[ CAS No. 112897-97-9 ] {[proInfo.proName]}

Name: 112897-97-9|(E)-3-(3,4-difluorophenyl)acrylic acid|97%
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Quality Control of [ 112897-97-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 112897-97-9 ]

Product Details of [ 112897-97-9 ]

CAS No. :	112897-97-9	MDL No. :	MFCD00010320
Formula :	C₉H₆F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HXBOHZQZTWAEHJ-DUXPYHPUSA-N
M.W :	184.14	Pubchem ID :	2733300
Synonyms :

Calculated chemistry of [ 112897-97-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.03
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	2.06
Log Po/w (WLOGP) :	2.79
Log Po/w (MLOGP) :	2.74
Log Po/w (SILICOS-IT) :	2.55
Consensus Log Po/w :	2.36

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.49
Solubility :	0.597 mg/ml ; 0.00324 mol/l
Class :	Soluble
Log S (Ali) :	-2.47
Solubility :	0.621 mg/ml ; 0.00337 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.42
Solubility :	0.7 mg/ml ; 0.0038 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.89

Safety of [ 112897-97-9 ]

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

Application In Synthesis of [ 112897-97-9 ]

* 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 [ 112897-97-9 ]
Downstream synthetic route of [ 112897-97-9 ]

[ 112897-97-9 ] Synthesis Path-Upstream 1~6

1
[ 141-82-2 ]
[ 34036-07-2 ]
[ 112897-97-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	for 4 h; Reflux	General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL,3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5percent w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O. 4.3.1. (E)-3-(3,4-Difluorophenyl)acrylic acid (2j). Yield: 1.70 g (92percent). 1H NMR (DMSO-d6, 400 MHz), d: 7.85e7.91 (m, 1H), 7.55e7.57 (m,1H), 7.56 (d, J16.0 Hz, 1H), 7.43e7.50 (m, 1H), 6.57 (d, J16.0 Hz,1H). 13C NMR (DMSO-d6, 101 MHz), d: 167.30, 150.35 (dd, 1JCF248 Hz, 2JCF13 Hz), 149.64 (dd, 1JCF244 Hz, 2JCF13 Hz),141.64, 132.03 (dd, 3JCF6 Hz, 4JCF4 Hz), 125.82 (dd, 3JCF7 Hz, 4JCF3 Hz), 120.68, 117.88 (d, 2JCF17 Hz), 116.65 (d, 2JCF18 Hz).

Reference： [1] Tetrahedron, 2016, vol. 72, # 46, p. 7256 - 7262
[2] Molecular Crystals and Liquid Crystals, 2010, vol. 528, p. 138 - 146
[3] Chemical Biology and Drug Design, 2013, vol. 81, # 2, p. 275 - 283
[4] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5726 - 5732

2
[ 110-89-4 ]
[ 34036-07-2 ]
[ 112897-97-9 ]

Reference： [1] Patent: US2003/148888, 2003, A1,
[2] Patent: US2003/120105, 2003, A1,

3
[ 348-61-8 ]
[ 79-10-7 ]
[ 112897-97-9 ]

Reference： [1] Russian Journal of Organic Chemistry, 1997, vol. 33, # 4, p. 563 - 564

4
[ 348-61-8 ]
[ 112897-97-9 ]

Reference： [1] Molecular Crystals and Liquid Crystals, 2010, vol. 528, p. 138 - 146

5
[ 112897-97-9 ]
[ 31105-90-5 ]

Yield	Reaction Conditions	Operation in experiment
99 % ee	With ammonium hydroxide; carbon dioxide In dimethyl sulfoxide at 37℃; for 12 h; Enzymatic reaction	General procedure: The suitable aldehyde 1j-l, 1n or 1o (0.5 mmol), malonic acid (1.0 mmol) and piperidine (0.01 mmol) were dissolved in DMSO (500 mL) and the mixture was heated in a microwave reactor (30 min, 60 C). After cooling, ammonia solution (9.5 mL, 13percent w/v,approx. 7 M, adjusted to pH 10.0 by slow addition of dry ice chunks) was added, followed by E. coli BL21(DE3) cells overproducing the required PAL (400 mg wet cell paste). The suspension was stirred at 37 C for several hours, monitoring the conversion by HPLC. For product isolation, the reaction mixture was acidified to pH <2.0 using aqueous H2SO4 (20percent w/v) and centrifuged (8000 rpm, 5 min) to remove cells and precipitated unconverted substrate. Dowex 50WX8 hydrogen form resin (5.0 g), packed in a disposable plastic column, was washed with deionised water (20 mL) and aqueous H2SO4 (20 mL, 5percent w/v). The supernatant from the biotransformation was loaded onto the resin (1 mL min1). The resin bed was washed with deionised water until the flow-through tested neutral, then the product was eluted with aqueous NH4OH (20 mL, 5percent w/v). Fractions containing the product were pooled and dried overnight in a centrifugal evaporator, to afford the corresponding L-phenylalanine L-3j-l, L-3n or L-3o as a white solid. 4.7.1. (S)-2-Amino-3-(3,4-difluorophenyl)propanoic acid (L-3j). Yield: 84 mg (84percent), 99percent ee by HPLC. 1H NMR (D2ONaOH,400 MHz), d: 7.03e7.18 (m, 2H), 6.90e6.99 (m, 1H), 3.36e3.44 (m,1H), 2.81e2.90 (dd, J13.6,6.0 Hz, 1H), 2.70e2.79 (dd, J13.6,7.2 Hz,1H). 13C NMR (D2ONaOH, 101 MHz), d: 182.06, 150.94 (dd, 1JCF243 Hz, 2JCF12 Hz), 150.09 (dd, 1JCF242 Hz, 2JCF13 Hz),135.33 (dd, 3JCF5 Hz, 4JCF3 Hz), 125.51 (dd, 3JCF6 Hz, 4JCF3 Hz),117.83 (d, 2JCF17 Hz), 116.97 (d, 2JCF17 Hz), 57.33, 39.94. HRMS(ESI), m/z: calcd mass 202.0680 [MH], found 202.0689 [MH].

Reference： [1] Tetrahedron, 2016, vol. 72, # 46, p. 7256 - 7262

6
[ 112897-97-9 ]
[ 376608-71-8 ]

Reference： [1] Patent: WO2013/144295, 2013, A1,
[2] Patent: WO2013/144295, 2013, A1,
[3] Patent: WO2013/144295, 2013, A1,
[4] Patent: WO2013/144295, 2013, A1,

[ 112897-97-9 ] Synthesis Path-Downstream 1~88

1
[ 60-12-8 ]
[ 112897-97-9 ]
3,4-Difluorocinnamic acid β-phenylethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4171 - 4178

2
[ 112897-97-9 ]
[ 211568-07-9 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1727 - 1730
[2]Tetrahedron,2002,vol. 58,p. 5761 - 5766

3
[ 112897-97-9 ]
[ 376608-66-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide;Reflux; Inert atmosphere;	General procedure: To a solution of appropriate substituted trans-cinnamic acid 2a-p (1 mmol) in dry dichloromethane the thionyl chloride (2 mmol)and a catalytic amount of DMF was added. The reaction mixturewas refluxed for 2-4 h under anhydrous conditions, the solventwas evaporated under vacuum to obtain corresponding substitutedcinnamoyl chlorides 3a-p which was further used for the next stepwithout further purification.
97%	With pyridine; thionyl chloride; In toluene; for 3h;	Add (E) -3- (3,4-difluorophenyl) acrylic acid (0.1mol) to toluene (0.5mol), add pyridine 0.01mol, and add thionyl chloride (0.12mol) dropwise within 1h After adding dropwise to the reaction solution, the reaction was refluxed for 2h, then toluene and pyridine were distilled off under reduced pressure, 50mL of distilled water was added, the reaction solution was extracted 3 times with ethyl acetate (50mL), the ethyl acetate solution was combined, and dried over anhydrous sodium sulfate After filtration, the filtrate was concentrated under reduced pressure to obtain (E) -3- (3,4-difluorophenyl) acryloyl chloride (19.59 g, 97%).
93%	With thionyl chloride; In acetonitrile;	The corresponding acid chloride, (E)-3-(3,4-difluorophenyl)acryloyl chloride, required as anintermediate was synthesized, as follows: (E)-3-(3,4-Difluorophenyl)acrylic acid (1 eq) wasdissolved in MeCN and treated with SOCl2 (3 eq) to yield the corresponding acid chloride(93%).

		100 g (0.54 moles) of (£)-3-(3,4-Difluorophenyl) acrylic acid was dissolved in 250 ml dichloromethane at about 25 to 30 C. A solution of the 276 g of oxalyl chloride (2.17 moles) in 100 ml dichloromethane was added slowly to reaction mixture in about 15 minutes. This was followed by the addition of a solution of 20 ml. DMF in 150 ml dichloromethane at 25C to 30 C in about 15 minutes. The reaction mixture stirred for about 2 h, solvent was distilled under reduced pressure below 40 C to obtain product in the form of a semisolid. The semisolid obtained was dissolved in about 100 ml acetone and used as such in next step.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4h;Inert atmosphere;	General procedure: Oxalyl chloride (0.63 mmol) was added to a well stirred solution of cinnamic acid (19a-l) in DCM (15 mL) kept at 0 C under nitrogen atmosphere. To this one or two drops (catalytic amount) of DMF was added and leave it to room temparature for 4 h. Triethylamine (2 eq) was added to a well stirred solution of benzophenone amine (2a &16, 200 mg, 0.63 and 0.57 mmol respectively) dissolved in THF (10 mL) kept at 0 oC under nitrogen atmosphere. To this cinnamoyl chloride dissolved in dry THF (30 mL) was added via syringe and leave it at room temparature and the mixture was stirred for 6 h. After the solvent was removed under reduced pressure and redissolved in CHCl3 (20 mL x 2) followed by addition of water (15 mL). The organic layer was separated and evaporated to dryness. The residue was washed with aq NaOH to remove any excess acid and extracted with CHCl3. The organic extract was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography using ethyl acetate/hexane to afford the pure product.
	With thionyl chloride; N,N-dimethyl-formamide; In benzene; for 4h;Reflux;	According to thegeneral esterification procedure, a solution of 3-4 di-fluoro cinnamic acid (3.0 g, 16 mmol, 1.0 eq) inSOCl2 (30 mL), DMF (1.5 mL) and dry benzene (16 mL) was refluxed for4 hours. The mixture was then concentrated invacuo. The residue was re-dissolved in dry benzene (50 mL) before pyridinewas added drop-wise followed by 3-butyn-1-ol (1.36 mg, 19.5 mmol, 1.2 eq). Thereaction was allowed to stir for 12 hours at room temperature under anatmosphere of argon. The resulting mixture was concentrated in vacuo re-dissolved in DCM (10 mL)washed with water (3 × 10 mL), washed with brine (3 × 10 mL), dried over MgSO4and concentrated in vacuo.Thecrude material was purified by column chromatography (EtOAc/petroleum ether10:90). Recrystallised from petroleum ether (100%) to give a white solid (2.2g,9.3 mmol, 58%).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;	General procedure: To the solution of substituted cinnamic acids (14a-o, 1.1 mmol) in dry dichloromethane was added the oxalyl chloride (3mmol) and a catalytic amount of N,N-dimethyl formamide(1 mol%) at 0 C and stirred for 3 h at room temperature. After completion of reaction excess of solvent and oxalyl chloride were removed under reduced pressure to get respected acid chlorides (15a-o). Acid chlorides (15a-o)were dissolved in dry tetrahydrofuran and added to the stock solutions of 2? amino Z- combretastatin A4 (13, 1.0 mmol) and triethylamine (3 mmol) in dry tetrahydrofuran at 0 C and stirred at room temperature for 12 h. After completion of reaction, the reaction mixturewas diluted with ethyl acetate and washed with water, brine solution, dried over sodium sulphate,filtered and filtrate was concentrated under reduced pressure to get crude compounds.Crude compounds weredissolved in dry THF and added the TBAF (1.0 M in THF, 2.5 mmol) at 0 C and stirred at room temperature for 1h. After completion of reaction monitored by TLC the reaction mixture was diluted with ethyl acetate and washed with water ,brine solution, dried over sodium sulphate,filtered and filtrate was concentrated under reduced pressure to get crude compound.Crude compound waspurified by column chromatography using ethyl acetate and hexane as elutents to afford respectedZ-2?-(cinnamamide)combretastatin A4 derivatives.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 5h;Inert atmosphere;	General procedure: To a solution of cinnamic acid (1a01e24, 1a26e27, 1a29)(1.0 mmol) in dry CH2Cl2 was added oxalyl chloride (5.0 equiv) anda catalytic amount of DMF (0.01 equiv). The reaction mixture wasstirred at room temperature for 5 h before the solvent wasremoved. The residuewas dried under high vacuum and used in thenext step without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5726 - 5732
[2]Patent: CN110894184,2020,A .Location in patent: Paragraph 0045-0048
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1417 - 1422
[4]Journal of the American Chemical Society,2018,vol. 140,p. 8037 - 8047
[5]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6013 - 6018
[6]Patent: WO2013/144295,2013,A1 .Location in patent: Page/Page column 23
[7]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2309 - 2314
[8]European Journal of Medicinal Chemistry,2015,vol. 101,p. 573 - 583
[9]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2957 - 2964
[10]European Journal of Medicinal Chemistry,2019,vol. 167,p. 414 - 425

4
[ 112897-97-9 ]
C₂₀H₁₇ClF₂NO₃PS [ No CAS ]