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Product Details of [ 1086400-66-9 ]

CAS No. :	1086400-66-9	MDL No. :	MFCD16817392
Formula :	C₉H₁₂F₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	222.19	Pubchem ID :	-
Synonyms :

Safety of [ 1086400-66-9 ]

Signal Word:	Class:	N/A
Precautionary Statements:	UN#:	N/A
Hazard Statements:	Packing Group:	N/A

Application In Synthesis of [ 1086400-66-9 ]

* 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 [ 1086400-66-9 ]
Downstream synthetic route of [ 1086400-66-9 ]

[ 1086400-66-9 ] Synthesis Path-Upstream 1~1

1
[ 1086400-66-9 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

Reference： [1] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[2] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[3] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[4] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[5] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[6] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5-6
[7] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5
[8] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5-6
[9] Patent: EP1997808, 2008, A1, . Location in patent: Page/Page column 5

[ 1086400-66-9 ] Synthesis Path-Downstream 1~6

1
[ 352-24-9 ]
[ 122-51-0 ]
[ 1086400-66-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With acetic anhydride at 100℃; for 8.5h;	74.A Step A: Ethyl (Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate Ac2O (50 mL) was added to a mixture of ethyl 4,4-difluoro-3-oxobutanoate (10.0 g, 60.2 mmol) and triethoxymethane (18.3 g, 123 mmol) and the mixture was stirred at 100 C for 8.5 h. After this time the EtOAc was removed using a Dean-Stark trap apparatus to give the title compound (12 g, 90%) as a yellow gum.
86%	With acetic anhydride at 90 - 100℃; for 8.5h; Industry scale;	2 Ethyl (2Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxo-butanoate Add acetic anhydride (166 kg, 1625 mol) to a mixture of ethyl 4,4-difluoroacetoacetate (33 kg, 199 mol) and triethyl orthoformate (60 kg, 407 mol) maintained at 90-100° C. Stir the mixture at 90-100° C. for 8.5 hours and remove ethyl acetate using a Dean-Stark apparatus. Concentrate the reaction mixture to give the title compound (37.8 kg, 86% yield, 97% GC purity). 1H NMR (500 MHz, CDCl3,) δ 7.88 (d, J=6 Hz, 1H), 6.3 (m, 1H), 4.3 (m, 4H), 1.4 (m, 3H), 1.32 (m, 3H).
	With acetic anhydride at 110℃; for 4h;	1.C.1 C. 3-(DLFLUOROMETHYL)-L-(5-FLUORO-PYRIMIDIN-2-YL)-LH-PYRAZOLE-4-CARBOXYLIC ACID (ADAMANTAN-I -YLMETHYL)-AMIDE (COMPOUND 3); Step 1. Ethyl 3-(difluoromethyl)-lH-pyrazole-4-carboxylate; A mixture of ethyl 4,4-difluoro-3-oxobutanoate (4.65 g, 0.028 moles), acetic anhydride (8.0 g, 0.078 moles) and triethylorthoformate (7.3 g, 0.049 moles) is heated at 110 °C for 4 h. The mixture is concentrated under vacuum to afford (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate as yellow oil. The oil is dissolved in EtOH(25 mL) and cooled in an ice bath. To this cooled stirred mixture is added anhydrous hydrazine (0.7 mL, 0. 022 mole) and the mixture is allowed to warm gradually to RT overnight. The mixture is concentrated under vacuum and the crude product is purified by silica gel column chromatography using 1-2 % MeOH / CH2Cl2 to afford the title compound as a yellow solid.

	With acetic anhydride at 100℃; for 12h;	66.1 Step 1: Preparation of (Z)-ethyl2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate To a freshly prepared solution of sodium ethoxide (prepared by addition of 1.11 g, 48.35 mmol Na metal in 8 mL EtOH) in EtOH was added a solution of ethyl difluoroacetate (5.0 g, 40.29 mmol) in EtOAc (9 mL) at rt and the reaction mixture was heated at 65° C. for 2 h. Then the reaction mixture was quenched with 1N HCl at rt and the pH was adjusted to 6-7. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 5.5 g of ethyl 4,4-difluoro-3-oxobutanoate which was taken to the next step without further purification. To a mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.5 g, 33.11 mmol) and triethyl orthoformate (i2 mE, 66.26 mmol) was added acetic anhydride (27.0 g, 265.0 mmol) and the reaction mixture was heated at 100° C. for 12 h. Then the reaction mixture was concentrated to afford 5.5 g of the title product which was taken to the next step without further purification.
	With acetic anhydride at 100℃; for 12h;	1 Step 1 : Preparation of (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate To a freshly prepared solution of sodium ethoxide (prepared by addition of 1.1 1 g, 48.35 mmol Na metal in 8 mL EtOH) in EtOH was added a solution of ethyl difluoroacetate (5.0 g, 40.29 mmol) in EtOAc (9 mL) at rt and the reaction mixture was heated at 65 °C for 2 h. Then the reaction mixture was quenched with IN HCl at rt and the pH was adjusted to 6-7. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 5.5 g of ethyl 4,4-difluoro-3-oxobutanoate which was taken to the next step without further purification. To a mixture of ethyl 4,4- difluoro-3-oxobutanoate (5.5 g, 33.1 1 mmol) and triethyl orthoformate (12 mL, 66.26 mmol) was added acetic anhydride (27.0 g, 265.0 mmol) and the reaction mixture was heated at 100 °C for 12 h. Then the reaction mixture was concentrated to afford 5.5 g of the title product which was taken to the next step without further purification.
	With acetic anhydride for 4h; Heating / reflux;
	With acetic anhydride at 100℃; for 8h; Reflux;	3 Example 3: Synthesis of intermediate (Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoic acid ethyl es 61.2 g (0.6 mol) of acetic anhydride was added to the reaction flask.When heated to 100 ° C, 33.2 g (0.2 mol) was added dropwisea mixture of ethyl difluoroacetate and 44.4 g (0.3 mol) of triethyl orthoformate,After the completion of the dropwise addition, the reaction was refluxed for 8 hours.Rotary evaporator distillation to remove solvent(Z)-Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2020/36949, 2020, A1 Location in patent: Page/Page column 93
[2]Current Patent Assignee: ELI LILLY & CO; ROCHE HOLDING AG - US2012/302608, 2012, A1 Location in patent: Page/Page column 5
[3]Current Patent Assignee: MINDIMMUNE THERAPEUTICS - WO2009/12482, 2009, A2 Location in patent: Page/Page column 78
[4]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - US2013/210844, 2013, A1 Location in patent: Paragraph 0558; 0559
[5]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/167444, 2014, A1 Location in patent: Page/Page column 39
[6]Current Patent Assignee: BASF SE - WO2005/123690, 2005, A1 Location in patent: Page/Page column 20-21
[7]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN109232534, 2019, A Location in patent: Paragraph 0079; 0080; 0081

2
[ 1086400-66-9 ]
[ 60-34-4 ]
[ 141573-95-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; xylene; at 15 - 25℃; for 0.666667h;Product distribution / selectivity;	Example P1: Preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid using process steps a) and b1); organic solvent = xylene: Process step a): 300mmol of methylhydrazine (in the form of a 35%(w/w) aqueous solution) and 60mmol NaOH (in the form .of a 30%(w/w) aqueous solution) are dissolved in 75 g water (total amount of water is 19.7 equivalents relative to the compound of formula II). A solution of 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester in 90 g xylene (2.8 equivalents relative to the compound of formula II) is added during 30 minutes at 15C. The reaction mixture is stirred for 10 minutes at 25C.
	In water; xylene; at 20 - 25℃;	Example Pl : Preparation of ethyl 3-difluoromethyl-l-methyl-lH-pyrazole-4- carboxylateA 0.25 mol solution of methylhydrazine 40% diluted in 50.0 g xylene and 4.7 g water was prepared. A solution of 0.25 mol of 2-[l-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3- oxo-butyric acid ethyl ester in 100.0 g xylene was added to the methylhydrazine over 30-60 minutes at a temperature of 20-25 0C. The reaction mixture was stirred for 15 min. The phases of the reaction mass were separated.
	With sodium chloride; In water; xylenes; at 20℃;	Process steps d) and e): 69.1 g (0.525 mol) of methylhydrazine (in the form of a 35% (w/w) aqueous solution), 16.9 g (0.278 mol) of NaCI and 100 g of xylenes were initially charged and the mixture was tempered at 20C. Simultaneously, a solution of 1 19.6 g (92.9%; 0.5 mol) of 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester in 200 g of xylenes was prepared. The latter solution was added to the mixture of methylhydrazine, NaCI and xylenes at ca. 20C within 30 minutes. Afterwards the reaction mixture was stirred for 15 minutes at 20C. The lower aqueous phase was separated. The residual organic phase (420.9 g) comprised 19.0% by weight of the desired product (quantitative HPLC analysis)

Reference： [1]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[2]Patent: WO2010/130532,2010,A1 .Location in patent: Page/Page column 19
[3]Patent: WO2011/113789,2011,A1 .Location in patent: Page/Page column 17
[4]Patent: WO2005/123690,2005,A1 .Location in patent: Page/Page column 20-21

3
[ 1086400-66-9 ]
[ 60-34-4 ]
[ 176969-34-9 ]
[ 1204298-65-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.

		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.
		Example P2: Preparation of 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic acid using process steps a) and b1): various organic solvents: In Example P2, different solvents are tested. Besides using different solvents, all other reaction conditions are as described in Example P1 above. Yields and regioselectivity are measured on the stage of the anion of the compound of formula . being in aqueous solution, i.e. after isolation of the aqueous phase and before adding said aqueous phase to the HCl-solution. For example 2, the amount of base-solution in step a) was replaced by water. For comparative example C1 (no organic solvent) the amount of organic solvent in step a) was replaced by water and the 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester was added in pure form. For comparative example C2 the water-miscible organic solvent ethanol was used.

Reference： [1]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[2]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[3]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[4]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[5]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[6]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5-6
[7]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5
[8]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5-6
[9]Patent: EP1997808,2008,A1 .Location in patent: Page/Page column 5

4
[ 1086400-66-9 ]
[ 151733-96-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine In ethanol at 0 - 20℃;	1.C.1 C. 3-(DLFLUOROMETHYL)-L-(5-FLUORO-PYRIMIDIN-2-YL)-LH-PYRAZOLE-4-CARBOXYLIC ACID (ADAMANTAN-I -YLMETHYL)-AMIDE (COMPOUND 3); Step 1. Ethyl 3-(difluoromethyl)-lH-pyrazole-4-carboxylate; A mixture of ethyl 4,4-difluoro-3-oxobutanoate (4.65 g, 0.028 moles), acetic anhydride (8.0 g, 0.078 moles) and triethylorthoformate (7.3 g, 0.049 moles) is heated at 110 °C for 4 h. The mixture is concentrated under vacuum to afford (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate as yellow oil. The oil is dissolved in EtOH(25 mL) and cooled in an ice bath. To this cooled stirred mixture is added anhydrous hydrazine (0.7 mL, 0. 022 mole) and the mixture is allowed to warm gradually to RT overnight. The mixture is concentrated under vacuum and the crude product is purified by silica gel column chromatography using 1-2 % MeOH / CH2Cl2 to afford the title compound as a yellow solid.
	With hydrazine hydrate In methanol at 70℃; for 3h;	74.B Step B: Ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate To a solution of ethyl (Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (11 g, 49.5 mmol) in MeOH (100 mL) at 0 C was added N2H4.H2O (7.6 g, 149 mmol) dropwise and the mixture was stirred at 70 C for 3 h. After this time the mixture was concentrated in vacuo to give the title compound (10 g, crude) as yellow gum. MS (ESI): 190.9 [M + H]+.

Reference： [1]Current Patent Assignee: MINDIMMUNE THERAPEUTICS - WO2009/12482, 2009, A2 Location in patent: Page/Page column 78
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2020/36949, 2020, A1 Location in patent: Page/Page column 93

5
[ 1086400-66-9 ]
[ 77-78-1 ]
ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate [ No CAS ]
[ 141573-95-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 : One-pot preparation of ethyl 3-(difluoromethyl)-1-methyl-1 H-pyrazole-4- carboxylate (DFPE)A mixture of toluene (450 ml) and hydrazine monohydrate (48.8 g, 0.98 mol) was stirred at 15-2O0C. 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester (175.3 g, 91.5% strength, 0.72 mol) was fed over 2 hours via a syringe pump while maintaining the temperature at 15-2O0C. The reaction mass was held at 15-2O0C for additional 30 minutes to complete the reaction.The reaction mixture was then warmed to 3O0C to dissolve the solid product. The bottom aqueous phase was decanted off. The organic phase was washed with 2% HCI (50 ml) to remove residual hydrazine. The two aqueous phases were combined and extracted with toluene (50 ml). The toluene extract contains additional 3-4% yield of ethyl 3-difluoromethylpyrazole-4-carboxylate and was combined with the product solution.The toluene solution of crude ethyl 3-difluoromethylpyrazole-4-carboxylate was stirred and cooled to 2O0C. Water (260 ml), tetramethylammonium chloride (10% aqueous solution, 15.0 g), and 25% NaOH solution (36-60 g) were added in sequence. Dimethyl sulphate (99.5%, 94.5 g, 0.75 mol) and additional 25% NaOH were fed simultaneously over 2 hours at 2O0C while maintaining the pH between 10.5 and 12.0. After 2 hours post reaction, the bottom aqueous phase was separated off.After solvent was evaporated off, the crude reaction mass was vacuum distilled to afford 46.5 g of ethyl 5-(difluoromethyl)-1-methyl-1 H-pyrazole-4-carboxylate (iso-DFPE) as a distillation fraction. The distillation residue contains 86.3 g of DFPE and less than 1.0 g of iso-DFPE, and can be hydrolyzed directly to produce the corresponding acid.

Reference： [1]Patent: WO2011/12620,2011,A2 .Location in patent: Page/Page column 18

6
[ 1086400-66-9 ]
[ 422-62-8 ]
[ 1226890-49-8 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium ethanolate In ethanol; cyclohexane; water; ethyl acetate	Ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate Ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate A mixture of 1.62 g (10 mmol) of 2,2,3,3,3-pentafluoropropanimidamide and 2.22 g (10 mmol) of ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (for preparation see WO 2005/123690) in 10 ml of ethanol is stirred under reflux for 4 days after adding 0.68 g (10 mmol) of sodium ethylate. Concentration by evaporation in vacuo is then carried out and the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases are washed successively with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification with a mixture of cyclohexane and ethyl acetate gives 1.26 g of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate (40%) as a white solid. 1H-NMR (400 MHz, d6-DMSO): δ=9.58 (s, 1H), 7.49 (t, 1H), 4.45 (q, 2H), 1.38 (t, 3H) ppm. HPLC-MSa): log P=3.42; mass (m/z)=321 [M+H]+.
	With sodium methylate In ethanol; cyclohexane; water; ethyl acetate	Ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate Ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate A mixture of 1.620 g (10 mmol) of 2,2,3,3,3-pentafluoropropanimidamide (commercially available) and 2.222 g (10 mmol) of ethyl (2Z)-2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate (for preparation see WO 2005/123690) in 10 ml of absolute ethanol is stirred under reflux for 4 days after adding 0.680 g (10 mmol) of sodium methylate. The mixture is then concentrated by evaporation in vacuo and the residue is taken up in 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases are washed successively with 5 ml of water and 5 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification with a mixture of cyclohexane and ethyl acetate gives 1.264 g (3.95 mM, 39.5% of theory) of ethyl 4-(difluoromethyl)-2-(pentafluoroethyl)pyrimidine-5-carboxylate as a white solid. 1H-NMR (400 MHz, d6-DMSO): δ=9.58 (s, 1H), 7.49 (t, 1H), 4.45 (q, 2H), 1.38 (t, 3H) ppm.

Reference： [1]Current Patent Assignee: BAYER AG - US2011/301181, 2011, A1
[2]Current Patent Assignee: BAYER AG - US2011/301181, 2011, A1

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P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1086400-66-9 ] {[proInfo.proName]}

Quality Control of [ 1086400-66-9 ]

Related Doc. of [ 1086400-66-9 ]

Product Details of [ 1086400-66-9 ]

Safety of [ 1086400-66-9 ]

Application In Synthesis of [ 1086400-66-9 ]

[ 1086400-66-9 ] Synthesis Path-Upstream 1~1

[ 1086400-66-9 ] Synthesis Path-Downstream 1~6

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry