321574-29-2|O-(4-(Trifluoromethyl)benzyl)hydroxylamine hydrochloride| Ambeed

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Quality Control of [ 321574-29-2 ] Purity: 97% SDS Specification

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Product Details of [ 321574-29-2 ]

CAS No. :	321574-29-2
Formula :	C₈H₉ClF₃NO
M.W :	227.61
SMILES Code :	Cl.NOCC1=CC=C(C=C1)C(F)(F)F
MDL No. :	MFCD00231881
InChI Key :	XLFMFCSFMQLFAY-UHFFFAOYSA-N
Pubchem ID :	18526040

Safety of [ 321574-29-2 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H315-H319-H228
Precautionary Statements:	P240-P210-P241-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313
Class:	4.1
UN#:	1325
Packing Group:	Ⅱ

Computational Chemistry of [ 321574-29-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	3
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	47.17
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	35.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	2.51
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.9
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.	2.79
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	2.0
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.95
Solubility	0.254 mg/ml ; 0.00112 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.9
Solubility	0.289 mg/ml ; 0.00127 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.07
Solubility	0.192 mg/ml ; 0.000845 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
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	No
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	No
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.	-5.91 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	1.0 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)	1.72

Application In Synthesis of [ 321574-29-2 ]

* 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 [ 321574-29-2 ]

[ 321574-29-2 ] Synthesis Path-Downstream 1~35

1
[ 880474-01-1 ]
[ 321574-29-2 ]
[ 880472-01-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 252 - 255.

2
[ 880473-81-4 ]
[ 321574-29-2 ]
[ 880471-17-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 252 - 255.

3
[ 880473-85-8 ]
[ 321574-29-2 ]
[ 880471-86-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 252 - 255.

4
[ 321574-29-2 ]
[ 80817-41-0 ]
(3Z,5E,13E,15E)-18-((5Z,6E,10E)-3,9-dihydroxy-4,8-dimethyl-5-(((4-(trifluoromethyl)benzyl)oxy)imino)dodeca-6,10-dien-2-yl)-9-ethyl-8,10-dihydroxy-3,17-dimethoxy-5,7,11,13-tetramethyloxacyclooctadeca-3,5,13,15-tetraen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.9 mg	With acetic acid; In methanol; at 15 - 20℃; for 4h;	The compound of Example 1 (56 mg) was dissolved in methanol (2 mL), and 0-(4- trifluoromethyl)benzyl)hydroxylamine hydrochloride (189 mg, Vyas Biosciences, India) was added with stirring at 15C -20 C. Acetic acid (0.5 mL) was added to the resulting reaction mixture and stirring was continued at the same temperature. After 4 h, ethyl acetate was added to the reaction mixture and organic layer was washed with saturated NaHC03 solution and brine. The organic layer was evaporated to dryness to obtain crude product (78 mg). The crude product was purified by flash chromatography. Column: Flash cartridge 4 g (redisep, silica gel); Mobile phase: 25 % ethyl acetate in petroleum ether; Yield: 24.9 mg; XH NMR (CDC13, 300 MHz): delta 7.61 (dd, 2H), 7.46 (dd, 2H), 6.70 (d, 1H), 6.54 (dd, 1H), 6.45 (br s, 1H), 6.23 (m, 1H), 6.17 (1H), 5.82 (br d, 1H), 5.72 (1H), 5.65 (IH), 5.49 (m, IH), 5.41 (IH), 5.29 (dd, IH), 5.16 (s, 2H), 3.89 (m, IH), 3.80 (IH), 3.76 (IH), 3.73 (IH), 3.64 (s, 3H), 3.60 (isomer peak), 3.24 (s, 3H), 3.20 (isomer peak), 2.87 (br dd, IH), 2.76 (br dd, IH), 2.38 (m, IH), 2.19 (m, IH), 2.11 (m, IH), 2.00 (br s, 3H), 1.98 (2H), 1.83 (br s, 3H), 1.73 (br d, 3H), 1.51 (m, IH), 1.27 (br d, 3H), 1.17 (d, 3H), 1.10 (3H), 1.08 (m, 2H), 1.04 (d, 3H), 0.96 (d, 3H) and 0.90 (3H); Mass: ESI-MS (-)ve mode [M+Cl]" :881.65.

References: [1]Patent: WO2014/118740,2014,A1 .Location in patent: Page/Page column 34; 35.

5
[ 321574-29-2 ]
1-phenyl-2-(4-(1-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)ethanone [ No CAS ]

References: [1]Patent: WO2014/192023,2014,A1 .

6
[ 321574-29-2 ]
1-(4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)ethanone O-(4-(trifluoromethyl)benzyl)oxime [ No CAS ]

References: [1]Patent: WO2014/192023,2014,A1 .

7
[ 321574-29-2 ]
1,1,1-trifluoro-3-(4-(1-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)propan-2-one [ No CAS ]

References: [1]Patent: WO2014/192023,2014,A1 .

8
[ 321574-29-2 ]
[ 99-93-4 ]
1-(4-hydroxyphenyl)ethanone O-(4-(trifluoromethyl)benzyl)oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium acetate; acetic acid; In ethanol; at 25℃; for 2h;Reflux;	To a solution of l-(4-hydroxyphenyl)ethanone (5.98 g, 43.9 mmol) in EtOH (100 ml) was added 0-(4-(trifluoromethyl)benzyl)hydroxylamine hydrochloride (10 g, 43.9 mmol) followed by addition of acetic acid (7.55 ml, 132 mmol) and sodium acetate (7.21 g, 88 mmol) at 25 C. The reaction mixture was refluxed for 2 hr. The reaction mixture was cooled to room temperature and solvent was evaporated under vacuum. The residue was poured into water. White solid separated was filtered, washed with water and dried over P205 under vacuum to yield 12.0 g, (88 %) of product as white solid. 1H NMR: CDC13,? 2.25 (s, 3H), 5.22 (s, 2H), 6.76-6.79 (m, 2H), 7.49-7.53 (m, 4H), 7.59 (d, /.= 8.4 Hz, 2H).
88%	With sodium acetate; acetic acid; In ethanol; for 2h;Reflux;	Step 3: Preparation of, 1-(4-hydroxyphenyl)ethanone O-(4-(trifluoromethyl)benzyl)oxime To a solution of 1-(4-hydroxyphenyl)ethanone (5.98 g, 43.9 mmol) in EtOH (100 ml) was added <strong>[321574-29-2]O-(4-(trifluoromethyl)benzyl)hydroxylamine hydrochloride</strong> (10 g, 43.9 mmol) followed by acetic acid (7.55 ml, 132 mmol) and sodium acetate (7.21 g, 88 mmol) at 25 C. and the reaction mixture was refluxed for 2 hr. The reaction mixture was cooled to room temperature and solvent was evaporated under vacuum. The residue was poured into water. White solid separated was filtered, washed with water and dried over P2O5 under vacuum to yield 12.0 g (88%) of product as white solid. 1H NMR: CDCl3, delta 2.25 (s, 3H), 5.22 (s, 2H), 6.76-6.79 (m, 2H), 7.49-7.53 (m, 4H), 7.59 (d, J=8.4 Hz, 2H).

References: [1]Patent: WO2014/192023,2014,A1 .Location in patent: Page/Page column 28.
[2]Patent: US2016/83380,2016,A1 .Location in patent: Paragraph 0216; 0217.

9
[ 321574-29-2 ]
ethyl 2-acetyl-5-hydroxybenzoate [ No CAS ]
ethyl 5-hydroxy-2-(1-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.8%	With sodium acetate; In ethanol; water; at 90℃; for 20h;	To a solution of ethyl 2-acetyl-5-hydroxybenzoate (0.300 g, 1.441 mmol) and 0-(4-(trifluoromethyl)benzyl)hydroxylamine (0.358 g, 1.873 mmol) in Ethanol (10 ml), another solution of sodium acetate (0.118 g, 1.441 mmol) in water (1.0 ml) was added and the reaction mixture was stirred at 90 C for 20 hours. The reaction mixture was cooled to 30C and ethanol was distilled out from the reaction mixture under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water & brine, dried over Na2S04 and evaporated under vacuum to yield crude product as pale red liquid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 10% EtOAc in Hexane) to yield 0.180 g (32;8 % yield) of pure product as yellow liquid. 1H NMR: CDC13,? 1.21-1.33 (m, 3H), 2.19 (s, 3H,), 4.15-4.23 (m, 2H), 5.18 (s, OH), 5.22 (s, 2H), 6.94 (dd, J= 8.4 Hz, 1H), 7.03 (d, J= 2.0 Hz, 1H), 7.17 (d, J= 8.4 Hz, 1H), 7.49 (d, J - 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H).

References: [1]Patent: WO2014/192023,2014,A1 .Location in patent: Page/Page column 34.

10
[ 321574-29-2 ]
ethyl 2-acetyl-5-hydroxybenzoate [ No CAS ]
ethyl 5-(2-oxo-2-phenylethoxy)-2-(1-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)benzoate [ No CAS ]

References: [1]Patent: WO2014/192023,2014,A1 .

11
[ 402-49-3 ]
[ 321574-29-2 ]

References: [1]Patent: WO2014/192023,2014,A1 .
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3064 - 3066.

12
2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-1,3-dione [ No CAS ]
[ 321574-29-2 ]

Yield	Reaction Conditions	Operation in experiment
55.3%	With hydrazine hydrate; In tetrahydrofuran; ethanol; at 25℃; for 1h;	To a solution of 2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-l,3-dione (5.1 g, 15.88 mmol) in THF (40 ml) and EtOH (40.0 ml) was added hydrazine monohydrate (1.557 ml, 31.8 mmol) and the reaction mixture was stirred for 1 hour at 25 C. The reaction mixture was poured into K2C03 solution (100 mL) and extracted with ethyl acetate. The combined organic layer was washed with water & brine solution, dried over Na2S04 and evaporated under vacuum to yield crude product as brown thick liquid. The crude product was added to ethereal HCl. The solid separated was filtered, washed with diethyl ether and dried over CaCl2 under vacuum to yield 2 g, (55.3 %) of product as off white solid. 1H NMR: MeOD,? 5.15 (s, 2H), 7.64 (d, J= 8.0 Hz, 2H), 7.74 (d, J= 8.0 Hz, 2H).
55.3%		Step 2: Preparation of O-(4-(trifluoromethyl)benzyl)hydroxylamine hydrochloride To a solution of 2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-1,3-dione (5.1 g, 15.88 mmol) in THF (40 ml) and EtOH (40.0 ml) was added hydrazine monohydrate (1.557 ml, 31.8 mmol) and the reaction mixture was stirred for 1 hour at 25 C. The reaction mixture was poured into K2CO3 solution (100 mL) and extracted with ethyl acetate. The combined organic layer was washed with water & brine solution, dried over Na2SO4 and evaporated under vacuum to yield crude product as brown thick liquid. The crude product was added to ethereal HC1. The solid separated was filtered, washed with diethyl ether and dried over CaC12 under vacuum to yield 2 g, (55.3%) of product as off white solid. 1H NMR: MeOD, oe 5.15 (s, 2H), 7.64 (d, J=8.0 Hz,2H), 7.74 (d, J=8.0 Hz, 2H).
165 mg		After 463 mg of hydroxyphthalimide (Aldrich), 0.4 ml of 4-(trifluoromethyl)benzyl alcohol (Aldrich), and 745 mg of triphenylphosphine (Aldrich) were dissolved in 8 ml of tetrahydrofurane under argon flow, 0.67 ml of diisopropyl azodicarboxylate (Aldrich) was slowly added at 0 C. The mixture was stirred at room temperature for 1 hour, and the solvent was concentrated under reduced pressure. The reaction liquid was diluted by 20 ml of ethyl acetate, followed by drying over magnesium sulfate and then filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) to obtain a compound. The obtained compound was dried and then dissolved in 8 ml of dichloromethane, and 0.16 ml of methyl hydrazine (TCI) was slowly added at 0 C. After the reaction liquid was stirred at room temperature for 2 hours, the temperature was again lowered to 0 C. The generated solid was then filtered out, and 1 ml of a 4 M-hydrochloric acid dioxane solution (Aldrich) was added to the residual filtrate, followed by filtration and drying, to obtain 165 mg of a white solid (yield: 26%). 52 mg of the obtained white solid and 100 mg of SAC-0906 obtained as obtained above were dissolved in 3 ml of pyridine (Aldrich) under argon flow, followed by stirring at 80 C. for 4 hours. After the temperature was lowered to room temperature, the reaction liquid was acidified by adding a 2 N hydrochloric acid solution, followed by extraction with 20 ml of diethyl ether, drying over magnesium sulfate, and filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) to obtain the target compound SAC-1107 (100 mg, yield: 63%). 1H-NMR (300 MHz, CDCl3) delta7.58 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 5.89-5.79 (m, 2H), 5.36-5.34 (m, 1H), 5.30-5.27 (m, 1H), 5.17 (m, 1H), 5.12 (s, 2H), 4.27-4.13 (m, 3H), 3.59-3.52 (m, 1H), 2.40-0.56 (m, 35H)

General procedure: To a solution of N-hydroxyphthalimide (NOP, 30.65 mmol) in DMF (30 mL), K2CO3 (61.30 mmol) and substituted benzyl bromide 1 (45.98 mmol) were added. The mixture was stirred at 80 C for 6 h, and then cooled to room temperature. The mixture was poured into ice-water (200 g), and the precipitate was filtered out and dried to give the crude intermediates 2 (yield: 73.2-94.8%) as off-white solids and used directly without further purification. A mixture of intermediates 2 (16.78 mmol) and hydrazine hydrate (80%, 33.56 mmol) in a mixture of dichloromethane (120 mL) and methanol (12 mL) was stirred at room temperature for 1.5 h. After filtration, the filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in ethanol (60 mL), and concentrated HCl (12 mol/L, 10 mL) was added. The mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure to give the crude O-benzylhydroxylamine hydrochlorides 3 (yield: 91.7-98.9%) which were used directly in the next step without further purification. To a solution of O-benzylhydroxylamine hydrochlorides or O-alkylhydroxylamine hydrochlorides 3 (10 mmol) in ethanol (50 mL), aq. K2CO3 (10%, 50 mL) was added. The mixture was stirred at room temperature for 10 min, and then pyrrolidin-3-one 4a or piperidin-4-one 4b (3 mmol) was added. The mixture was stirred at room temperature for additional 10 h, and then concentrated under reduced pressure. The residue was purified by MPLC to give the key intermediates 5 (yield: 46.3-59.6%). A mixture of 5a-j or 4c (1.28 mmol), 5-nitrofuran-2-carboxylic acid 6 (1.41 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI, 1.91 mmol), 1-hydroxybenzotriazole (HOBT, 1.91 mmol) and triethylamine (TEA, 6.4 mmol) in dichloromethane (20 mL) was stirred at room temperature for 5 h. Water (20 mL) was added to the mixture, and the mixture was extracted with dichloromethane (20 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluted with petroleum ether:ethyl acetate=3:1 to give oxime-functionalized nitrofuranylamides 7a-j (yield: 44.5-60.4%) and nitrofuranylamide 7k (yield: 48.2%) as off-white solids.

References: [1]Patent: WO2014/192023,2014,A1 .Location in patent: Page/Page column 28.
[2]Patent: US2016/83380,2016,A1 .Location in patent: Paragraph 0214; 0215.
[3]Patent: US2014/378399,2014,A1 .Location in patent: Paragraph 0117.
[4]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3064 - 3066.

13
[ 349-95-1 ]
[ 321574-29-2 ]

References: [1]Patent: US2014/378399,2014,A1 .

14
[ 321574-29-2 ]
[ 1446092-98-3 ]
C₃₉H₅₀F₃NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With pyridine; at 20℃; for 14h;Inert atmosphere;	After 463 mg of hydroxyphthalimide (Aldrich), 0.4 ml of 4-(trifluoromethyl)benzyl alcohol (Aldrich), and 745 mg of triphenylphosphine (Aldrich) were dissolved in 8 ml of tetrahydrofurane under argon flow, 0.67 ml of diisopropyl azodicarboxylate (Aldrich) was slowly added at 0 C. The mixture was stirred at room temperature for 1 hour, and the solvent was concentrated under reduced pressure. The reaction liquid was diluted by 20 ml of ethyl acetate, followed by drying over magnesium sulfate and then filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) to obtain a compound. The obtained compound was dried and then dissolved in 8 ml of dichloromethane, and 0.16 ml of methyl hydrazine (TCI) was slowly added at 0 C. After the reaction liquid was stirred at room temperature for 2 hours, the temperature was again lowered to 0 C. The generated solid was then filtered out, and 1 ml of a 4 M-hydrochloric acid dioxane solution (Aldrich) was added to the residual filtrate, followed by filtration and drying, to obtain 165 mg of a white solid (yield: 26%). 52 mg of the obtained white solid and 100 mg of SAC-0906 obtained as obtained above were dissolved in 3 ml of pyridine (Aldrich) under argon flow, followed by stirring at 80 C. for 4 hours. After the temperature was lowered to room temperature, the reaction liquid was acidified by adding a 2 N hydrochloric acid solution, followed by extraction with 20 ml of diethyl ether, drying over magnesium sulfate, and filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography using a mixed eluent of ethyl acetate/hexane (1:5) to obtain the target compound SAC-1107 (100 mg, yield: 63%). 1H-NMR (300 MHz, CDCl3) delta7.58 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 5.89-5.79 (m, 2H), 5.36-5.34 (m, 1H), 5.30-5.27 (m, 1H), 5.17 (m, 1H), 5.12 (s, 2H), 4.27-4.13 (m, 3H), 3.59-3.52 (m, 1H), 2.40-0.56 (m, 35H)

References: [1]Patent: US2014/378399,2014,A1 .Location in patent: Paragraph 0114; 0117.

15
[ 2993-57-9 ]
[ 321574-29-2 ]