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[ CAS No. 162401-62-9 ] {[proInfo.proName]}

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Chemical Structure| 162401-62-9
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Product Details of [ 162401-62-9 ]

CAS No. :162401-62-9 MDL No. :MFCD04621687
Formula : C12H12F2O4 Boiling Point : -
Linear Structure Formula :- InChI Key :IGFDIFLMMLWKKY-UHFFFAOYSA-N
M.W : 258.22 Pubchem ID :2394006
Synonyms :
Chemical Name :3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid

Calculated chemistry of [ 162401-62-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.42
Num. rotatable bonds : 6
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 58.79
TPSA : 55.76 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.51 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.02
Log Po/w (XLOGP3) : 3.33
Log Po/w (WLOGP) : 3.55
Log Po/w (MLOGP) : 1.81
Log Po/w (SILICOS-IT) : 2.58
Consensus Log Po/w : 2.66

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.39
Solubility : 0.105 mg/ml ; 0.000408 mol/l
Class : Soluble
Log S (Ali) : -4.18
Solubility : 0.0172 mg/ml ; 0.0000664 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -2.87
Solubility : 0.351 mg/ml ; 0.00136 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.23

Safety of [ 162401-62-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H317-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 162401-62-9 ]

* 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 [ 162401-62-9 ]
  • Downstream synthetic route of [ 162401-62-9 ]

[ 162401-62-9 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 151103-09-2 ]
  • [ 162401-62-9 ]
YieldReaction ConditionsOperation in experiment
97% With sodium chlorite; aminosulfonic acid In water; acetic acid at 20℃; for 1 h; 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol) and sulfamic acid (7.3 g, 75 mmol) were dissolved in glacial acetic acid (50 ml) and the solution added with a solution of sodium chlorite (8.2 g, 75 mmol) in water (15 ml).
The reaction mixture was stirred at room temperature for 1 hr then water (300 ml) was added so obtaining the precipitation of a solid that was filtered and dried at 40° C. under vacuum (12 g, 48 mmol, 97percent yield).
97% With dihydrogen peroxide; potassium hydroxide In methanol at 65℃; for 1 h; At 65 30percent hydrogen peroxide (1ml) was added 3- cyclopropylmethoxy-4-difluoromethoxy benzaldehyde (1.70g, 7mmol), 50percent potassium hydroxide (3.14g, 28mmol) and methanol ( 10ml) was prepared, stirred IH .. After completion of the reaction, water was added to dilute concentrated hydrochloric acid was adjusted to PH 2, there are a lot of white solid precipitated, filtered to give pure 3- cyclopropylmethoxy-4-difluoromethoxy-benzoic acid (z-7,1.75g yield97percent)
97.3% With sodium chlorite; aminosulfonic acid In water; acetic acid at 20℃; for 1 h; 24.2 g (100 mmol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde and 14.6 g (150 mmol) of aminoSulfonic acid was dissolved in 200 mL of glacial acetic acid and to the solution was slowly added 13.6 g (150 mmol) of sodium chlorite in 30 mL of water solubleThe reaction mixture was stirred at room temperature for 1 hour and then water was added to give a solid precipitate which was filtered, washed with pure waterDried to give 25.1 g of an off-white solid, yield 97.3percent
97% With sodium chlorite; aminosulfonic acid; acetic acid In water at 0 - 10℃; for 0.5 h; To the reaction flask, 240 mL of glacial acetic acid, 80 g (0.33 mol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde and 48 g (0.49 mol, 1.48 eq) of sulfamic acid were added to the reaction flask and cooled to 0-10 with stirring ° C, and then 53.4g (0.59mol, 1.78eq) of aqueous solution of 120mL sodium chlorite was added dropwise to the system. The temperature was controlled at 0-10 .After the addition was completed, the mixture was incubated for 0.5 h. Then 500 mL of water was added to the system and stirred at room temperature for 1 h. The solid was rinsed with water and dried to obtain 82.7 g of a white solid with a yield of 97percent and a purity of 99.8percent.
90.1% With manganese(IV) oxide; hypochloric acid In tetrahydrofuran; water at 48℃; 3) step 2) to give 3-cyclopropyl-methoxy-4-difluoromethoxy benzaldehyde (24.2g, 100mmol) and an oxidant (12.1 g of) the oxidation reaction, the oxidizing agent by a mass ratio of 4 : 1 MnO2 and HClO composition, the oxidationSolvent for the reaction by the volume ratio of 1: 5 composed of water and THF. The reaction temperature of the oxidation was 48 deg.] C, after the reaction, the reactionSolution was poured into ice-water, adjusted to pH 2, the filter cake was recrystallized from methanol to give 3-cyclopropyl-methoxy-4-difluoromethoxy-benzoicAcid, 23.3g, 90.1percent yield, purity of 99.68percent.
85% at 5 - 20℃; 40 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde 160 mL of glacial acetic acid and 32.0 g of sulphamic acid (2.0 eq) were loaded in a reactor. The mixture was cooled at 5-10°C and the temperature was not allowed to exceed 20°C, adding slowly a previously prepared solution of 44.77 g of sodium chloride and 61 mL of deionised water. After the addition, the reaction was kept for 1 hour at 15-20°C. 450 mL of deionised water was loaded and then it was cooled at 0-5°C and kept for 1 h at this temperature. The solid was filtered and washed four times with 200 mL of deionised water. The product was dried for 15 h at 40°C, obtaining 36 g (yield 85percent) of 3- (cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (II) as solid.
85%
Stage #1: at 20℃; for 0.5 h;
Stage #2: With sodium chlorite; aminosulfonic acid; sodium chloride In water at 5 - 20℃;
Acetic acid (20 mL) and 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (5.0 g, 0.02πο1) were added to the reaction flask and stirred at room temperature for 0.5 hour. Then, sulfamic acid (2.4 g, 0.025 mol, the reaction solution was cooled to 5 ° C and then 20 wtpercent aqueous sodium chlorite solution (11.2 g, containing sodium chloride 2.24 g, 0.025 mol) was added and then allowed to react at room temperature. TLC Methoxy-4-difluoromethoxybenzaldehyde was dissolved and quenched by the addition of water (100 mL). After stirring for 1 hour, the filter was washed with water and dried to give a white solid 3-cyclopropylmethoxy-4 - difluoromethoxybenzoic acid (4.5 g, yield 85percent, purity 98.6percent, HPLC chromatogram shown in Figure 4). The product was confirmed to be the target product 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid as shown in Figure 5
7.6 g With potassium permanganate; potassium carbonate In water; acetone at 60℃; for 1 h; To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMnO4 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60° C. for 1 h. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added, and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HCl 37percent (pH=1) and extracted twice with EtOAc. The organic phase was dried over Na2SO4 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83percent yield). This product was used without any further purification.
7.6 g With potassium permanganate In water; acetone at 60℃; for 1 h; To a solution of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (8.6 g, 35.5 mmol) in acetone (120 ml) and water (60 ml), KMn04 (13.1 g, 70.8 mmol) was added and the reaction was heated at 60°C for lh. K2CO3 (9 g, 65.2 mmol) and water (100 ml) were added and the resulting mixture was filtered through a celite pad. The filtrate was acidified with HC1 37percent (pH = 1) and extracted twice with EtOAc. The organic phase was dried over Na2S04 and the solvent was removed under vacuum affording 3-(cyclopropylmethoxy)-4- (difluoromethoxy)benzoic acid (7.6 g, 29.4 mmol, 83percent> yield). This product was used without any further purification.
0.51 kg at 70 - 80℃; for 3 h; Large scale 644 g of the compound of formula I and 3.15 kg of glacial acetic acid were added to the reaction flask,Dropping 0.92 kg of 30percent hydrogen peroxide; heating to 70 ° C for 1 hour,And then heated to 80 ° C for 2 hours or more; then cooled to 30 ° C,Slowly pour into 9.00kg of drinking water, precipitation of solid; cooling to 5-10 , adding 0.36kg sodium thiosulfate aqueous solution, stirring crystallization 0.5 hours, pumping, drying, drying,To give 0.51 kg of the compound of formula II.(HPLC purity 99.3percent, 0.1percent single impurities, 3,4 isomers less than 0.03percent).

Reference: [1] Patent: US2008/15226, 2008, A1, . Location in patent: Page/Page column 10
[2] Patent: CN105523954, 2016, A, . Location in patent: Paragraph 0025; 0027
[3] Patent: CN105254559, 2016, A, . Location in patent: Paragraph 0043; 0044
[4] Patent: CN103304408, 2016, B, . Location in patent: Paragraph 0038; 0039
[5] Patent: CN105523922, 2016, A, . Location in patent: Paragraph 0023; 0029; 0033
[6] Patent: WO2014/60464, 2014, A1, . Location in patent: Page/Page column 15
[7] Patent: CN106883118, 2017, A, . Location in patent: Paragraph 0038; 0049-0051
[8] Patent: WO2004/22536, 2004, A1, . Location in patent: Page 36-37
[9] Patent: US2013/79313, 2013, A1, . Location in patent: Paragraph 0966
[10] Research on Chemical Intermediates, 2013, vol. 39, # 5, p. 2107 - 2113
[11] Patent: WO2013/45280, 2013, A1, . Location in patent: Page/Page column 244
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[13] Patent: US2014/275551, 2014, A1, . Location in patent: Paragraph 0054
[14] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[15] Patent: CN106916061, 2017, A, . Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042
[16] Patent: CN102964297, 2018, B, . Location in patent: Paragraph 0020-0021; 0277; 0280
  • 2
  • [ 1895-39-2 ]
  • [ 162401-62-9 ]
YieldReaction ConditionsOperation in experiment
81.4%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5 h;
Stage #2: With water; sodium hydroxide In methanol at 50℃; for 2 h;
A solution of 2.1 g of anhydrous potassium carbonate was added to 10 mL Anhydrous N,N-dimethylformamide, and the temperature was raised to 100 °C. Under stirring, a solution of 2.22 g of 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester (V) was added to a solution of 3.05 g of sodium 2-chloro-2,2-difluoroacetate in 10 mL of anhydrous N,N-dimethylformamide solution was slowly added to the above reaction system. The reaction temperature was maintained and the reaction was stirred for 0.5 hour and then allowed to cool to room temperature. Add ethyl acetate, water, 50mL, shaking layered, The aqueous layer was extracted with 2X30 mL of ethyl acetate, the organic phases were combined, washed with water, Saturated brine, dried over anhydrous sodium sulfate, concentrate. The concentrated oily solution was dissolved in 10 mL of methanol, Add 3mol/L aqueous solution of sodium hydroxide 5mL, heated to 50 °C, The reaction was stirred for 2 hours. Concentrated under reduced pressure, with 6mol/L hydrochloric acid to adjust to strong acid to form a white precipitate, which was cooled to 5 °C for 2 hours, suction, washing, Dried to give 2.1 g of a white solid, 81.4percent yield.
Reference: [1] Patent: CN104177253, 2016, B, . Location in patent: Paragraph 0044; 0045
  • 3
  • [ 680184-55-8 ]
  • [ 124-38-9 ]
  • [ 162401-62-9 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With ethylmagnesium chloride In tetrahydrofuran; 1,2-dimethoxyethane for 1 h; Reflux
Stage #3: With hydrogenchloride In tetrahydrofuran; 1,2-dimethoxyethane; waterAcidic conditions
At room temperature, Ethylene glycol dimethyl ether (100 ml) was dissolved in compound (I) (0.1 mol, 29.3 g) in a 250 ml three-necked flask, A solution of ethylmagnesium chloride (EtMgCl, 0.11 mol) in THF was then added dropwise. After dripping, Heated to reflux for 1 hour, Then cooled to 20 ° C, Put into dry ice. After the reaction, The reaction solution was added with dilute hydrochloric acid to adjust to acidic, EtOAc (80 ml x 3) extraction, Anhydrous Na2SO4 dried, And then filtered and concentrated to give carboxylic acid compound (II) (24.5 g, yield 95percent).
Reference: [1] Patent: CN104513196, 2017, B, . Location in patent: Paragraph 0032; 0033; 0034; 0035; 0036; 0037; 0038-0041
  • 4
  • [ 151103-08-1 ]
  • [ 162401-62-9 ]
Reference: [1] Research on Chemical Intermediates, 2013, vol. 39, # 5, p. 2107 - 2113
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[3] Patent: WO2014/60464, 2014, A1,
[4] Patent: US2014/275551, 2014, A1,
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[6] Patent: CN105254559, 2016, A,
[7] Patent: CN102964297, 2018, B,
[8] Patent: US2013/79313, 2013, A1,
[9] Patent: WO2013/45280, 2013, A1,
  • 5
  • [ 139-85-5 ]
  • [ 162401-62-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 793 - 816
[2] Patent: US2014/275551, 2014, A1,
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 22, p. 7332 - 7339
[4] Patent: CN105254559, 2016, A,
[5] Patent: CN105523922, 2016, A,
[6] Patent: CN102964297, 2018, B,
  • 6
  • [ 4049-39-2 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN105523954, 2016, A,
[2] Patent: CN104177253, 2016, B,
  • 7
  • [ 1381886-14-1 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN105523954, 2016, A,
[2] Patent: CN104177253, 2016, B,
  • 8
  • [ 58123-77-6 ]
  • [ 162401-62-9 ]
Reference: [1] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
[2] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
  • 9
  • [ 157942-12-6 ]
  • [ 162401-62-9 ]
Reference: [1] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
[2] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
  • 10
  • [ 1392191-29-5 ]
  • [ 162401-62-9 ]
Reference: [1] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
[2] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
  • 11
  • [ 1243391-44-7 ]
  • [ 162401-62-9 ]
Reference: [1] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
[2] Synthesis (Germany), 2012, vol. 44, # 23, p. 3598 - 3602
  • 12
  • [ 25934-52-5 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN105523954, 2016, A,
  • 13
  • [ 121-33-5 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN106883118, 2017, A,
  • 14
  • [ 162401-70-9 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN106883118, 2017, A,
  • 15
  • [ 405-05-0 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN103304408, 2016, B,
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