Home Cart 0 Sign in  
X

[ CAS No. 1514-87-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
3d Animation Molecule Structure of 1514-87-0
Chemical Structure| 1514-87-0
Chemical Structure| 1514-87-0
Structure of 1514-87-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 1514-87-0 ]

Related Doc. of [ 1514-87-0 ]

Alternatived Products of [ 1514-87-0 ]

Product Details of [ 1514-87-0 ]

CAS No. :1514-87-0 MDL No. :MFCD00000775
Formula : C3H3ClF2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :AWUPLMYXZJKHEG-UHFFFAOYSA-N
M.W :144.50 Pubchem ID :73935
Synonyms :

Calculated chemistry of [ 1514-87-0 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.67
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 22.76
TPSA : 26.3 Ų

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) : -6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.56
Log Po/w (XLOGP3) : 0.85
Log Po/w (WLOGP) : 1.83
Log Po/w (MLOGP) : 0.89
Log Po/w (SILICOS-IT) : 1.29
Consensus Log Po/w : 1.28

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.14
Solubility : 10.5 mg/ml ; 0.0725 mol/l
Class : Very soluble
Log S (Ali) : -0.99
Solubility : 14.9 mg/ml ; 0.103 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.16
Solubility : 10.1 mg/ml ; 0.0698 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.3

Safety of [ 1514-87-0 ]

Signal Word:Danger Class:3,8
Precautionary Statements:P210-P280-P305+P351+P338-P310 UN#:2924
Hazard Statements:H225-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1514-87-0 ]

* 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 [ 1514-87-0 ]
  • Downstream synthetic route of [ 1514-87-0 ]

[ 1514-87-0 ] Synthesis Path-Upstream   1~28

  • 1
  • [ 1514-87-0 ]
  • [ 201230-82-2 ]
  • [ 76-04-0 ]
Reference: [1] RSC Advances, 2016, vol. 6, # 57, p. 51834 - 51844
  • 2
  • [ 1514-87-0 ]
  • [ 381-73-7 ]
  • [ 433-53-4 ]
  • [ 76-04-0 ]
Reference: [1] Patent: EP1574496, 2005, A1, . Location in patent: Page/Page column 2; 3
  • 3
  • [ 67-56-1 ]
  • [ 354-24-5 ]
  • [ 381-73-7 ]
  • [ 433-53-4 ]
  • [ 1514-87-0 ]
  • [ 76-04-0 ]
Reference: [1] Patent: EP1574496, 2005, A1, . Location in patent: Page/Page column 3; 4
  • 4
  • [ 1514-87-0 ]
  • [ 381-73-7 ]
  • [ 433-53-4 ]
  • [ 76-04-0 ]
Reference: [1] Patent: EP1574496, 2005, A1, . Location in patent: Page/Page column 2; 3
  • 5
  • [ 67-56-1 ]
  • [ 354-24-5 ]
  • [ 381-73-7 ]
  • [ 433-53-4 ]
  • [ 1514-87-0 ]
  • [ 76-04-0 ]
Reference: [1] Patent: EP1574496, 2005, A1, . Location in patent: Page/Page column 3; 4
  • 6
  • [ 404582-64-5 ]
  • [ 1514-87-0 ]
YieldReaction ConditionsOperation in experiment
67% at 200℃; for 2 h; Synthesis of methyl chlorodifluoroacetate (CH3O(CO)CF2Cl) from 1-chloro-1,1,2,2-tetrafluoro-2-methoxyethane (CH3OCF2CF2Cl): The reaction was carried out in the same manner as in Example 3, except that CH3OCF2CF2Cl was used as a starting material, to obtain 1.34 mmol (67percent) of CH3O(CO)CF2Cl.
Reference: [1] Patent: US2006/25639, 2006, A1, . Location in patent: Page/Page column 4
  • 7
  • [ 354-24-5 ]
  • [ 1514-87-0 ]
Reference: [1] Patent: US5405991, 1995, A,
  • 8
  • [ 598-99-2 ]
  • [ 1514-87-0 ]
  • [ 431-44-7 ]
Reference: [1] Chemistry Letters, 1987, p. 1145 - 1148
  • 9
  • [ 754-28-9 ]
  • [ 1514-87-0 ]
  • [ 404582-64-5 ]
Reference: [1] Journal of Fluorine Chemistry, 2001, vol. 112, # 1, p. 145 - 148
[2] Journal of Fluorine Chemistry, 2002, vol. 116, # 1, p. 65 - 69
  • 10
  • [ 404582-64-5 ]
  • [ 74-87-3 ]
  • [ 354-27-8 ]
  • [ 1514-87-0 ]
Reference: [1] Journal of Fluorine Chemistry, 2003, vol. 120, # 2, p. 131 - 134
  • 11
  • [ 67-56-1 ]
  • [ 1895-39-2 ]
  • [ 1514-87-0 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 113, # 1, p. 47 - 50
  • 12
  • [ 67-56-1 ]
  • [ 76-04-0 ]
  • [ 1514-87-0 ]
Reference: [1] Journal of Organic Chemistry, 1964, vol. 29, p. 1439 - 1444
[2] Journal of Organic Chemistry, 1978, vol. 43, p. 2643 - 2651
  • 13
  • [ 598-99-2 ]
  • [ 1514-87-0 ]
Reference: [1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 2796,2798; engl. Ausg. S. 2832
  • 14
  • [ 754-28-9 ]
  • [ 74-87-3 ]
  • [ 354-27-8 ]
  • [ 1514-87-0 ]
  • [ 404582-64-5 ]
Reference: [1] Journal of Fluorine Chemistry, 2003, vol. 120, # 2, p. 131 - 134
  • 15
  • [ 754-28-9 ]
  • [ 74-87-3 ]
  • [ 593-53-3 ]
  • [ 354-27-8 ]
  • [ 1514-87-0 ]
Reference: [1] Tetrahedron, 2001, vol. 57, # 19, p. 4111 - 4114
  • 16
  • [ 67-56-1 ]
  • [ 354-27-8 ]
  • [ 1514-87-0 ]
Reference: [1] Journal of the Chemical Society - Series Chemical Communications, 1992, # 11, p. 807 - 808
  • 17
  • [ 67-56-1 ]
  • [ 354-24-5 ]
  • [ 381-73-7 ]
  • [ 433-53-4 ]
  • [ 1514-87-0 ]
  • [ 76-04-0 ]
Reference: [1] Patent: EP1574496, 2005, A1, . Location in patent: Page/Page column 3; 4
  • 18
  • [ 1514-87-0 ]
  • [ 105-39-5 ]
  • [ 352-23-8 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 52, p. 7689 - 7690
[2] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 247
  • 19
  • [ 1514-87-0 ]
  • [ 609-73-4 ]
  • [ 384-22-5 ]
Reference: [1] Journal of Fluorine Chemistry, 1991, vol. 55, # 2, p. 225 - 228
  • 20
  • [ 1514-87-0 ]
  • [ 121-17-5 ]
  • [ 320-88-7 ]
Reference: [1] Journal of Fluorine Chemistry, 1994, vol. 66, # 2, p. 167 - 170
  • 21
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 percent) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); δH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1.
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10percent EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH(400 MHz, CDCl3) 6.60 (t, J= 72 Hz, 1H, OCHF2), 6.64(t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1H, H5), 7.76–7.78 (m, 2H, H2, H6),9.96 (s, 1H, CHO); δC (125MHz, CDCl3) 115.2 (t, J =259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21percent)as a colourless crystalline solid; mp 94–95 °C (recrystallized from EtOAc); δH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); δC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm–1.
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7673 - 7688
[2] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 35
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
  • 22
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
Reference: [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
  • 23
  • [ 1514-87-0 ]
  • [ 151103-08-1 ]
  • [ 127842-54-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 16, p. 2149 - 2152
  • 24
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
79.4% at 60 - 65℃; for 3 h; The 138.1g (1mol) 3,4- dihydroxybenzaldehyde was added to a concentration of 1L 7mol / L sodium hydroxide solution was added phase transfer catalyst tetrabutylammonium 16.6 g Ammonium, chloro-difluoro-acetic acid methyl ester 180.5g (1.3mol), stirred, solution was reacted at 60 -65 3 hours the reaction is complete, diluted with 1L of water and twice with 500mL ethyl acetate, the aqueous layer was collected, concentrated hydrochloric add was adjusted to pH 2 with 1.5L extracted three times with ethyl acetate, ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to dryness and the residue with petroleum ether - ethyl acetate (3: l) recrystallization, white crystals 149.4g, yield 79.4percent, 99.45percent purity.,
57% With caesium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 0.5 h; Microwave irradiation; Green chemistry Method (a): A suspension of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in an. DMF (15 mL) was stirred under nitrogen atmosphere for 10 min.
Then, Cs2CO3 (3.26 g, 10 mmol) and methyl chlorodifluoroacetate (1.73 g, 12 mmol) were added.
The mixture was stirred at 60-70 °C for 6 h.
After cooling to room temperature, the solution was poured into water (30 mL) and extracted with ethylacetate (3 * 20 mL), washed with brine (3 * 10 mL), dried (MgSO4) and concentrated under reduced pressure.
The obtained oil was purified by Silicagel (100-200 mesh) column chromatography using a mixture of ethylacetate/exane (15:85) as the eluent.
The pure product was obtained as a white solid. Yield: 39percent (lit.:15-30percent).
27
Mp: 86-88 °C.
Method (b):
The 4-(difluoromethoxy)-3-hydroxybenzaldehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaldehyde (0.415 g, 3 mmol)in an. DMF (5 mL), Cs2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate(0.520 g, 3.6 mmol) were added; then the mixturewas irradiated with microwaves, under pressure, increasing theemitted power until 300W in 2 min and at the same time coolingby compressed air to avoid the temperature increasing over 90 C; the irradiation was carried on for further 3 min and then the mixturewas cooled to room temperature, with compressed air, in1 min. The cycle was repeated five times for a total reaction timeof 30 min. The mixture was poured into water (100 mL) andextracted with ethyl acetate (3 20 mL); the organic phase waswashed with water (20 mL), brine (20 mL), dried (MgSO4) and concentratedunder reduced pressure, yielding a brown oil which waspurified by Silicagel (100–200 mesh) column chromatographyeluting with an ethylacetate/exane mixture (15:85). The pureproduct was obtained as a light gray solid. Yield: 57percent (lit. 15–30percent).27 Mp: 86–88 C. 1H NMR (CDCl3): d 6.05 (br s, 1H, OH, 1H disappearswith D2O), 6.65 (t, 1H, J = 72.6 Hz, OCHF2), 7.26 (d, 1H,J = 8.2 Hz, H-5 Ar), 7.45 (dd, 1H, J = 8.2 Hz, 2.0 Hz, H-6 Ar), 7.12(d, 1H, J = 2.0 Hz, H-2 Ar), 9.90 (s, 1H, CHN). IR (KBr) cm1:1687 (CO), 3305 (OH). Anal. C8H6F2O3 (C, H, N).
57% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 0.5 h; Microwave irradiation The 4-(difiuoromethoxy)-3-hydroxybenzaidehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3,4-dihydroxybenzaIdehyde (0.415 g, 3 mmol) in an. DMF (5 mL), CS2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate (0.520 g, 3.6 mmol) were added; then the mixture was irradiated with microwaves, under pressure, increasing the potency until 300 W in 2 minutes and cooling by compressed air to avoid the temperature increasing over 90 °C; the irradiation was carried on for further 3 minutes and then the mixture was cooled to room temperature, with compressed air, in 1 minute. The cycle was repeated five time for a total reaction time of 30 minutes, The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL); the organic phase was washed with water (20 mL), brine (20 mL), dried (MgS04) and concentrated under reduced pressure, yielding a brown oil which was purified by silicagel (100-200 mesh) column chromatography eluting with an ethylacetate /exane mixture (15:85). The pure product was obtained as a light grey solid. (0324) Yield; 57percent (lit.: 15-30percent). Mp: 86-88 °C. -NMR (CDC13): δ 6.05 (br s, IH, OH, 1H disappears with D20), 6.65 (t, J = 72.6 Hz, OCHF2)f 7.26 (d, J = 8.2 Hz, IH, H-5 Ar), 7.45 (dd, J = 8.2, 2.0 Hz, 1H( H-6 Ar), 7.12 (d, J = 2.0 Hz, H-2 Ar), 9.90 (s, IH, CH=N). IR (KBr) (cm's): 1687 (OO), 3305 (OH). Anal. (C8H6F203) C, H. (percent calculated/found) C: 51.07/ 50.96; H: 3.21/ 331.
38% With potassium carbonate In N,N-dimethyl-formamide EXAMPLE 10
Preparation of 4-difluoromethoxy-3-hydroxybenzaldehyde
3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol, Aldrich), methyl chlorodifluoroacetate (0.52 g, 3.62 mmol, Aldrich) and potassium carbonate (0.50 g, 3.62 mmol) were combined in DMF (5.0 mL) under an argon atmosphere.
After stirring at 60°-65° C. for 3 h, DMF was removed in vacuo and the residue was partioned between aqueous 3N HCl and ether.
The aqueous layer was extracted three times with ether.
The combined organic extracts were washed with water, with brine, were dried (MgSO4), filtered and evaporated.
The residue was purified by flash chromatography (silica gel, 25percent ethyl acetate/hexanes) to provide the title compound as a white solid (0.20 g, 38percent).
mp 83°-85° C.
33% With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 3 h; To a solution of 3,4-hydroxybenzaldehyde [1 (Figure2), 1.38 g, 10 mmol] in dimethylformamide (DMF) (20 mL)were added methyl chlorodifluoroacetate (1.39 mL, 13 mmol)and cesium carbonate (4.23 g, 13 mmol). After the mixturerhad been stirred at 70 °C for 3 h under an air atmosphere,DMF was removed in vacuo. The residue was portionedbetween aqueous 3 N HCl and ethyl acetate. Layers wereseparated, and the aqueous layer was extracted with ethylacetate (3 × 30 mL). Combined organic layers were washedwith brine, dried over Na2SO4, and concentrated in vacuo. Thecrude product was purified by flash chromatography (5:1hexane/EtOAc) to afford compound 2 (0.61 g, 33percent) as awhite solid: 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.45 (dd, J = 4.0, 8.4 Hz, 1H), 7.28 (d, J =8.4 Hz, 1H), 6.67 (t, J = 72.8 Hz, 1H), 6.17 (br s, 1H).

Reference: [1] Patent: CN105254559, 2016, A, . Location in patent: Paragraph 0035; 0036
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3426 - 3435
[3] Patent: WO2015/121212, 2015, A1, . Location in patent: Paragraph 46-47
[4] Patent: US5731477, 1998, A,
[5] Biochemistry, 2018, vol. 57, # 30, p. 4518 - 4525
[6] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 11, p. 1457 - 1461
[7] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 16, p. 2149 - 2152
  • 25
  • [ 1514-87-0 ]
  • [ 139-85-5 ]
  • [ 127842-54-0 ]
  • [ 151103-08-1 ]
YieldReaction ConditionsOperation in experiment
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3,4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 0C for 16 h and then diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCOs, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH (400 MHz, CDCI3) 6.60 (t, J = 72 Hz, 1 H, OCHF2), 6.64 (t, J = 72 Hz, 1 H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.76-7.78 (m, 2H, HZ, H6), 9.96 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.2 (t, J = 259 Hz), 1 15.4 (t, J = 259 Hz), 121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; vmax 794, 1038, 1381 , 1509, 1698, cm"1. Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21 percent) as a colourless crystalline solid; mp 94-95 0C (recrystallized from EtOAc); δH (500 MHz, CDCI3) 5.82 (s, 1 H, OH), 6.65 (t, J = 72.0 Hz, 1 H, CHF2), 7.27 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1 H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1 H, HZ), 9.92 (s, 1 H, CHO); δc (125 MHz, CDCI3) 115.6 (t, J = 259 Hz), 117.1 , 119.2, 123.1 , 134.6, 142.9, 147.8, 190.9; vmax 1087, 1237, 1508, 1592, 1686, 2859, 3313 cm"1.
13% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16 h; Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCO3, water, brine, dried and concentrated. Theresidue was purified by column chromatography, eluting with 10percent EtOAc/petrol togive 3,4-bis(difluoromethoxy)benzaldehyde (1.1 g, 13percent) as a colourless oil; δH(400 MHz, CDCl3) 6.60 (t, J= 72 Hz, 1H, OCHF2), 6.64(t, J = 72 Hz, 1H, OCHF2), 7.42 (d, J5,6 = 8.0 Hz, 1H, H5), 7.76–7.78 (m, 2H, H2, H6),9.96 (s, 1H, CHO); δC (125MHz, CDCl3) 115.2 (t, J =259 Hz), 115.4 (t, J = 259 Hz),121.5, 122.2, 128.5, 134.2, 142.4, 147.0 189.7; nmax 794, 1038, 1381, 1509, 1698, cm–1.Further elution provided 4-difluoromethoxy-3-hydroxybenzaldehyde (1.43 g, 21percent)as a colourless crystalline solid; mp 94–95 °C (recrystallized from EtOAc); δH (500 MHz, CDCl3)5.82 (s, 1H, OH), 6.65 (t, J = 72.0 Hz, 1H, CHF2), 7.27 (d, J5,6= 8.0 Hz, 1H, H5), 7.44 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.54 (d, J2,6 = 2.0 Hz, 1H, H2),9.92 (s, 1H, CHO); δC (125MHz, CDCl3) 115.6 (t, J =259 Hz), 117.1, 119.2, 123.1, 134.6, 142.9, 147.8, 190.9; nmax 1087, 1237, 1508, 1592, 1686,2859, 3313 cm–1.
Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7673 - 7688
[2] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 35
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
  • 26
  • [ 1514-87-0 ]
  • [ 121-33-5 ]
  • [ 162401-70-9 ]
YieldReaction ConditionsOperation in experiment
41% With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 16 h; Methyl chlorodifluoroacetate (1.4 ml_, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 ml_). The suspension was heated to 65-70 0C for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41 percent) as a colourless oil; δH (400 MHz, CDCI3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1 H, OCHF2), <n="39"/>7.30 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.45 (dd, J5,6 = 8.0, J = 2.0 Hz, 1 H, H6), 7.50 (d, J = 2.0 Hz, 1 H, HZ), 9.93 (s, 1 H, CHO); δc (100 MHz, CDCI3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
41% With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 16 h; Methyl chlorodifluoroacetate (1.4 mL, 13mmol) was added to a suspension of vanillin (15) (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) inDMF (10 mL). The suspension was heated to 65–70 °C for 16 h and the suspension was diluted with water. The aqueousphase was extracted with EtOAc and the combined organic fractions were washedwith saturated aqueous NaHCO3, water, brine, dried and concentrated.The residue was purified by column chromatography, eluting with 10percentEtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41percent) asa colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1H, OCHF2), 7.30 (d, J5,6= 8.0 Hz, 1H, H5), 7.45 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.50 (d, J2,6 = 2.0 Hz, 1H, H2),9.93 (s, 1H, CHO); δC (100MHz, CDCl3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0,134.5, 144.9, 151.5, 190.8. 
Reference: [1] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 37-38
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
[3] Patent: WO2009/98283, 2009, A1, . Location in patent: Page/Page column 131
  • 27
  • [ 1514-87-0 ]
  • [ 5326-34-1 ]
  • [ 154057-13-3 ]
YieldReaction ConditionsOperation in experiment
57% With potassium fluoride; copper(I) iodide In N,N-dimethyl-formamide Step A
2-Nitro-4-methylbenzotrifluoride
A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110° C. for 2 days.
The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate.
The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4.
The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57percent) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+).
400 MHz 1 H NMR (CDCl3) δ2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
Reference: [1] Patent: US5262412, 1993, A,
  • 28
  • [ 1514-87-0 ]
  • [ 4983-28-2 ]
  • [ 1192813-64-1 ]
YieldReaction ConditionsOperation in experiment
43% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h; To a solution of 93 mg (0.71 mmol) of 4-hydroxy-1-methyl piperidine in 1.0 ml of N,N-dimethylformamide, 0.28 g (0.86 mmol) of cesium carbonate and 0.32 mg (2.2 mmol) of methyl chlorodifluoroacetate were added, and the reaction solution was stirred at 100° C. for 1 hour.
After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate.
The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to provide 55 mg of the title compound as a colorless oil (yield: 43percent).
1H-NMR spectrum (500 MHz, CDCl3) δ ppm: 8.53 (2H, s), 6.62 (1H, t, J=71 Hz).
Reference: [1] Patent: US2013/109653, 2013, A1, . Location in patent: Paragraph 0817-0819
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 1514-87-0 ]

Fluorinated Building Blocks

Chemical Structure| 383-62-0

[ 383-62-0 ]

Ethyl 2-chloro-2,2-difluoroacetate

Similarity: 0.95

Chemical Structure| 76-04-0

[ 76-04-0 ]

Chlorodifluoroacetic acid

Similarity: 0.84

Chemical Structure| 1895-39-2

[ 1895-39-2 ]

Sodium 2-chloro-2,2-difluoroacetate

Similarity: 0.82

Fluorination Reagents

Chemical Structure| 2834-23-3

[ 2834-23-3 ]

Chlorodifluoroaceticanhydride

Similarity: 0.93

Chemical Structure| 1895-39-2

[ 1895-39-2 ]

Sodium 2-chloro-2,2-difluoroacetate

Similarity: 0.82

Aliphatic Chain Hydrocarbons

Chemical Structure| 383-62-0

[ 383-62-0 ]

Ethyl 2-chloro-2,2-difluoroacetate

Similarity: 0.95

Chemical Structure| 76-04-0

[ 76-04-0 ]

Chlorodifluoroacetic acid

Similarity: 0.84

Chemical Structure| 1895-39-2

[ 1895-39-2 ]

Sodium 2-chloro-2,2-difluoroacetate

Similarity: 0.82

Chlorides

Chemical Structure| 383-62-0

[ 383-62-0 ]

Ethyl 2-chloro-2,2-difluoroacetate

Similarity: 0.95

Chemical Structure| 76-04-0

[ 76-04-0 ]

Chlorodifluoroacetic acid

Similarity: 0.84

Chemical Structure| 1895-39-2

[ 1895-39-2 ]

Sodium 2-chloro-2,2-difluoroacetate

Similarity: 0.82

Esters

Chemical Structure| 383-62-0

[ 383-62-0 ]

Ethyl 2-chloro-2,2-difluoroacetate

Similarity: 0.95