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Chemical Structure| 117738-77-9 Chemical Structure| 117738-77-9

Structure of 117738-77-9

Chemical Structure| 117738-77-9

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Product Details of [ 117738-77-9 ]

CAS No. :117738-77-9
Formula : C8H4ClNO2
M.W : 181.58
SMILES Code : O=C(O)C1=CC=C(C#N)C=C1Cl
MDL No. :MFCD11036377
InChI Key :VTROYYKGGOPEPS-UHFFFAOYSA-N
Pubchem ID :231894

Safety of [ 117738-77-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 117738-77-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 43.13
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

61.09 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.15
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.73
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.91
Log Po/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.

1.55
Log Po/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

1.83
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.63

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.36
Solubility 0.793 mg/ml ; 0.00437 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.

-2.63
Solubility 0.426 mg/ml ; 0.00235 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

-2.47
Solubility 0.611 mg/ml ; 0.00337 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.

-6.18 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

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

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)

1.59

Application In Synthesis of [ 117738-77-9 ]

* 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.

  • Downstream synthetic route of [ 117738-77-9 ]

[ 117738-77-9 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 21423-81-4 ]
  • [ 24377-95-5 ]
  • [ 117738-77-9 ]
  • 3
  • [ 21423-81-4 ]
  • [ 117738-77-9 ]
  • 2-chloro-terephthalamic acid [ No CAS ]
  • 4
  • [ 117738-77-9 ]
  • [ 104-94-9 ]
  • [ 730960-68-6 ]
  • 2-<i>p</i>-anisidino-terephthalamic acid [ No CAS ]
  • 5
  • [ 117738-77-9 ]
  • [ 62-53-3 ]
  • [ 874521-39-8 ]
  • 6
  • [ 117738-77-9 ]
  • [ 156-43-4 ]
  • 4-cyano-2-<i>p</i>-phenetidino-benzoic acid [ No CAS ]
  • 7
  • [ 117738-77-9 ]
  • [1-(3-Amino-2,2-dimethyl-3-phenyl-propionyl)-piperidin-4-yl]-acetic acid benzyl ester [ No CAS ]
  • [ 180181-91-3 ]
  • 8
  • [ 7664-93-9 ]
  • [ 21423-81-4 ]
  • dichromate [ No CAS ]
  • [ 24377-95-5 ]
  • [ 117738-77-9 ]
  • 2-chloro-terephthalamic acid [ No CAS ]
  • 9
  • [ 181074-22-6 ]
  • [ 79-37-8 ]
  • [ 117738-77-9 ]
  • [ 22162-53-4 ]
  • [ 220461-91-6 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; hexane; dichloromethane; ethyl acetate; EXAMPLE 77 3-Chloro-4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzonitrile To a cooled suspension of <strong>[117738-77-9]2-chloro-4-cyanobenzoic acid</strong> (9.1 g) in a mixture of dichloromethane (40 ml) and dimethylformamide (3.88 ml) was added dropwise a solution of oxalyl chloride (4.6 ml) in dichloromethane (10 ml) at 0 C. The stirred reaction was allowed to warm to room temperature over a one hour period. A cloudy solution of 2-chloro-4-cyanobenzoyl chloride was utilized without further purification. To a stirred suspension of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (7.32 g) and diisopropylethylamine (13.6 ml) in dichloromethane (35 ml) was added under nitrogen the cloudy solution of 2-chloro-4-cyanobenzoyl chloride. After one hour at room temperature, the mixture was diluted with dichloromethane and washed sequentially with water, 5% sodium bicarbonate, and 50% saturated brine, After drying over anhydrous sodium sulfate, the solvent was removed in vacuo to afford a crude product (18.0 g). Purification by column chromatography on silica gel (250 g), eluding with 20% ethyl acetate/hexane, followed by 25% ethyl acetate/hexane, yielded the title compound (13.56 g) as a straw yellow foam, MS (EI), m/z: 347 (M)+.
  • 10
  • [ 117738-77-9 ]
  • [ 164148-75-8 ]
  • [ 181074-21-5 ]
  • 11
  • [ 98-64-6 ]
  • [ 117738-77-9 ]
  • 4-chloro-<i>N</i>-(2-chloro-4-cyano-benzoyl)-benzenesulfonamide [ No CAS ]
  • 12
  • (-)-trans-acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-1-methyl-pyrrolidin-2-ylmethyl ester [ No CAS ]
  • [ 117738-77-9 ]
  • (+)-trans-2-chloro-4-cyano-benzoic acid 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h; Example 36: (+Hrans-2-Chloro-4-cyano-benzoic acid 2-(2-acetoxymethyl-1 -methylpyrrol- idin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester; A mixture of the compound of example (6)(3.84 g, 10 mmol), 2-chloro-4-cyano- benzoic acid (2.48 g, 13 mmol), DCC (4.51 g, 21 mmol) and DMAP (1.34 g, 10 mmol) were dissolved in dichloromethane (50 ml_) and stirred at room temperature for 12 hrs. The reaction mixture is cooled to 0 0C, the precipitated dicyclohexylurea was filtered and the organic layer concentrated and the residue purified by column chromatography with 1 % methanol in chloroform and 0.01 % ammonia as eluent to give the compound, (+)-^rans-2-chloro-4- cyanobenzoic acid 2-(2-acetoxymethyl-1 -methylpyrrolidin-3-yl)-6-acetyl-3,5- dimethoxyphenyl ester. <n="58"/>Yield: 3.5 g (62 %);1H NMR (CDCI3, 300MHz): delta 8.19 (d, 1 H), 7.79 (s, 1 H), 7.69 (d, 1 H), 6.45 (s, 1 H), 4.10 (m, 1 H), 3.93 (s, 6H), 3.48 (m, 2H), 3.11 (m, 1 H), 2.72 (m, 1 H), 2.48 (s, 3H), 2.35 (s, 3H), 2.10 (m, 1 H), 1.92 (m, 2H), 1.74 (s, 3H); MS (ES+): m/z 515 (M+1 ).
  • 13
  • [ 117738-77-9 ]
  • [ 267242-14-8 ]
  • 14
  • [ 117738-77-9 ]
  • {6-[4-(<i>tert</i>-butoxycarbonylamino-imino-methyl)-2-chloro-benzoylamino]-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid [ No CAS ]
  • 15
  • [ 117738-77-9 ]
  • [ 267242-11-5 ]
  • 16
  • [ 117738-77-9 ]
  • [6-(4-carbamimidoyl-2-chloro-benzoylamino)-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl]-acetic acid; compound with trifluoro-acetic acid [ No CAS ]
  • 17
  • [ 117738-77-9 ]
  • {1-[3-(4-Carbamimidoyl-2-chloro-benzoylamino)-2,2-dimethyl-3-phenyl-propionyl]-piperidin-4-yl}-acetic acid benzyl ester [ No CAS ]
  • 18
  • [ 117738-77-9 ]
  • {1-[3-(4-Carbamimidoyl-2-chloro-benzoylamino)-2,2-dimethyl-3-phenyl-propionyl]-piperidin-4-yl}-acetic acid [ No CAS ]
  • 19
  • [ 117738-77-9 ]
  • [ 721431-53-4 ]
  • 20
  • [ 117738-77-9 ]
  • [ 23045-42-3 ]
  • 21
  • [ 117738-77-9 ]
  • 9-amino-acridine-3-carboxamide oxime [ No CAS ]
  • 22
  • [ 117738-77-9 ]
  • 7-ethoxy-9-chloro-acridine-3-carbonitrile [ No CAS ]
  • 23
  • [ 117738-77-9 ]
  • <i>p</i>-anisidino-terephthalic acid [ No CAS ]
  • 26
  • [ 117738-77-9 ]
  • [ 181074-22-6 ]
YieldReaction ConditionsOperation in experiment
100% With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 2.5h; <strong>[117738-77-9]2-Chloro-4-cyanobenzoic acid</strong> (58.2 mg, 320 muiotaetaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 48 mu, 15 muiotaetaomicron) were added. The mixture was stirred for 2.5 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 2-chloro-4-cyanobenzoyl chloride as yellow oil (64 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(5-amino-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7- tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-16ABp, 80 mg, 188 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N,N- diisopropylethylamine (41.4 mg, 56 mu, 320 muiotaetaomicron) was added, followed by a solution of 2- chloro-4-cyanobenzoyl chloride (vide supra, 51 mg, 256 muiotaetaomicron) in dichloromethane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 35:65 to 100:0) to yield, after drying in vacuo (40C, 5 mbar), the title compound as a light yellow solid (96 mg, 87%). HPLC (method LCMS_fglm) tR = 1.22 min. MS (ES+) m/z 588.5 [M+H].
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2 - 3h; Example No.6: Preparation of 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4- oxadiazol-5-yl)benzonitriIe; To a 25OmL RBF equi with a stir bar was charged with <strong>[117738-77-9]2-chloro-4-cyanobenzoic acid</strong> (3.0 g, 16.52 mmol), anhydrous DCM (80 mL), and DMF (0.064 mL, 0.826 mmol). Oxalyl chloride (8.26 mL, 16.52 mmol) (2M solution in DCM) was then added slowly and the mixture was stirred under nitrogen at ambient temperature. Upon addition of the oxalyl chloride, gas evolution began and the suspended solid began to dissolve. After about 2-3 hours, the reaction became translucent. The mixture was concentrated in vacuo. The resulting crude material was dissolved in pyridine (50 mL). To this was added (Z)-3-chloro-N'- hydroxy-4-isopropoxybenzimidamide (1.258 g, 5.50 mmol). The mixture was heated to about 100 0C under an atmosphere of nitrogen for about 16 hrs. The resulting mixture was cooled to ambient temperature. Pyridine was removed under reduced pressure and the resulting material was triturated in DCM and MeOH mixture (about 1: 1). The resulting precipitate was left standing for a few minutes at ambient temperature then was collected via filtration, washed with a mixture of 1:1 DCM/MeOH, and then with straight MeOH and dried in a vacuum oven for about 48 hrs to yield 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4- oxadiazol-5-yl)benzonitrile (1.529g, 4.09 mmol) as a beige solid. 1H NMR (400 MHz, DMSO) delta ppm 8.39 (d, J = 1.53 Hz, IH), 8.35 (d, J = 8.15 Hz, IH), 8.09 (dd, J = 8.14, 1.53 Hz, IH), 8.05 (d, / = 2.11 Hz, IH), 8.00 (dd, J = 8.63, 2.12 Hz, IH), 7.39 (d, J = 8.82 Hz, IH), 4.82 (sept, J = 6.04 Hz, IH), 1.35 (d, J = 6.01 Hz, 6H).
With oxalyl dichloride; N,N-dimethyl-formamide; In hexane; dichloromethane; at 0 - 20℃; for 1h; EXAMPLE 77 3-Chloro-4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-benzonitrile To a cooled suspension of <strong>[117738-77-9]2-chloro-4-cyanobenzoic acid</strong> (9.1 g) in a mixture of dichloromethane (40 ml) and dimethylformamide (3.88 ml) was added dropwise a solution of oxalyl chloride (4.6 ml) in dichloromethane (10 ml) at 0 C. The stirred reaction was allowed to warm to room temperature over a one hour period.. A cloudy solution of 2-chloro-4-cyanobenzoyl chloride was utilized without further purification.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h; To a cooled suspension of <strong>[117738-77-9]2-chloro-4-cyanobenzoic acid</strong> (9.1 g) in a mixture of dichloromethane (40 ml) and dimethylformamide (3.88 ml) was added dropwise a solution of oxalyl chloride (4.6 ml) in dichloromethane (10 ml) at 0 C. The stirred reaction was allowed to warm to room temperature over a one hour period. A cloudy solution of 2-chloro-4-cyanobenzoyl chloride was utilized without further purification.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere; Preparation No.5: Preparation of 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4- oxadiazol-5-yl)benzonitrile; To a 250 mL round bottom flask equipped with a stir bar and charged with 2-chloro-4- cyanobenzoic acid (3.0 g, 16.52 mmol), was added anhydrous DCM (80 mL), and DMF (0.064 mL, 0.826 mmol). Oxalyl chloride (8.26 mL, 16.52 mmol) (2M solution in DCM) was then added slowly and the mixture was stirred under nitrogen at ambient temperature. Upon addition of the oxalyl chloride, gas evolution began and the suspended solid began to dissolve. After about 2-3 h, the reaction became translucent. The mixture was concentrated in vacuo. The resulting crude material was dissolved in pyridine (50 mL). To this was added (Z)-3- chloro-A^-hydroxy-4-isopropoxybenzimidamide (1.258 g, 5.50 mmol). The mixture was heated to about 100 C under an atmosphere of nitrogen for about 16 h. The resulting mixture was cooled to ambient temperature. Pyridine was removed under reduced pressure and the resulting material was triturated in DCM and MeOH mixture (about 1 : 1). The resulting precipitate was left standing for a few minutes at ambient temperature then was collected via filtration, washed with a mixture of 1 : 1 DCM/MeOH, and then with straight MeOH and dried in a vacuum oven for about 48 h to yield 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)- 1,2,4- oxadiazol-5-yl)benzonitrile (1.529g, 4.09 mmol, 25%) as a beige solid. .H NMR (400 MHz, DMSO) delta ppm 8.39 (d, J = 1.53 Hz, 1H), 8.35 (d, J = 8.15 Hz, 1H), 8.09 (dd, J = 8.14, 1.53 Hz, 1H), 8.05 (d, J = 2.11 Hz, 1H), 8.00 (dd, J = 8.63, 2.12 Hz, 1H), 7.39 (d, J = 8.82 Hz, 1H), 4.82 (sept, J = 6.04 Hz, 1H), 1.35 (d, J = 6.01 Hz, 6H).

  • 27
  • [ 98592-34-8 ]
  • [ 117738-77-9 ]
YieldReaction ConditionsOperation in experiment
97% Lithium hydroxide (1.12 g, 26.69 mmol) was added to a solution of 2-chloro-4-cyano-benzoic acid methyl ester (2.60 g, 13.29 mmol) in dioxan/water (4:1, 100ml). The mixture was stirred at room temperature for 3h and concentrated in vacuo. The residue was partitioned between 1N hydrochloric acid and chloroform and the organic layer was washed with brine and concentratedin vacuo. The residue was recrystallised from a mixture of dioxan and pet. ether to give a pale orange solid identified as 2-chloro-4-cyanobenzoic acid (2.33 g, 97%).
63.3% Intermediate 125b was dissolved in a 0.5molar 1 : 1 mixture of MeOH / THF and LiOH.H20 (302 mg, 7.21 mmol. The reaction was stirred for 5hrs before the solvent was removes under vaccuum.The residue was suspended in water and acidified with aqueous HCI (2M). A pink precipitate was filtered off and dried under HV + cold trap to yield intermediate 125c (569.2 mg, 3.04 mmol, 63.3 % yield) as pinkish solid.1 H NMR (400 MHz, DMSO-c 6) delta ppm 13.95 (br. S., 1 H), 8.18 (s, 1 H), 7.85 - 7.96 (m, 2 H). RtMSi= 1.21 min., [M+H]+ = 182.1.
55% With lithium hydroxide; water; In tetrahydrofuran; for 18h; 2-Chloro-4-cyanobenzoic acid Lithium hydroxide monohydrate (1.18g, 28mmol) was added to a solution of 2-chloro-4-cyanobenzoic acid methyl ester (2.61g, 13mmol) in a mixture of THF and water (4:1, 100ml) and stirred for 18h. The mixture was reduced in vacuo, the residue was acidified with 1N hydrochloric acid and extracted with a mixture of methanol and chloroform (5:95). The organic extracts were washed with brine, dried and reduced. The residue was recrystallized from dioxan/pet. ether to give a pale orange solid identified as 2-chloro-4-cyanobenzoic acid, yield 1.34g, 55%.
With sodium hydroxide; In methanol; water; EXAMPLE 76 2-Chloro-4-cyanobenzoic Acid To a stirred solution of 2-chloro-4-cyanobenzoic acid, methyl ester (24.3 g) in methanol (150 ml) was added 2.5N sodium hydroxide (54.5 ml). After stirring at room temperature. for 45 minutes, the solvent was removed in vacuo. The residue was dissolved in water, cooled in an ice bath, and made acidic with 2N hydrochloric acid (14 ml). The resulting precipitate was filtered and dried in vacuo to yield the title compound as a solid (22.55 g) m.p. 154-158 C.
To a stirred solution of 2-chloro-4-cyanobenzoic acid, methyl ester (24.3 g) in methanol (150 ml) was added 2.5N sodium hydroxide (54.5 ml). After stirring at room temperature. for 45 minutes, the solvent was removed in vacuo. The residue was dissolved in water, cooled in an ice bath, and made acidic with 2N hydrochloric acid (14 ml). The resulting precipitate was filtered and dried in vacuo to yield the title compound as a solid (22.55 g) m.p. 154-158 C.

YieldReaction ConditionsOperation in experiment
37% Example 294A 4-cyano-2-chlorobenzoic acid Under a nitrogen atmosphere, Zn(CN)2 (58 mg, 0.50 mmol) and 4-bromo-2-chlorobenzoic acid (200 mg, 0.90 mmol) were added to dry dimethylformamide (5 mL), followed by tetrakis(triphenylphosphine)palladium(0) (43 mg, 0.036 mmol). The resulting yellow slurry was heated to 80 C. overnight. After it was cooled to room temperature, it was diluted with ethyl ether (20 mL), and washed with water (2*10 mL). Then the ethereal portion was collected, dried with Na2SO4, filtered and concentrated in vacuo to give 2-chloro-4-cyanobenzoic acid (60 mg, 37% yield) as a white solid. Reference: Magidson, O. J.; Trawin, A. I. Chem Ber. 1936, 69, 537-544.
  • 29
  • [ 46004-37-9 ]
  • [ 117738-77-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium carbonate; sodium nitrite; In water; ethyl acetate; EXAMPLE 75 2-Chloro-4-cyanobenzoic Acid, Methyl Ester 2-chloro-4-aminobenzoic acid, methyl ester (13.95 g) was suspended in a mixture of water (65 ml) and concentrated hydrochloric acid (15.7 ml). After stirring at room temperature for 10 minutes, the suspension was cooled to 0 C. A solution of sodium nitrite (5.71 g) in water (37 ml) was gradually added over 20 minutes, maintaining a reaction temperature of 0 C. After stirring at 0 C. for 35 minutes, the reaction mixture was partially neutralized by the addition of solid sodium carbonate (3.16 g) to afford a cold solution of the diazonium salt. To a pre-cooled solution of copper(I) cyanide (8.4 g) and sodium cyanide (9.19 g) in water (112 ml) was gradually added the above solution of diazonium salt over a 45-50 minute period. The diazonium salt solution was maintained at 0 C. during the addition. The resulting mixture was stirred for 18 hours at room temperature. A precipitate was filtered, air-dried, dissolved in ethyl acetate (250 ml), and filtered to remove insoluble matter. The organic phase was dried over anhydrous magnesium sulfate, and the solvent removed in vacuo to afford a crude product as a brown solid (13.2)g). The crude product was purified by column chromatography on silica gel (250 g), eluding with 5-10% ethyl acetate/hexane to yield the title compound (10.9 g) as a solid, m.p. 90-92 C.; MS (EI), m/z: 195 (M)+.
  • 30
  • [ 181074-22-6 ]
  • [ 21423-81-4 ]
  • [ 117738-77-9 ]
  • [ 529-34-0 ]
  • ethyl rac-(6-(N-(4-aminoiminomethyl-2-chlorobenzoyl)amino)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetate hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With pyridine; thionyl chloride; In tetrahydrofuran; hexane; toluene; 5.7 g (31.4 mmol) of <strong>[117738-77-9]2-chloro-4-cyano-benzoic acid</strong>, which was prepared by oxidation of 3-chloro-4-methyl-benzonitrile (according to Chem. Ber. 1936, 69, 537, the disclosure of which is incorporated herein by reference), were dissolved in 300 ml toluene, and 10.25 g (86.2 mmol) thionyl chloride were added. After 4 hours heating with reflux the same amount of thionyl chloride was added and heating was continued overnight. The solvent was removed under reduced pressure, the residue dissolved in 100 ml toluene, and again it was concentrated in vacuo to leave the crude acid chloride as a yellow oil. Yield: 4.1 g (65%) A solution of 0.98 g (3.96 mmol) of the tetralone 98 and 3.3 ml dry pyridine in 33 ml dry THF was cooled with ice, and a solution of 1.0 g (5.0 mmol) of the crude 2-chloro-4-cyanobenzoyl chloride in 33 ml dry THF was added dropwise. The mixture was warmed slowly to room temperature, stirred over night, and poured into ice-cold water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and with brine, successively, and dried over sodium sulfate. The product was concentrated under reduced pressure, and the residue was stirred with hexane to give the crystalline nitrile (280), which was filtered and dried in vacuo at 50 C. Yield: 1.5 g (92%) of beige crystalline solid, m.p. 173-175 C.
  • 31
  • ethyl 2-chloro-4-cyanobenzoate [ No CAS ]
  • [ 117738-77-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium hydroxide; In ethanol; (41-2) In 15 ml of ethanol was dissolved 1.1 g (5.0 mmol) of ethyl 2-chloro-4-cyanobenzoate, and 10 ml of a 1N aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred overnight. To the resulting reaction mixture was added 11 ml of 1N hydrochloric acid and the mixture was extracted with 50 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.91 g (5.0 mmol) of the title compound as white crystal. 1H-NMR (CDCl3) delta; 8.05 (d, J=8.1 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J=8.1 Hz, 1H). CI-MS (m/z); 182
  • 32
  • [ 7664-93-9 ]
  • [ 2457-76-3 ]
  • [ 117738-77-9 ]
YieldReaction ConditionsOperation in experiment
With urea; sodium nitrite; In water; Synthesis of 2-chloro-4-cyanobenzoic acid (used in the synthesis of Compound 25) To a stirred suspension of 4-amino-2-chlorobenzoic acid (10 g, supplied by Aldrich) in water (150 ml) and concentrated sulphuric acid (20 ml) at -2C was added a solution of sodium nitrite (4.8 g) in water (75 ml) at -2C. After the solid had dissolved, urea was added to destroy excess nitrous acid. The resulting solution was added to a stirred solution of copper (I) cyanide (9.0 g) and potassium cyanide (13.0 g) in water (30 ml) at 60-70C and the mixture was heated to 85-90C for 1 hour. The hot mixture was filtered. The filtrates were cooled and the product was filtered off. 1.3 g of 2-chloro-4-cyanobenzoic acid was obtained. Nuclear magnetic resonance spectrum (NMR) was as follows: 'H (ppm from TMS in (CD3)2CO, integral, number of peaks): 7.85, 1H, dd; 8.0, 1H, d; 8.05 1H, d. Mass spectrum M+1 182.
  • 33
  • [ 1701-57-1 ]
  • [ 117738-77-9 ]
  • [ 1092844-15-9 ]
  • 34
  • (-)-trans-acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-yl methyl ester [ No CAS ]
  • [ 117738-77-9 ]
  • (+)-trans-2-chloro-4-cyano-benzoic acid 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h; Example 36 (+)-trans-2-Chloro-4-cyano-benzoic Acid 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl Ester A mixture of the compound of example (6)(3.84 g, 10 mmol), <strong>[117738-77-9]2-chloro-4-cyano-benzoic acid</strong> (2.48 g, 13 mmol), DCC (4.51 g, 21 mmol) and DMAP (1.34 g, 10 mmol) were dissolved in dichloromethane (50 mL) and stirred at room temperature for 12 hrs. The reaction mixture is cooled to 0 C., the precipitated dicyclohexylurea was filtered and the organic layer concentrated and the residue purified by column chromatography with 1% methanol in chloroform and 0.01% ammonia as eluent to give the compound, (+)-trans-<strong>[117738-77-9]2-chloro-4-cyanobenzoic acid</strong> 2-(2-acetoxymethyl-1-methylpyrrolidin-3-yl)-6-acetyl-3,5-dimethoxyphenyl ester. Yield: 3.5 g (62%); 1H NMR (CDCl3, 300 MHz): delta 8.19 (d, 1H), 7.79 (s, 1H), 7.69 (d, 1H), 6.45 (s, 1H), 4.10 (m, 1H), 3.93 (s, 6H), 3.48 (m, 2H), 3.11 (m, 1H), 2.72 (m, 1H), 2.48 (s, 3H), 2.35 (s, 3H), 2.10 (m, 1H), 1.92 (m, 2H), 1.74 (s, 3H); MS (ES+): m/z 515 (M+1).
  • 35
  • [ 117738-77-9 ]
  • (S)-methyl 1-(2-chloro-4-cyanobenzoyl)pyrrolidine-2-carboxylate [ No CAS ]
 

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