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Structure of 1088994-22-2

Chemical Structure| 1088994-22-2

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Product Details of [ 1088994-22-2 ]

CAS No. :1088994-22-2
Formula : C12H10N2O2
M.W : 214.22
SMILES Code : CC1=CC(C(O)=O)=C(C=C1)C1=NC=CC=N1
MDL No. :MFCD14706695
InChI Key :WKBKHXGASBZRMI-UHFFFAOYSA-N
Pubchem ID :44517264

Safety of [ 1088994-22-2 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 1088994-22-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 12
Fraction Csp3 0.08
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 1.0
Molar Refractivity 59.39
TPSA ?

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

63.08 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.63
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

1.76
Log Po/w (WLOGP)?

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

2.15
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.

1.43
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

2.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.85

Water Solubility

Log S (ESOL):?

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

-2.7
Solubility 0.427 mg/ml ; 0.002 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.

-2.7
Solubility 0.425 mg/ml ; 0.00199 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

-3.94
Solubility 0.0248 mg/ml ; 0.000116 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

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

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.

-6.36 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.

0.56

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)

1.78

Application In Synthesis of [ 1088994-22-2 ]

* 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.

  • Upstream synthesis route of [ 1088994-22-2 ]
  • Downstream synthetic route of [ 1088994-22-2 ]

[ 1088994-22-2 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 1088994-20-0 ]
  • [ 1088994-22-2 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With sodium hydroxide; water In 2-methyltetrahydrofuran at 72℃; for 1.5 h;
Stage #2: at 7 - 10℃;
5-Methyl-2-pyrimidin-2-ylbenzoic acid (E-4)A solution of Ejψ from the previous step was charged to a visually clean 100 L flask through an in-line filter, concentrated and solvent switched to 2-MeTHF (-15 L). To this solution was added water (20 L) and then sodium hydroxide (10N) (2.60 L, 26.0 mol). After the <n="47"/>addition the reaction turned red and the heat source was set to 720C. The mixture was aged at this temperature for 1.5 hours after which complete conversion was observed by HPLC analysis. The reaction was cooled and transferred to a 50 L extractor. The flask was rinsed with 4 L of water and 10 L of MTBE which was added to the stirring mixture in the extractor. The layers were cut, and the aqueous phase was washed twice with 10 L of MTBE. The aqueous layer was then re-introduced into the reactor (100 L) through an in-line filter for the acidification. 2.3L of 12 N HCl was added slowly to the cold mixture which causes an exotherm from 7 to 10°C. This caused a beige precipitate to form (pH = 1). This precipitate was filtered. The beige filter cake was washed twice with 3 mL/g of cold water. Then the cake was washed with 3 mL/g of cold 15percent MTBE/Heptane and 15percent PhMe/Heptane. Finally it was washed with 1.5 mL/g of room temperature MTBE and twice with room temperature 3 mL/g Heptane. The solid was then dried under a stream of N2 for 2 days to provide E-4 as a light beige powder (2.15 kg, 10.04 mol, 97 percent yield). HPLC analysis reveals the product to be 99.2percent purity. Heavy metal analysis revealed 264ppm of Pd and 19.7ppm of Fe. Data for Ej4: 1H NMR (500 MHz, DMSOd6): 12.65 (s, 1 H); 8.85-8.82 (m, 2 H); 7.78 (dd, J = 7.89, 2.34 Hz, 1 H); 7.49-7.37 (m, 3 H); 2.40 (s, 3 H).
97%
Stage #1: With water; sodium hydroxide In 2-methyltetrahydrofuran at 72℃; for 1.5 h;
Stage #2: With hydrogenchloride In water
5-Methyl-2-pyrimidin-2-ylbenzoic acid (B-4) A solution of B1I from the previous step was charged to a visually clean 100 L flask through an in-line filler, concentrated and solvent switched to 2-MeTHF (-15 L). To this solution was added water (20 L) and then sodium hydroxide (10 N) (2.60 L, 26.0 mol). After the addition the reaction turned red and the heat source was set to 72 0C. The mixture was aged at this temperature for 1.5 h after which complete conversion was observed by HPLC analysis. The reaction was cooled and transferred to a 50 L extractor. The flask was rinsed with 4 L of water and 10 L of MTBE which was added to the stirring mixture in the extractor. The layers were cut, and the aqueous phase was washed twice with 10 L of MTBE. The aqueous layer was then reintroduced into the reactor (100 L) through an in-line filter for the acidification. 2.3 L of 12 N HCl was added slowly to the cold mixture which causes an exotherm from 7 to 10 0C. This caused a beige precipitate to form (pH = 1). This precipitate was filtered. The beige filter cake <n="32"/>was washed twice with 3 mL/g of cold water. Then the cake was washed with 3 mL/g of cold 15percent MTBE/Heptane and 15percent PhMe/Heptane. Finally it was washed with 1.5 mL/g of room temperature MTBE and twice with room temperature 3 mL/g Heptane. The solid was then dried under a stream of N2 for 2 days to provide B-4 as a light beige powder (2.15 kg, 10.04 mol, 97 percent yield). HPLC analysis reveals the product to be 99.2percent purity. Heavy metal analysis revealed 264ppm of Pd and 19.7ppm of Fe. Data for B^: lH NMR (500 MHz, DMSO-d6): 12.65 (s, 1 H); 8.85-8.82 (m, 2 H); 7.78 (dd, J - 7.89, 2.34 Hz, 1 H); 7.49-7.37 (m, 3 H); 2.40 (s, 3 H).
65% With water; sodium hydroxide In 2-methyltetrahydrofuran at 72℃; To a solution of methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (p60, 231 mg, 1.01 mmol) in 2-Me-THF (4 mL) water (2.5 mL) and sodium hydroxide solution (10 N) (1.25 mL) were added. The reaction turned red, the mixture was heated to 72°C and stirred at that temperature overnight. The reaction was gone to completion; therefore it was cooled down to RT and transferred to an extractor washing with water and diethyl ether. The layers were separated and the aqueous phase was back-extracted twice with diethyl ether. The aqueous layer was acidified with HCI (12 N). A precipitated was formed, that was filtered washing with water and dried affording 5-methyl-2-(pyrimidin-2-yl)benzoic acid (p61 , 140 mg, y= 65percent) as white solid. MS (mlz): 214.0 [MH]+.
59.98 g With water; sodium hydroxide In tetrahydrofuran at 70℃; for 4 h; Methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (86.1 g; 377 mmol) are dissolved in THF (350 ml) followed by the addition of water (350 ml) and aq. NaOH (190 ml; 4M). The reaction mixture is heated to 70°C for 4 hours. The organic solvent is distilled off under reduced pressure andthe aq. phase is extracted with DCM. Then the aq. phase is cooled to 0°C and the pH is adjusted to pH = 1 by careful addition of aq. 2M hydrochloric acid solution which results in the formation of a suspension. The solid is filtered off and dried at high vacuum to give 59.98 g of the title compound as a beige solid; tR [mm] = 0.58; [M+H] = 215.14.

References: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 61 - 68.
[2] Patent: WO2008/147518, 2008, A1, . Location in patent: Page/Page column 43; 45-46.
[3] Patent: WO2009/143033, 2009, A1, . Location in patent: Page/Page column 30-31.
[4] Patent: CN105461699, 2016, A, . Location in patent: Paragraph 0754; 0755; 0756; 0757; 0758; 0759.
[5] Patent: WO2019/43407, 2019, A1, . Location in patent: Page/Page column 90.
[6] Patent: WO2015/83094, 2015, A1, . Location in patent: Page/Page column 19.
  • 2
  • [ 1373917-20-4 ]
  • [ 1088994-22-2 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride; water In acetonitrile at 10 - 22℃; for 50 h; 5-Methyl-2-(pyrimidin-2-yl)benzoic Acid (3)To a 150 mL three neck round bottom flask, equipped with overhead stirrer, thermocouple and HCl-scrub, was charged 12 N HCl solution (17.1 mL, 8 equiv) and was cooled to 10 °C. Acetonitrile (5 mL, 1 V) was added. Then, biaryl nitrile 2 (5.00 g) was added in portion at 10-15 °C. The reaction mixture was aged at 10-15 °C for 2 h, and slowly warmed to 22°C and aged at the same temperature for 48 h (100 Apercent conversion). The reaction mixture was cooled to 0 °C. 20 wtpercent of NaCl solution was added drowise. The resulting slurry was aged at 0-5°C for 6 h. The crystalline solid was collected by filtration, rinsed with water and cold EtOAc, dried under vacuum with nitrogen sweep to give product 3 (4.95 g, 90percent isolated yield, 98.9 LCAP purity).HPLC MethodColumn: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 μιη particle size,Column Temp.: 25 °C; Flow Rate: 1.5 mL/min; Detection: 230 nm; Mobile Phase: A: Water0.1percent H3P04, B: AcetonitrileMobile Phase Program: Time A0 90percent5 min 5percent6 min 5percent6.1 min 90percent8 min 90percentCompound A-3: 2.19 min
References: [1] Patent: WO2012/58129, 2012, A1, . Location in patent: Page/Page column 16-17.
  • 3
  • [ 1373917-20-4 ]
  • [ 1088994-22-2 ]
References: [1] Organic Letters, 2014, vol. 16, # 22, p. 5890 - 5893.
  • 4
  • [ 103440-52-4 ]
  • [ 1088994-22-2 ]
References: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 61 - 68.
[2] Patent: WO2015/83094, 2015, A1, .
[3] Patent: WO2008/147518, 2008, A1, .
[4] Patent: WO2009/143033, 2009, A1, .
[5] Patent: WO2019/43407, 2019, A1, .
  • 5
  • [ 1088994-18-6 ]
  • [ 1088994-22-2 ]
References: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 61 - 68.
[2] Patent: CN105461699, 2016, A, .
[3] Patent: WO2008/147518, 2008, A1, .
[4] Patent: WO2009/143033, 2009, A1, .
[5] Patent: WO2019/43407, 2019, A1, .
  • 6
  • [ 52548-14-8 ]
  • [ 1088994-22-2 ]
References: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 61 - 68.
[2] Patent: WO2015/83094, 2015, A1, .
[3] Patent: WO2008/147518, 2008, A1, .
[4] Patent: WO2009/143033, 2009, A1, .
  • 7
  • [ 42872-83-3 ]
  • [ 1088994-22-2 ]
References: [1] Organic Letters, 2014, vol. 16, # 22, p. 5890 - 5893.
  • 8
  • [ 42872-83-3 ]
  • [ 1088994-22-2 ]
References: [1] Patent: WO2012/58129, 2012, A1, .
  • 9
  • [ 90971-88-3 ]
  • [ 1088994-22-2 ]
References: [1] Patent: CN105461699, 2016, A, .
  • 10
  • [ 6967-82-4 ]
  • [ 1088994-22-2 ]
References: [1] Patent: CN105461699, 2016, A, .
 

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