946428-00-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 65℃;	Preparation 18; 6-Bromobenzothiophene-3-carboxylic acid methyl ester and 6-Bromobenzothiophene-2- carboxylic acid methyl ester; A solution of the mixture of 6-Bromobenzothiophene-3-carboxylic acid and 6- Bromobenzothiophene-2-carboxylic acid (6.5 g, 25.28 mmol) and sulfuric acid (4.65 g, <n="28"/>47.43 mmol) in MeOH (100 niL) is heated to 65 C overnight. A light brown solid is visualized. The solution is cooled to room temperature and the solid formed is filtered off and washed with MeOH to give 5.6 g (83%) of the mixture of: 6-Bromobenzothiophene- 3-carboxylic acid methyl ester and 6-Bromobenzothiophene-2-carboxylic acid methyl ester in a ratio 7:3. ES/MS m/e 272 (M+2).

References: [1]Patent: WO2007/140174,2007,A2 .Location in patent: Page/Page column 26-27.

2
[ 2365-48-2 ]
[ 57848-46-1 ]
[ 360576-01-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 15.0h;	General procedure: To a stirred solution of compound 1a-1n (9.90 mmol) in DMF (20 mL) were added methyl thioglycolate (10.9 mmol) and potassium carbonate (39.6 mmol). The resulting mixture was stirred at 60 C for 15 h. The DMF was removed under reduced pressure,water (50 mL) was added and the mixture was extracted with ethylacetate (2 x 40 mL). The combined organic layers were dried withsodium sulfate, filtered, and the solvents were removed under reduced pressure to afford the title compound 2a-2n [31,34].
94%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 1.0h;	Add 4--bromo-2--fluorobenzaldehyde (100g, 493mmol) and2--methyl thioglycolate(120g, 1.13mol) was dissolved in DMF (1.0L), sodium hydride (59.2g, 1.48mol, 60%) was added at 0 C, and after stirring for 1 hour, ice water (2.0L) was added.It was extracted 4 times with ethyl acetate (1.0 L), and the organic layers were combined and washed once with a saturated sodium chloride solution.The solvent was distilled off under reduced pressure and subjected to column chromatography (PE: EA = 100: 1).Purification gave compound 1 (125 g, yield 94%).
92%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 15.0h;	General procedure: To a stirred solution of compound 1a or 1b(9.90 mmol)in DMF(20 mL) was added methyl thioglycolate (10.9 mmol) and potassiumcarbonate (39.6 mmol). The resulting mixture was stirred at60 C for 15 h. The DMF was removed under reduced pressure,water (50 mL) was added and the mixture was extracted with ethylacetate (2 x 40 mL). The combined organic layers were dried withsodium sulfate, filtered, and the solvents were removed underreduced pressure to afford the title compound 2a or 2b.

90%		TEA (1.29g, 12.85mmol) and mercapto-acetic acid methyl ester (1.14 g, 10.83mmol) were added to acetonitrile (50mL) previously purged with argon (10 minute). This was followed by the addition of 4-bromo-2-fluoro-benzaldehyde (2g, 9.852mmol) and the resulting mixture was heated to reflux at 85C overnight. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was cooled, concentrated, basified with 10%NaOH solution and extracted with ethyl acetate to afford the crude product. Purification by column chromatography on silica gel (5% ethyl acetate in hexane) afforded 2.4g of the product (90% yield).1H NMR (CDC13, 300 MHz): 88.18-8.0 (dd, 2H), 7.8-7.7 (d, 1H), 7.65-7.59 (dd, 1H), 4.1-4.0 (s, 3H).
64.8%	With triethylamine; In dimethyl sulfoxide; at 80℃; for 3.0h;	4-Bromo-2-fluorobenzaldehyde (808 mg, 4.00 mmol) was dissolved in dimethylsulfoxide (5.00 mL)Methyl mercaptoacetate (375 muL),Triethyl amine (1.5 mL) was added,And the mixture was stirred at 80 C. for 3 hours.20 mL of purified water was added, and the precipitated white solid was collected by filtration,And washed with purified water to obtain Compound 8 in a yield of 700 mg (yield 64.8%).
61%	With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3.0h;	To a solution of 4-bromo-2-fluorobenzaldehyde (10 g, 49 mmol) and methyl 2- mercaptoacetate (7.8 g, 74 mmol) in dimethylsulfoxide (100 mL) was added potassium carbonate (13 g, 99 mmol) portionwise at room temperature. The resulting mixture was stirred at 70 C for 3 hours. On completion, the mixture was poured into ice-water, resulting in formation of a solid. The mixture was stirred for 30 min., and the solid was collected by filtration, washed with water and dried in vacuo. The residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 7: 1] to give compound B-110 (8.1 g, 61% yield) as a white solid.
46%	With sodium hydride;	Ausgehend von 6. [54] [G] (32.2 mmol) 4-Brom-2-fluorbenzaldehyd werden mit 1.93 g [(48.] 3 mmol) Natriumhydrid (60%-ig in Paraffinoel) und 3.76 g (35.5 mmol) Mercaptoessigsaeuremethylester nach der allgemeinen Arbeitsvorshrift A 4.06 g (46 % d. Th. ) der Titelverbindung erhalten. 1H-NMR (200 MHz, [DMSO-D6)] : [6] = 8.42 (d, 1H), [8.] 22 (s, [1H),] 7.98 (d, [1H),] 7.65 (dd, 1H), 3. [90] (s, 3H). HPLC (Methode [1)] : Rt = 5.3 min. MS (ESIpos) : [M/Z] = 270 (M(+]

References: [1]European Journal of Medicinal Chemistry,2019,vol. 174,p. 236 - 251.
[2]Patent: CN110229146,2019,A .Location in patent: Paragraph 0099-0103.
[3]European Journal of Medicinal Chemistry,2017,vol. 125,p. 538 - 550.
[4]Patent: WO2012/149413,2012,A1 .Location in patent: Page/Page column 58.
[5]Journal of Medicinal Chemistry,2016,vol. 59,p. 264 - 281.
[6]Journal of Medicinal Chemistry,2015,vol. 58,p. 7241 - 7257.
[7]Patent: JP2015/89879,2015,A .Location in patent: Paragraph 0016; 0047; 0048.
[8]Patent: WO2016/100184,2016,A1 .Location in patent: Paragraph 00285-00286.
[9]Patent: WO2004/13136,2004,A1 .Location in patent: Page/Page column 37-38.
[10]Patent: WO2003/104227,2003,A1 .Location in patent: Page 49.
[11]Journal of Medicinal Chemistry,2007,vol. 50,p. 4793 - 4807.
[12]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1010 - 1014.

3
[ 360576-01-8 ]
[ 19075-58-2 ]

Yield	Reaction Conditions	Operation in experiment
96%		General procedure: The solution of compound 2a or 2b (1.1 mmol) in water (10 mL)was stirred and then potassium hydroxide pellets (5.4 mmol) wasadded, which was refluxed for 3 h. The aqueous layer was thenacidified to pH 1 with 1 M hydrochloric acid solution. The aqueouslayer was extracted with dichloromethane (3 15 mL). The combinedorganic layers were dried with sodium sulfate, filtered, andthe solvents were removed under reduced pressure to afford thetitle compound 3a or 3b.
96%	With potassium hydroxide; In water; for 3.0h;Reflux;	General procedure: The solution of compound 2a-2n (1.1 mmol) in water (10 mL)was stirred and then potassium hydroxide pellets (5.4 mmol) wereadded, which was refluxed for 3 h. The aqueous layer was thenacidified to pH 1 with 1M hydrochloric acid solution. The aqueouslayer was extracted with dichloromethane (3 x 15 mL). The combinedorganic layers were dried with sodium sulfate, filtered, andthe solvents were removed under reduced pressure to afford thetitle compound 3a-3n [31,34].
94%		Ausgehend von 4.0 g (14.8 mmol) [6-BROM-L-BENZOTHIOPHEN-2-CARBONSaeUREMETHYL-] ester (aus Beispiel 9A) werden nach der allgemeinen Arbeitsvorschrift B 3.55 g (94 % d. Th. ) des gewuenschten Produkts erhalten. 1H-NMR (400 MHz, [DMSO-D6): No. = 13. ]48 (br. [S,] [1H),] 8. 38 (s, [1H),] 8.22 (s, [1H),] 7.96 (d, 1H), 7.63 [(M,] 1H). HPLC (Methode [1)] : Rt = 4.5 min.

93.5%		A solution of 4.0 g (14.8 mmol) of <strong>[360576-01-8]methyl 6-bromo-1-benzothiophene-2-carboxylate</strong> in 40 ml of a 1:1 mixture of THF and 2 N potassium hydroxide solution is stirred at room temperature for 2 h. The solvent is removed in vacuo, and the residue is acidified with concentrated hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and dried in vacuo at 50 C. 3.55 g (93.5% of theory) of the desired product are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=13.48 (broad s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.63 (m, 1H). HPLC (method 1): Rt=4.5 min.
84%		LiOH.H20 (1.85g, 44mmol) and water (20mL) were added to a stirred solution of <strong>[360576-01-8]6-bromo-benzo[b]thiophene-2-carboxylic acid methyl ester</strong> (I-25a: 2.4g, 8.85mmol) in THF (25mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was concentrated, acidified with 2N HCl, filtered and the residue was washed with n-hexane to afford 1.9g of the product (84% yield).1H NMR (DMSO-D6, 300 MHZ): 814.0-14.03 (b, 1H), 8.4-8.39 (d, 1H), 8.28- 8.1 (d, 1H), 8.18-8.0 (d, 1H), 7.78-7.62 (dd, 1H). LCMS Purity: 99%, m/z = 255.9 (M+l)
272 mg	With lithium hydroxide monohydrate; In methanol; water; at 75℃; for 2.0h;	A mixture of 300 mg of <strong>[360576-01-8]methyl 6-bromobenzo[b]thiophene-2-carboxylate</strong>, 100 mg of lithium hydroxide monohydrate, 3 ml of water, and 9 ml of methanol was stirred for 2 hours at 75C. The reaction mixture was concentratedunder reduced pressure. Water was added to the residues, and the residue was washed three times with tert-butylmethyl ether. Concentrated hydrochloric acid was added to the aqueous layer, and then extraction was performed threetimes by using chloroform. The collected organic layer was washed with saturated saline, dried over magnesium sulfate,and then concentrated under reduced pressure, thereby obtaining 272 mg of 6-bromobenzo[b]thiophene-2-carboxylicacid (hereinafter, described as a "compound 12 of the present invention"). 1H-NMR (DMSO-D6) delta:13.61 (br s, 1H), 8.38 (d, 1H, J = 1.9 Hz0, 8.11 (s, 1H), 7.95 (d, 1H, J = 8.5 Hz), 7.62 (dd, 1H, J= 8.5, 1.9 Hz).

References: [1]European Journal of Medicinal Chemistry,2017,vol. 125,p. 538 - 550.
[2]European Journal of Medicinal Chemistry,2019,vol. 174,p. 236 - 251.
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 264 - 281.
[4]Patent: WO2003/104227,2003,A1 .Location in patent: Page 47, 48.
[5]Patent: US2007/37844,2007,A1 .Location in patent: Page/Page column 7.
[6]Patent: WO2012/149413,2012,A1 .Location in patent: Page/Page column 58-59.
[7]Patent: WO2004/13136,2004,A1 .Location in patent: Page/Page column 39.
[8]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1010 - 1014.
[9]Patent: EP2926660,2015,A1 .Location in patent: Paragraph 0260; 0261.

4
[ 57848-46-1 ]
[ 360576-01-8 ]

Yield	Reaction Conditions	Operation in experiment
46.4%		3.76 g (35.5 mmol) of methyl mercaptoacetate are slowly added dropwise to a suspension of 1.93 g (48.3 mmol) of sodium hydride (as 60% suspension in mineral oil) in 65 ml of DMSO at room temperature. After hydrogen evolution ceases, a solution of 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde in 10 ml of DMSO is added. After 10 min, the reaction mixture is stirred into 200 ml of ice-water, and the resulting precipitate is isolated. The solid is washed twice with water and dried in vacuo at 50 C. 4.06 g (46.4% of theory) of the title compound are obtained. 1H-NMR (200 MHz, DMSO-d6): delta 8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H), 7.65 (dd, 1H), 3.90 (s, 3H). HPLC (method 1): Rt=5.3 min. MS (ESIpos): m/z=270 (M+).

References: [1]Patent: US2007/37844,2007,A1 .Location in patent: Page/Page column 7.

5
[ 360576-01-8 ]
[ 31166-44-6 ]
C₂₂H₂₂N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium phosphate;bis(tri-tert-butylphosphine)palladium(0); In ISOPROPYLAMIDE; at 100℃;	A mixture of methyl -bromo-l-benzothiophene-^-carboxylate (60 mg, 0.21 mmol), Cbz- piperazine (0.100 mL, 0.52 mmol) and K3PO4 (220 mg) in DMAc (1 mL) was degassed by the freeze- pump-thaw method. Next, Pd[P(tert-butyl)3]2 (20 mg) was added and the mixture stirred at 100C overnight. The crude mixture was partitioned between EtOAc and sat'd NaCl, the organic layer dried (Na2SO4) and concentrated. Chromatography on SiO2 (EtOAc/CH2Cl2, 0:100 to 10:90) gave 42 mg (47%) of the ethyl ester coupled product. A mixture of this ester in 2: 1: 1 THF/MeOH/water (2 mL) was treated with LiOH (10 mg, 0.24 mmol) and stirred overnight, then partitioned between EtOAc and 1 M citric acid. The organic layer was dried (Na2SO4) and concentrated. The residue was dissolved in DMF (1 mL) and treated with EDC (25 mg, 0.13 mmol), HOBt (15 mg, 0.11 mmol), and 1,2-phenylenediamine (25 mg, 0.23 mmol), then stirred overnight. The reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3, dried (Na2SO4), concentrated and finally triturated with ether to provide the desired product: 1H NMR (600 MHz, DMSO-^6) delta 9.75 (s, 1 H), 8.13 (s, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.36 (m, 5 H), 7.32 (m, 1 H), 7.17 (dd, J = 9.1, 2.3 Hz, 1 H), 6.95 (t, J = 7.8 Hz, 1 H), 6.75 (dd, J = 9.4, 1.2 Hz, 1 H), 6.57 (t, J = 7.6 Hz, 1 H), 5.10 (s, 2 H), 4.93 (s, 2 H), 3.55 (br, 4 H), 3.25 (br, 4 H); MS cal'd 487 (MH+), exp 487 (MH+).

References: [1]Patent: WO2006/115845,2006,A1 .Location in patent: Page/Page column 87.

7
[ 360576-01-8 ]
[ 17347-32-9 ]

References: [1]Patent: WO2012/149413,2012,A1 .
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 264 - 281.
[3]European Journal of Medicinal Chemistry,2017,vol. 125,p. 538 - 550.

8
[ 360576-01-8 ]
[ 1422739-53-4 ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

9
[ 360576-01-8 ]
[ 1422739-48-7 ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

10
[ 360576-01-8 ]
[ 1422739-49-8 ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

11
[ 360576-01-8 ]
[ 374933-76-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With LAB; In tetrahydrofuran; hexane; for 0.08333330000000001h;	Ester 9 (6.8 g, 25.0 mmol) was dissolved in THF (anhydrous, 50 mL) and cooled to 0 oC. Lithium dimethylammonium borohydride3 (50 mL, 50.0 mmol, 1.0 M THF/hexane) was added drop-wise. After 5 min of stirring, the reaction was complete as judged by TLC and was quenched with HCl (3.0 M) under vigorous stirring until the evolution of gas ceased. The organic layer was separated, and the aqueous layer extracted with EtOAc (3x). The combined organic layers were washed with water and brine followed by drying (Na2SO4). Evaporation of solvent gave a yellow solid, which was recrystallized from isopropanol/water to give the desired primary alcohol as white crystals. (5.7 g, 94% yield), mp 111-113 oC. IR (thin film, cm-1) 3203, 3071, 2901, 2853, 1577, 1523, 1444, 849, 841; 1H NMR (CDCl3) delta 7.95 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 1.5, 8.5 Hz, 1H), 7.17 (d, J = 1.0 Hz, 1H), 4.91 (s, 2H), 1.97 (br s, 1H); 13C NMR (CDCl3) delta 145.8, 141.6, 138.5, 128.0, 125.1, 124.8, 121.1, 118.3, 60.9; HRMS (EI) for C9H7BrOS [M]+ calcd, 241.9401, found, 241.9404 (error = 1.2 ppm).
74.7%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 25℃; for 3.0h;Cooling with ice;	Lithium aluminum hydride (756 mg, 19.9 mmol)Was suspended in tetrahydrofuran (20.0 mL)And the mixture was stirred under ice cooling.Compound 8 (1.79 g, 6.64 mmol) synthesized by the method shown in Example 3-1 was dissolved in tetrahydrofuran (20.0 mL).The resulting solution of Compound 8 was added to a solutionThe solution was slowly added dropwise to a lithium aluminum hydride solution under ice cooling, followed by stirring at room temperature for 3 hours.Saturated sodium sulfate aqueous solution was added excessively,It was dehydrated with sodium sulfate powder.After filtration with a glass filter, the solvent was distilled off under reduced pressure,The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/1, volume ratio) as an elution solvent,Compound 9 was obtained in a yield of 1.20 g (yield: 74.7%).

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 7241 - 7257.
[3]Patent: JP2015/89879,2015,A .Location in patent: Paragraph 0016; 0037; 0047; 0049.

12
[ 360576-01-8 ]
C₁₀H₉BrO₃S₂ [ No CAS ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

13
[ 360576-01-8 ]
[ 912332-92-4 ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

14
[ 360576-01-8 ]
C₁₈H₁₆BrNO₂S [ No CAS ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

15
[ 360576-01-8 ]
[ 1422739-51-2 ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

16
methyl thioglycolate [ No CAS ]
[ 57848-46-1 ]
[ 360576-01-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; In dimethyl sulfoxide; at 80 - 90℃; for 2.0h;	The literature procedure of Fedi et al.2 was followed for the synthesis of 9. To a two-neck round bottom flask fitted with a condenser was added 4-bromo-2-fluorobenzaldehyde (14.8 g, 72.9 mmol) and DMSO (100 mL, anhydrous). Methyl thioglycolate (8 mL, 89.5 mmol) and triethylamine (30 mL, 215.2 mmol) were added and the reaction heated to 80-90 oC over 2 h. The reaction was allowed to cool before being poured into vigorously stirring ice-water (3500 mL). After 1 h of stirring, the solid was filtered and dried before recrystallization from ethanol (250 mL) to give pale yellow crystals (16.1 g, 81% yield), mp 113-115 oC. IR (thin-film, cm-1) 3012, 2952, 2913, 2849, 1717, 1510, 1434, 1384, 1307, 1259, 1168, 1090, 1060, 858, 803, 752, 713; 1H NMR (CDCl3) delta 8.013 (d, J = 1.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.51 (dd, J = 1.5, 9.0 Hz, 1H), 3.95 (s, 3H); 13C NMR (CDCl3) delta 163.0, 143.6, 137.5, 134.1, 130.3, 128.8, 126.7, 125.5, 121.4, 52.8.

References: [1]Tetrahedron Letters,2013,vol. 54,p. 1482 - 1485.

17
[ 360576-01-8 ]
C₁₅H₁₀BrNOS [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1010 - 1014.

18
[ 360576-01-8 ]
6-bromo-N-phenylbenzo[b]thiophene-2-carboxamide 1,1-dioxide [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1010 - 1014.

19
[ 360576-01-8 ]
6-bromo-2-(bromomethyl)benzo[b]thiophene [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7241 - 7257.
[2]Patent: JP2015/89879,2015,A .

20
[ 360576-01-8 ]
(6-bromo-1-benzo[b]thien-2-ylmethyl)phosphonic acid diethyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7241 - 7257.
[2]Patent: JP2015/89879,2015,A .

21
[ 360576-01-8 ]
N,N-dimethyl-4-[(1E)-2-(6-bromo-1-benzothiophen-2-yl)ethenyl]benzenamine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7241 - 7257.
[2]Patent: JP2015/89879,2015,A .

22
[ 360576-01-8 ]
(E)-5-(2-(6-bromobenzo[b]thiophen-2-yl)vinyl)-N,N-dimethylpyridin-2-amine [ No CAS ]