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[ CAS No. 188582-62-9 ]

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2D3D

Chemical Structure| 188582-62-9

Chemical Structure| 188582-62-9

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Product Details of [ 188582-62-9 ]

CAS No. :	188582-62-9	MDL No. :	MFCD00143265
Formula :	C₇H₆BrFO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	205.02	Pubchem ID :	-
Synonyms :

Computed Properties of [ 188582-62-9 ]

TPSA :Topological Polar Surface Area	-	H-Bond Acceptor Count :	-
XLogP3 :	-	H-Bond Donor Count :	-
SP3 :	-	Rotatable Bond Count :	-

Safety of [ 188582-62-9 ]

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 [ 188582-62-9 ]

Upstream synthesis route of [ 188582-62-9 ]
Downstream synthetic route of [ 188582-62-9 ]

[ 188582-62-9 ] Synthesis Path-Upstream 1~6

1
[ 188582-62-9 ]
[ 128577-47-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524

2
[ 188582-62-9 ]
[ 76283-09-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 100℃; for 0.166667 h;	The above compound (7.00 g, 34.1 mmol) was dissolved into 48percent hydrobromic acid (35 mL), and the resultant was caused to react at 100° for 10 minutes. After the end of the reaction, the resultant was neutralized with potassium carbonate. Thereafier, extraction with ethyl acetate was carried out, and this extraction layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to yield a compound (8.35 g, 91percent). 1H-NMR (CDC13): 4.46 (s, 2H, HnCH2), 7.25-7.29 (m, 3H, Ar).

Reference： [1] Patent: US2017/15684, 2017, A1, . Location in patent: Paragraph 0144; 0145; 0146

3
[ 188582-62-9 ]
[ 134057-95-7 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 9, p. 931 - 943

4
[ 188582-62-9 ]
[ 57848-46-1 ]

Reference： [1] Advanced Synthesis and Catalysis, 2014, vol. 356, # 8, p. 1741 - 1746

5
[ 188582-62-9 ]
[ 881189-74-8 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 9, p. 931 - 943

6
[ 73183-34-3 ]
[ 188582-62-9 ]
[ 1082066-29-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere	3.1.1. Preparation of (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) At 90° C. under N₂ atmosphere, to a stirred solution of 4-bromo-2-fluorophenylmethanol (500 mg, 2.44 mmol) in dioxane (5 mL) were added B₂Pin₂ (929 mg, 3.66 mmol), Pd(dppf)Cl₂.DCM (198 mg, 0.24 mmol) and KOAc (717 mg, 7.32 mmol). After being stirred at 90° C. overnight, the reaction mixture was cooled down to room temperature and partitioned between EA and H₂O. The layers were separated and the organic layer was washed with brine, dried over Na₂SO₄. Solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0˜20 ethyl acetate in petroleum ether) to provide (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) (300 mg, 48percent) as a yellow oil.

Reference： [1] Patent: US2018/194762, 2018, A1, . Location in patent: Paragraph 0740-0741
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 4984 - 4995

[ 188582-62-9 ] Synthesis Path-Downstream 1~7

1
[ 57848-46-1 ]
[ 188582-62-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanol; sodium tetrahydroborate at -5 - 20℃;	6.6.8.b To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15 g, 79.36 mmol) in MeOH (100 ml.) at 00C to -5°C, added NaBH4 (6.0 g, 158.73 mmol) in equal portions and stirred at room temperature. The reaction mixture was diluted with ice cold water (100 mL) and concentrated under reduced pressure. The obtained aqueous residue was extracted with ethyl acetate (2*200 mL); the ethyl acetate layer was washed with brine solution (50 mL), dried over anhydrous NaSO4. filtered and concentrated to afford a colorless oil (15 g, 99%).
99%	With methanol; sodium tetrahydroborate at -5 - 23℃; for 1h;	A111.1; A118.3 Step 3: To a stirred solution of 4-Bromo-2-fluoro benzaldehyde (15 g, 79.36 mmol) in MeOH (100 mL) at -5 °C to 0 °C was added NaBH4 (6.0 g, 158.73 mmol) in equal portions and stirred at RT for 1 h until the starting material was completely consumed, as evidenced by TLC analysis. The reaction mixture was then diluted with ice cold water (100 mL) and concentrated under reduced pressure. The residue obtained on concentration was extracted with EtOAc (2x200 mL) and separated. The combined EtOAc layers were washed with brine solution (50 mL), dried over anhydrous NaS04, filtered and concentrated to afford (4-bromo-2-fluorophenyl)methanol (30 g, 99 % (from 2 batches))] as colorless oil (TLC solvent system: 30% EtOAc in PE; Rf: 0.3).
99%	With sodium tetrahydroborate In methanol at 20℃; for 0.5h;	2 Production of (4-bromo-2-fluorophenyl)methanol Into methanol (50 mL) was dissolved 4-bromo-2- fluorobenzaldehyde (10.0 g, 48.8 mmol), and thereafter the resultant was caused to react with NaBH4 (3.69 g, 97.6 mmol) at room temperature for 30 minutes. Thereafter, water (50 mL) was added thereto and, afier extraction with ethyl acetate, the extraction layer was washed with water. The obtained compound was subjected to the next step without purification.and a saturated saline solution, then dried over anhydrousmagnesium sulfate, and concentrated under a reduced pressure to yield a compound (12.9 g, 99%). The obtained compound was subjected to the next step without purification.

95%	With methanol; sodium tetrahydroborate at -5 - 20℃; for 1h;	Synthesis of (4-bromo-2-fluorophenyl)methanol Synthesis of (4-bromo-2-fluorophenyl)methanol To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15 g, 79.4 mmol) in MeOH (100 mL) at -5X to OX was added NaBH4 (6.0 g, 9 mmol) in portions and stirred at RT for 1 h until the starting material was completely consumed, as evidenced by TLC analysis. The RM was then diluted with ice cold water (100 mL) and concentrated under reduced pressure. The residue obtained on concentration was extracted with EtOAc (2 x 200 mL) and separated. The EtOAc layer was washed with brine (50 mL), dried over anhydrous NaS04, filtered and concentrated to afford (4-bromo-2-fluorophenyl)methanol (29 g, from 2 batches each of 15 g of of 4-bromo-2-fluoro benzaldehyde, 95%) as colorless oil. TLC system: EtOAcPE (3:7), Rf: 0.3
	With hydrogenchloride; borane Ν,Ν-diethylaniline complex 1.) THF, 5 h, reflux; Yield given. Multistep reaction;
	With sodium tetrahydroborate In methanol at 20℃; for 2h;	R.i To a solution of 4-bromo-2-fluorobenzaldehyde (25 g, 0.123 mol) in methanol (250 ml) was added NaBH4 (7.02 g, 0.1847 mol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with 25 ml of water and solvent evaporated under reduced pressure. The compound was extracted with ethyl acetate, organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (25 g) as an oil. This was directly taken for next step without further purification.
	Stage #1: 4-bromo-2-fluorobenzaldehyde With sodium tetrahydroborate In methanol at 0 - 20℃; for 1h; Stage #2: With water In methanol	D.i Sodium borohydride (4.63 g, 0.1219 mol) was added to a solution of 4-bromo-2- fluorobenzaldehyde (16.5 g, 0.0813 mol) in methanol (200 mL) at 00C. The resulting mixture was stirred for 1 h at RT before being quenched with water. Solvent (methanol) was concentrated under reduced pressure before the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (15.3 g) as a pale yellow liquid.
16.8 g	With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃; for 5h; Inert atmosphere;	1-1 Sodium borohydride (9.4 g), methanol (8.0 g) and THF (55 mL) were mixed under dry nitrogen and cooled to 0 ° C. Under cooling,2-Fluoro-4-bromobenzaldehyde (16.8 g) and THF (30 mL) were slowly added, and the mixture was returned to room temperature and stirred for 5 hours. Subsequently, a solution of cyclopentanone (27.7 g) dissolved in THF (80 mL) was slowly added under cooling, and then the temperature was slowly raised to room temperature. The reaction solution was cooled to 0° C., 10% hydrochloric acid (200 mL) was slowly added, ethyl acetate (300 mL) was added for liquid separation, and the organic layer was washed 3 times with saturated brine (300 mL). After anhydrous sodium sulfate was added and dried, sodium sulfate was removed by filtration. The organic solvent was distilled off under reduced pressure to give 16.8 g of 2-fluoro-4-bromobenzbenzyl alcohol as a transparent liquid.Obtained.
	With methanol; sodium tetrahydroborate at 0℃;	1 Step 1: (4-bromo-2-fluorophenyl)methanol. A solution of 4-bromo-2- fluorobenzaldehyde (10.2 g, 50 mmol) in MeOH (500 mL) was cooled to 0°C and NaBH4 (5.70 g, 151 mmol) added over 10 min. The solution was stirred for 16h. The excess MeOH was removed and the crude mixture was partitioned between EtOAc (500 mL) and 1N NaOH (500 mL). The 1N NaOH was washed with an additional portion of EtOAc (300 mL). The combined organics were dried over Na2SO4 and concentrated to afford the title compound as a viscous oil to white solid which was in the next step without further purification.

Reference： [1]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2010/127856, 2010, A1 Location in patent: Page/Page column 92
[2]Current Patent Assignee: MEDIFRON DBT KR - WO2013/68461, 2013, A1 Location in patent: Page/Page column 115; 118; 119
[3]Current Patent Assignee: STELLA CHEMIFA CORPORATION; OSAKA CITY UNIVERSITY - US2017/15684, 2017, A1 Location in patent: Paragraph 0141; 0142; 0143
[4]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2016/82930, 2016, A1 Location in patent: Page/Page column 26
[5]Salunkhe, Ashok M.; Burkhardt, Elizabeth R. [Tetrahedron Letters, 1997, vol. 38, # 9, p. 1519 - 1522]
[6]Current Patent Assignee: ANIMEDA - WO2005/123748, 2005, A1 Location in patent: Page/Page column 92-93
[7]Current Patent Assignee: ASTRAZENECA PLC - WO2007/69986, 2007, A1 Location in patent: Page/Page column 73-74
[8]Current Patent Assignee: DIC CORP. - JP2020/66582, 2020, A Location in patent: Paragraph 0358-0359
[9]Current Patent Assignee: UNIVERSITY OF UTAH; CURZA GLOBAL LLC - WO2020/150385, 2020, A1 Location in patent: Paragraph 00669

2
[ 18162-48-6 ]
[ 188582-62-9 ]
[ 930785-23-2 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With 1H-imidazole In dichloromethane at 0 - 20℃; for 16.08h;	24 ((4-Bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane A mixture of (4-bromo-2-fluorophenyl)methanol (30.0 g, 146 mmol) and imidazole (14.9 g, 219 mmol) in dichloromethane (200 mL) was cooled to 0° C. and tert-butyl-chlorodimethylsilane (24.2 g, 161 mmol) was added. The mixture was stirred for 5 minutes, the cooling bath removed and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into chilled water (300 mL), mixed and the organic layer was separated. The aqueous layer was extracted with dichloromethane (30 mL3) and the combined organic layers were washed with saturated NaCl (20 mL3), dried over Na2SO4, filtered and concentrated under reduced pressure to give ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (46.0 g, 98.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.34 (m, 1H), 7.31-7.28 (m, 1H), 7.19 (dd, J=1.8, 9.6 Hz, 1H), 4.74 (s, 2H), 0.97 (s, 9H), 0.16 (s, 6H).
98%	With 1H-imidazole In dichloromethane at 20℃; for 0.166667h;	1.1 A mixture of (4-bromo-2-fluorophenyl)methanol (20 g, 98 mmol) and imidazole (7.31 g, 107 mmol) in methylene chloride (100 mL) was treated with /tvV-butyl dimethyl silyl chloride (16.17 g, 107 mmol) in methylene chloride (100 mL) over 10 min. at rt. A white precipitate immediately formed which was removed by filtration. The filtrate was concentrated under reduced pressure and the remainder dissolved in heptane (100 mL). The organic phase was washed with water (2 x 40 mL), brine (2 x 40 mL), dried over NaSCri and concentrated under reduced pressure. The remainder was dissolved in c-hexane and passed through a silica pad (100 g) and then the solvent was removed under reduced pressure to afford Compound 1-B as a yellowish oil (30.51 g, 98% yield). NMR (400 MHz, CDCb) d ppm 0.12 (s, 6H), 0.95 (s, 9H), 4.74 (s, 2H), 7.14 - 7.22 (m, 1H), 7.28 - 7.32 (m, 1H), 7.34 - 7.42 (m, 1H).
97%	With 1H-imidazole; dmap at 20℃;	16a 16a (4-Bromo-2-fluoro-benzyloxy)-te/f-butyl-dimethyl-silaneTo 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) tert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated.Yield: 7.70 g (97% of theory)Rf-value: 0.9 (silica gel, mixture C).

97%	With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃;	6.a To 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) fert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. Yield: 7.70 g (97% of theory); Rrvalue: 0.9 (silica gel, mixture C).
75%	With 1H-imidazole In dichloromethane at 0 - 25℃;	(4-bromo-2-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane (SI-9) To a solution of compound SI-8 (12 g, 58.8 mmol) and imidazole (6.4 g, 94.1 mmol) inCH2Cl2 (200 mL) was added TBDMSCl (9.77 g, 64.8 mmol) at 0 oC over 1 hour and thenthe solution was stirred at room temperature overnight. Then, the reaction was quenchedwith water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography to obtain pure compound SI-9 (14 g, 75%) as a white solid. ESI-MS m/z 319 [M+H]+ calc. for C13H20BrFOSi. This intermediate was used in the next step without further characterization.
70%	With 1H-imidazole In dichloromethane at 20℃; for 1h;	Synthesis of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane Synthesis of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane A stirred solution of 4-bromo-2-fluoro benzaldehyde (49 g, 239 mmol, 1 eq) in DCM (400 mL) was treated with imidazole (32.5 g, 478 mmol, 2 eq) followed by TBDMS chloride (39.6 g, 263 mmol, 1.1 eq). The resulting solution was stirred at RT for 1 h, quenched with water (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 χ 100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2S04) and concentrated. The residue upon purification by column chromatography (silica gel 100-200, EtOAc/PE; 10:90) afforded ((4-bromo-2-fluorobenzyl)oxy)(tert- butyl)dimethylsilane (53 g, 70%) as a brown liquid. TLC system: EtOAc/ PE (1 :9), R,: 0.6
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 10h;	29.i Example 29; 2-Butoxy-7,8-dihydro-9-[3-fluoro-4-{4-[3-(methoxycarbonylmethyl)phenoxymethyl]piperidin-1 -yl}methylbenzyl]-8-oxoadenine; [Show Image] Step (i); 4-Bromo-1-(tert-butyldimethylsiloxymethyl)-2-fluorobenzene; [Show Image] 4-Bromo-2-fluoro-1-(methoxycarbonyl)benzene 3.0g (12.9mmol) was dissolved in THF (50ml) and thereto was added portion wise under ice cooling lithium aluminum hydride 732mg (19.3mmol). After 1.5 hours, the reaction was quenched with 1N aqueous sodium hydroxide. After filtration over Celite, the filtrate was concentrated and thereto was added water. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over Na2SO4, concentrated and dried in vacuo. The residue was dissolved in DMF (30ml) and thereto were added imidazole 871mg (12.8mmol) and TBSC1 1.93g (12.8mmol), followed by stirring at room temperature for 10 hours. After concentration, thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the titled compound 2.7 g (8.5mmol) as a colorless transparent oil. Yield 69% 1H NMR (DMSO-d6) δ 7.35 (1H, dd, J = 7.7, 7.7 Hz), 7.27 (1H, dd, J = 1.8, 8.3 Hz), 7.16 (1H, dd, J = 1.8, 9.6 Hz), 4.72 (2H, s), 0.92 (9H, s), 0.10 (6H, s).
	With 1H-imidazole In N,N-dimethyl-formamide for 16h;	2 Step 2: ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane. To a crude solution of 4-bromo-2-fluorophenyl)methanol (10.1 g, 49.3 mmol) in DMF (250 mL) was added TBSCl (11.1 g, 73.9 mmol) followed by Imidizole (6.71 g, 98.5 mmol). The solution was stirred for 16h. The crude solution was partitioned between EtOAc (500 mL) and LiCl (500 mL). The LiCl was discarded and the organic layer was washed with additional LiCl (2x250 mL). The combined organics were dried over Na2SO4 and concentrated to afford a crude oil which was purified via colomn chromatagrohy (Hexanes:EtOAc) to afford the title compound as a clear oil.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2019/322647, 2019, A1 Location in patent: Paragraph 0254; 0255
[2]Current Patent Assignee: NEUROCRINE BIOSCIENCES INC - WO2021/62246, 2021, A1 Location in patent: Page/Page column 84-85
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2008/22979, 2008, A1 Location in patent: Page/Page column 90
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/103478, 2009, A1 Location in patent: Page/Page column 42
[5]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524]
[6]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2016/82930, 2016, A1 Location in patent: Page/Page column 28
[7]Current Patent Assignee: ASTRAZENECA PLC; Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP1939202, 2008, A1 Location in patent: Page/Page column 56-57
[8]Current Patent Assignee: UNIVERSITY OF UTAH; CURZA GLOBAL LLC - WO2020/150385, 2020, A1 Location in patent: Paragraph 00669; 00670

3
[ 112704-79-7 ]
[ 188582-62-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2-fluoro-4-bromobenzoic acid With borane In tetrahydrofuran at 0 - 85℃; Stage #2: With hydrogenchloride In methanol; water at 25℃; for 2h;	(4-bromo-2-fluoro-phenyl)methanol (SI-8) To a solution of commercially available 4-bromo-2-fluoro-benzoic acid (SI-7) (15 g, 68.5mmol) in THF (250 mL) was added BH3 (1.0 M in THF, 140 mL, 140 mmol) at 0 oC andthen the solution was stirred at 85 oC overnight. Then, the reaction was quenched withMeOH and 1 N HCl and stirred at room temperature for an additional 2 hours. The mixturewas extracted with EtOAc and the organic layer was washed with brine, dried overanhydrous Na2SO4, filtered and concentrated to give the crude product which was purifiedby column chromatography to obtain pure compound SI-8 (12 g, 86%) as a yellow oil. ESIMSm/z 205 [M+H]+ calc. for C7H6BrFO. This intermediate was used in the next stepwithout further characterization.
	Stage #1: 2-fluoro-4-bromobenzoic acid With borane-THF In tetrahydrofuran at 20℃; Stage #2: With citric acid In tetrahydrofuran; water at 0℃;	S.i BH3 (1 M, in THF, 205 mL) was added to 4-bromo-2-fluoro benzoic acid (15 g, 0.0684 mol) in dry THF (150 mL) under a nitrogen atmosphere. The resulting mixture was stirred at RT overnight, after which the reaction mixture was cooled to 0°C and quenched with aqueous citric acid. Solvents (THF) were evaporated from the reaction mixture and the resulting aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with 10% NaHCO3, water and brine, dried over sodium sulfate and then concentrated under reduced pressure to afforded 14.7 g of the sub-title compound as pale yellow liquid. This was employed directly in the next step without further purification.

Reference： [1]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524]
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2007/69986, 2007, A1 Location in patent: Page/Page column 94

4
[ 188582-62-9 ]
[ 761446-44-0 ]
[ 1418201-67-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 80℃; for 2.5h;	A.5.1 (2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)phenyl)methanol To a mixture of (4-bromo-2-fluorophenyl)methanol (7.3 g, 34.9 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (15.1 g, 71.3 mmol) and Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.42 g, 1.74 mmol) in dioxane (104 ml) were added water (83.4 ml) and a 2M sodium carbonate solution (52.3 ml, 105 mmol). The reaction mixture was heated at 80 °C, stirred for 2.5 hours, cooled to room temperature and filtered through a glass fiber paper. The solid was washed with a mixture of ethyl acetate and water. The filtrate was extracted with ethyl acetate and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified on silica eluting with a gradient formed from n-heptane and ethyl acetate (10 to 80 ) to provide 7.07 g (98 ) of the title compound as an off-white solid. MS (m/e): 207.5 (M+H)+
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Sealed tube; Microwave irradiation;	1B; 3.1.a.1 a. STEP 1: PREPARATION OF (2-FLUORO-4-(l-METHYL-liZ-PYRAzoL-4- YL)PHENYL)METHANOL. a. STEP 1: PREPARATION OF (2-FLUORO-4-(l-METHYL-liZ-PYRAzoL-4- YL)PHENYL)METHANOL.(4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL)was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [l, -Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160 °C for 10 min. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the title compound as a beige, crystalline solid.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Microwave irradiation; Sealed tube;	Preparation of 4-(4-(chloromethyl)-3-fluorophenyl)-1-methyl-1H-pyrazole (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1′-bis(diphenylphosphino)ferrocene]-dichloro-palladium (II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160° C. for 10 min. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid. To a flame-dried round bottom flask equipped with a magnetic stir bar was added (2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)methanol (3.9 g, 19 mmol). Dichloro-methane (60 mL) was added, and to the suspension was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (5 mL, 38 mmol). The mixture was stirred at room temperature for 2 h, and then the solvent was removed by evaporation under reduced pressure. Residual volatiles were removed under high vacuum to afford the title compound as an amorphous beige solid. LCMS: RT=0.0.66 min, >99% (at) 254 nm, >99% (at) 220 nm; m/z (M+1)+=255. 1H NMR (400 MHz, CDCl3, δ (ppm)): 8.2 (s; 1H), 7.9 (s; 1H), 7.5-7.4 (m; 3H), 4.8 (s; 2H), 3.8 (s; 3H).

	With [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Sealed tube;	3 (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1 -methyl-4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1 ‘-Bis(diphenylphosphino)ferrocene]dichloro-palladium(ll) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160 °C for 10 mm. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Microwave irradiation; Sealed tube;	3 j00630j (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1 -methyl-4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1 ‘-Bis(diphenylphosphino)ferrocene] dichloro-palladium (II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160 °C for 10 mm. The water layerwas removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Microwave irradiation;	3. INTERMEDIATE 1: PREPARATION OF 4-(4-(CHLOROMETHYL)-3-FLUOROPHENYL)-1-METHYL-1H-PYRAZOLE (INTERMEDIATE 1) 3. INTERMEDIATE 1: PREPARATION OF 4-(4-(CHLOROMETHYL)-3-FLUOROPHENYL)-1-METHYL-1H-PYRAZOLE (INTERMEDIATE 1) The overall synthesis for the preparation of Intermediate 1 is shown below. (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1'-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160° C. for 10 min. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid. To a flame-dried round bottom flask equipped with a magnetic stir bar was added (2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)methanol (3.9 g, 19 mmol). Dichloromethane (60 mL) was added, and to the suspension was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (5 mL, 38 mmol). The mixture was stirred at room temperature for 2 h, and then the solvent was removed by evaporation under reduced pressure. Residual volatiles were removed under high vacuum to afford the title compound as an amorphous beige solid. LCMS: RT=0.0.66 min, >99% 254 nm, >99% 220 nm; m/z (M+1)+=255. 1H NMR (400 MHz, CDCl3, δ (ppm)): 8.2 (s; 1H), 7.9 (s; 1H), 7.5-7.4 (m; 3H), 4.8 (s; 2H), 3.8 (s; 3H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/28483, 2015, A1 Location in patent: Page/Page column 23; 24
[2]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2013/63549, 2013, A1 Location in patent: Paragraph 00490; 00663; 00664
[3]Current Patent Assignee: VANDERBILT UNIVERSITY - US2013/123236, 2013, A1 Location in patent: Paragraph 0673; 0674
[4]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2013/103931, 2013, A1 Location in patent: Paragraph 00307; 00445; 00446
[5]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2013/106795, 2013, A1 Location in patent: Paragraph 00491; 00629; 00630
[6]Current Patent Assignee: VANDERBILT UNIVERSITY - US2014/194471, 2014, A1 Location in patent: Paragraph 0485; 0486

5
[ 188582-62-9 ]
[ 134057-95-7 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 931 - 943

6
[ 188582-62-9 ]
[ 881189-74-8 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 931 - 943

7
[ 73183-34-3 ]
[ 188582-62-9 ]
[ 1082066-29-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;	3.1.1. Preparation of (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) At 90 C. under N2 atmosphere, to a stirred solution of 4-bromo-2-fluorophenylmethanol (500 mg, 2.44 mmol) in dioxane (5 mL) were added B2Pin2 (929 mg, 3.66 mmol), Pd(dppf)Cl2.DCM (198 mg, 0.24 mmol) and KOAc (717 mg, 7.32 mmol). After being stirred at 90 C. overnight, the reaction mixture was cooled down to room temperature and partitioned between EA and H2O. The layers were separated and the organic layer was washed with brine, dried over Na2SO4. Solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0?20 ethyl acetate in petroleum ether) to provide (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) (300 mg, 48%) as a yellow oil.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 179,p. 449 - 469
[2]Patent: US2018/194762,2018,A1 .Location in patent: Paragraph 0740-0741
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4984 - 4995
[4]Bioorganic Chemistry,2019,vol. 91

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P321
P322
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P378
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H200	Unstable explosive
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H316	Causes mild skin irritation
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H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
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H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere