[ CAS No. 405-79-8 ] {[proInfo.proName]}

Name: 405-79-8|4-Fluorophenoxyacetic Acid|98%
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Quality Control of [ 405-79-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 405-79-8 ]

Product Details of [ 405-79-8 ]

CAS No. :	405-79-8	MDL No. :	MFCD00004304
Formula :	C₈H₇FO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZBIULCVFFJJYTN-UHFFFAOYSA-N
M.W :	170.14	Pubchem ID :	67882
Synonyms :		Chemical Name :	4-Fluorophenoxyacetic Acid

Calculated chemistry of [ 405-79-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.47
TPSA :	46.53 Å²

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) :	-6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.42
Log Po/w (XLOGP3) :	1.64
Log Po/w (WLOGP) :	1.71
Log Po/w (MLOGP) :	1.48
Log Po/w (SILICOS-IT) :	1.5
Consensus Log Po/w :	1.55

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.1
Solubility :	1.35 mg/ml ; 0.00794 mol/l
Class :	Soluble
Log S (Ali) :	-2.23
Solubility :	1.0 mg/ml ; 0.00589 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.19
Solubility :	1.1 mg/ml ; 0.00646 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.55

Safety of [ 405-79-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 405-79-8 ]

* 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 [ 405-79-8 ]

[ 405-79-8 ] Synthesis Path-Downstream 1~88

1
[ 111-87-5 ]
[ 405-79-8 ]
[ 1542-86-5 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 3708; engl. Ausg. S. 3664

2
[ 405-79-8 ]
[ 405-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; thionyl chloride; In toluene;	EXAMPLE 3 Preparation of Para-fluorophenoxyacetyl chloride STR18 Into a 100 ml round bottom flask equipped with a magnetic stirrer, reflux condenser equipped with a connector to a 50% sodium hydroxide trap, 6.81 g (0.040 mole) para-fluorophenoxyacetic acid (the product of Example 2), 2.96 ml (0.044 mole) thionyl chloride, and about 40 ml toluene were placed. The reaction mixture was stirred at reflux for two hours, allowed to cool to room temperature, and then concentrated to give 7.2 g of the product, a brown liquid.
	With sodium hydroxide; thionyl chloride; In toluene;	EXAMPLE 3: Preparation of STR16 Para-fluorophenoxyacetyl chloride Into a 100 ml round bottom flask equipped with a magnetic stirrer, reflux condenser equipped with a connector to a 50% sodium hydroxide trap, 6.81 g (0.040 mole) para-fluorophenoxyacetic acid (the product of Example 2), 2.96 ml (0.044 mole) thionyl chloride, and about 40 ml toluene. The reaction mixture was stirred at reflux for two hours, allowed to cool to room temperature, and then concentrated to give 7.2 g of the product, a brwon liquid.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;	To the solution of (4-fluorophenoxy)acetic acid (8.5 g, 0.05 mol) in anhydrous dichloromethane (120 ml) was added oxalyl chloride (8.9 ml, O.lmol) and DMF (0.02 ml). The reaction mixture was stirred at room temperature for 1 h and concentrated. The residue was dissolved in anhydrous dichloromethane (60 ml). To this solution was added piperazine (1.9 g, 22 mmol) and triethylamine (11 ml, 0.08 mol). The reaction mixture was stirred overnight. The precipitate was filtered out, washed with methanol, and dried to afford the title compound quantitatively (9.16 g) as a white solid. 1H-NMR 400MHz, (DMSOd6): delta 5.48 (d, 8H)3 4.85 (s, 4H), 6.95 (m, 4H), 7.1 l(m, 4H)

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3783 - 3805
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2006,vol. 181,p. 2135 - 2145
[3]Journal of the American Chemical Society,1955,vol. 77,p. 3924
[4]Journal of Medicinal Chemistry,1996,vol. 39,p. 1039 - 1048
[5]Journal of Medicinal Chemistry,2004,vol. 47,p. 2157 - 2165
[6]Tetrahedron,2004,vol. 60,p. 12231 - 12237
[7]Patent: US4620867,1986,A
[8]Patent: US4479900,1984,A
[9]Patent: WO2007/97871,2007,A2 .Location in patent: Page/Page column 14
[10]European Journal of Medicinal Chemistry,2009,vol. 44,p. 4726 - 4733
[11]Journal of Medicinal Chemistry,2010,vol. 53,p. 2038 - 2050
[12]Journal of Fluorine Chemistry,2012,vol. 142,p. 24 - 28
[13]Phosphorus, Sulfur and Silicon and the Related Elements,2013,vol. 188,p. 663 - 671
[14]Journal of Heterocyclic Chemistry,2015,vol. 52,p. 173 - 179
[15]Journal of Heterocyclic Chemistry,2016,vol. 53,p. 183 - 187
[16]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 1506 - 1513
[17]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3931 - 3938

3
[ 405-79-8 ]
[ 777-87-7 ]

Yield	Reaction Conditions	Operation in experiment
55 g (90%)	With sodium chloride; sulfuric acid; sodium hydrogencarbonate; In ethanol; hexane;	EXAMPLE 155 Preparation of ethyl-p-fluorophenoxy-acetate To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25 C. to give 55 g (90%) of the subject product as colorless crystals, mp 32-33 C.
55 g (90%)	With sodium chloride; sulfuric acid; sodium hydrogencarbonate; In ethanol; hexane;	EXAMPLE 155 Preparation of ethyl-p-fluorophenoxy-acetate To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25 C to give 55 g (90%) of the subject product as colorless crystals, mp 32-33 C.

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 3708; engl. Ausg. S. 3664
[2]Patent: US4170597,1979,A
[3]Patent: US4085272,1978,A

4
[ 405-79-8 ]
[ 2923-60-6 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

5
[ 405-79-8 ]
[ 399-41-7 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 3708; engl. Ausg. S. 3664
[2]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

6
[ 405-79-8 ]
[ 653-33-8 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

7
[ 405-79-8 ]
[ 1426-73-9 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 3708; engl. Ausg. S. 3664

8
[ 405-79-8 ]
[ 399-40-6 ]

Reference： [1]Zhurnal Obshchei Khimii,1959,vol. 29,p. 3708; engl. Ausg. S. 3664

9
[ 405-79-8 ]
[ 396-15-6 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

10
[ 405-79-8 ]
[ 100-35-6 ]
[ 351-69-9 ]

Reference： [1]Journal of the American Chemical Society,1956,vol. 78,p. 3121

11
[ 371-41-5 ]
[ 79-11-8 ]
[ 405-79-8 ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: Compounds B1-7 were prepared by similar procedures. In atypical synthesis of B1, monochloroacetic acid (0.04 mol,3.78 g) was dissolved in deionized water (15 mL) under thecondition of stirring and an ice bath. Then NaOH (25 %) wasadded dropwise until the pH value was adjusted to 9-10, thena solution of sodium chloroacetate was obtained. To a solutionof NaOH (0.03 mol, 1.20 g), deionized water (15 mL) andethanol (5 mL), phenol (0.04 mol, 3.76 g) was slowly addedunder stirring. After addition, the mixture was stirred for20 min, then the above sodium chloroacetate was addeddropwise, and heated to 105 C and refluxed for 5 h. Thereaction mixture was cooled to room temperature. The pHvalue of the mixture was acidified to 1-2 with diluted hydrochloricacid. The precipitate was filtered, washed with dilutedhydrochloric acid many times, and recrystallized and dried invacuum, resulting in a white solid product of thephenoxyacetic acid (B1)
52%		General procedure: A mixture of NaOH (0.04 mol, 1.60 g), deionized water (20 mL) and ethanol (20 mL) were poured into a 150 mL three-necked flask, then phenol (0.04 mol, 3.76 g) was slowly added under stirring. Twenty minutes later, the above sodium chloroacetate was added dropwise. The reaction solution was heated to 105 C and refluxed for 5 h. After cooling down, the pH value of the mixture was acidified to 1-2 with diluted hydrochloric acid. The precipitate was collected by filtration and washed with diluted hydrochloric acid many times. Recrystallized and dried under a vacuum, resulting in a white solid product of the phenoxyacetic acid (4a).
	With sodium hydroxide; In water;	General procedure: Equimolar quantities of 2-chloro acetic acid/3-chloro propionicacid (0.05 mol) and appropriate phenol (1a-q) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH(0.12 mol in 25 mL water) was slowly added with constant stirring.The solution was stirred for 2 h until the solution turned clear,brown or yellow and then the reaction mixture was evaporatedin a evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified byadding con. HCl. The precipitated aryloxy acetic/propionic acidwas filtered and recrystallized from water or ethanol

With sodium hydroxide; In water; at 85 - 90℃; for 2h;

General procedure: Overall the phenoxyacetic acids were commercially available, except for 4-methylphenoxyacetic acid and 4-methoxyphenoxyacetic acid. The latter phenoxyacetic acids were synthesized via a general synthetic route as described elsewhere [1,2,3]. In short, the appropriate substituted phenol (20 mmol) was added to anaqueous solution of NaOH (10 mL). Chloroacetic acid (34 mmol) was added and the reaction was heated (85-90 C) under reflux for 2 h and subsequently cooled to room temperature to yield a thick precipitation with a pH of 12. The reaction was acidified with concentrated HCl to a pH of 2 and extracted to diethyl ether (100 mL). The organic phase was extracted thrice with 100 mL of sodium carbonate solution (5%). The pooled aqueous phases were acidified to a pH of 2 with HCl to yield a precipitate. The desired phenoxyacetic acid was collected by filtration and left to dry overnight in the fume hood. Analytical pure samples were obtained after recrystallization from methanol.

Reference： [1]Journal of Fluorescence,2015,vol. 25,p. 849 - 859
[2]Luminescence,2015,vol. 30,p. 677 - 685
[3]European Journal of Organic Chemistry,2013,p. 4399 - 4404
[4]Journal of Molecular Structure,2014,vol. 1074,p. 487 - 495
[5]Journal of the American Chemical Society,1943,vol. 65,p. 1555
[6]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4597 - 4601
[7]European Journal of Medicinal Chemistry,2009,vol. 44,p. 4726 - 4733
[8]Bioorganic Chemistry,2015,vol. 59,p. 151 - 167
[9]Journal of Heterocyclic Chemistry,2016,vol. 53,p. 183 - 187
[10]Research on Chemical Intermediates,2016,vol. 42,p. 5269 - 5280
[11]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5951 - 5955

12
[ 67-56-1 ]
[ 405-79-8 ]
[ 55444-93-4 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1981,vol. 20,p. 629 - 631
[2]Journal of the Indian Chemical Society,1981,vol. 58,p. 1082 - 1083

13
[ 6921-64-8 ]
[ 405-79-8 ]
[ 345931-08-0 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1981,vol. 20,p. 1013 - 1015

14
[ 102-71-6 ]
[ 405-79-8 ]
[ 67026-07-7 ]

Reference： [1]Pharmaceutical Chemistry Journal,1986,vol. 20,p. 555 - 558
Khimiko-Farmatsevticheskii Zhurnal,1986,vol. 20,p. 952 - 956

15
[ 55444-93-4 ]
[ 405-79-8 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide monohydrate; In methanol; water; for 2h;Reflux;	General procedure: To a stirred solution of methyl ester (2a-i, 1 mmol) in MeOH-H2O (3 : 1, 4 mL) was added LiOH?H2O (2 mmol), and the resulting mixture was refluxed for 2 h. After cooling, the solvent was removed under reduced pressure, the residue was acidified with 10% HCl aq. The aqueous mixture was extracted with EtOAc (5 mL x 6), and the organic extracts were combined, dried over Na2SO4, and evaporated to give the carboxylic acid. To a stirred solution of amide (3a-n, 3' and 3'', 1 mmol) in CH2Cl2 (5 mL) was added TFA (8 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with satd. NaHCO2 aq., and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (5 mL x 10), and the organic layer and extracts were combined, dried over K2CO3, and evaporated to give the amine. To a stirred solution of the carboxylic acid prepared above in CH2Cl2 (5 mL) was added CDI (1 mmol), and the reaction mixture was stirred at room temperature for 1 h. To the mixture was added a solution of the amine prepared above in CH2Cl2 (2 mL), and the resulting solution was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (15 g, hexane : acetone = 5 : 1 ~ 3 : 1) to give substituted acetamide.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1982,vol. 21,p. 154 - 156
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3732 - 3735

16
[ 32376-34-4 ]
[ 79-11-8 ]
[ 405-79-8 ]

Reference： [1]Organic Mass Spectrometry,1993,vol. 28,p. 1167 - 1178

17
[ 405-79-8 ]
[ 908093-98-1 ]
(4-Fluoro-phenoxy)-acetic acid benzhydryl ester [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1981,vol. 20,p. 904 - 906

18
[ 405-79-8 ]
[ 2210-79-9 ]
1-<p-Fluor-phenoxyacetoxy>-3-<O-m-tolyloxy>-2-propanol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1968,vol. 11,p. 904 - 907

19
[ 116-02-9 ]
[ 405-79-8 ]
[ 58327-09-6 ]

Reference： [1]Arzneimittel-Forschung/Drug Research,1975,vol. 25,p. 1686 - 1692

20
[ 405-79-8 ]
[ 59-46-1 ]
[ 54393-10-1 ]

Reference： [1]Arzneimittel-Forschung/Drug Research,1975,vol. 25,p. 1686 - 1692

21
[ 405-79-8 ]
[ 75-03-6 ]
[ 777-87-7 ]

Reference： [1]Organic Preparations and Procedures International,1996,vol. 28,p. 480 - 483

22
[ 405-79-8 ]
[ 180048-73-1 ]
(4-fluoro-phenoxy)-acetic acid 2-(4-methanesulfonyl-phenyl)-1,1-dimethyl-2-oxo-ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3181 - 3186

25
[ 405-79-8 ]
[ 10034-85-2 ]
[ 371-41-5 ]

Reference： [1]Journal of the American Chemical Society,1958,vol. 80,p. 5960,5963
[2]Journal of the American Chemical Society,1958,vol. 80,p. 5960,5963

27
4-carboxymethoxy-benzenediazonium-tetrafluoroborate [ No CAS ]
[ 405-79-8 ]

Reference： [1]Patent: US2854479,1956,

28
[ 405-79-8 ]
1-[(4-methylphenyl)methyl]-6-ethylpiperazin-2-one [ No CAS ]
6-Ethyl-4-[2-(4-fluoro-phenoxy)-acetyl]-1-(4-methyl-benzyl)-piperazin-2-one [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2000,vol. 83,p. 1825 - 1845

29
[ 405-79-8 ]
[ 50-00-0 ]
[ 371-41-5 ]
[ 201230-82-2 ]

Reference： [1]International Journal of Chemical Kinetics,2001,vol. 33,p. 612 - 616

30
[ 2065-37-4 ]
[ 405-79-8 ]
2-bromo-3-(4-fluorophenoxymethyl)-1,4-naphthoquinone [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 5941 - 5946

31
[ 405-79-8 ]
[ 69833-09-6 ]
2-bromo-3-(4-fluorophenoxymethyl)-5-methoxy-1,4-naphthoquinone [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 5941 - 5946

32
[ 405-79-8 ]
[ 19685-09-7 ]
(4-fluoro-phenoxy)-acetic acid 4-ethyl-4-hydroxy-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-9-yl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3739 - 3741

33
[ 405-79-8 ]
[ 19685-09-7 ]
(4-fluoro-phenoxy)-acetic acid 4-ethyl-9-[(4-fluoro-phenoxy)-acetoxy]-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-4-yl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3739 - 3741

34
[ 405-79-8 ]
[ 78287-14-6 ]
(4-fluoro-phenoxy)-acetic acid 4-ethyl-4-hydroxy-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-11-ylmethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3739 - 3741

35
[ 405-79-8 ]
[ 78287-14-6 ]
(4-fluoro-phenoxy)-acetic acid 4-ethyl-11-[(4-fluoro-phenoxy)-acetoxymethyl]-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-4-yl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3739 - 3741

36
[ 405-79-8 ]
[ 710328-09-9 ]
2-(4-fluoro-phenoxy)-N-[4-methyl-2-(4-methyl-piperazin-1-yl)-quinolin-6-yl]-acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4099 - 4102

37
[ 777-87-7 ]
[ 405-79-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydroxide; In ethanol; water;Reflux;	General procedure: Compounds (3a-j,0.02mol) were dissolved in ethanol (15mL), sodium hydroxide (0.035mol) in water (5mL) was added, and the mixture was refluxed for 5-9h. The reaction mixture was cooled and acidified with 2N hydrochloric acid. The precipitate was filtered, washed with water, and finally recrystallized from methanol to afford desired compounds (4a-j). Compound (4a) is takenas a representative example to explain physical and characterization data.
	With potassium hydroxide; In ethanol; water;	EXAMPLE 2 Preparation of Para-fluorophenoxyacetic acid STR17 A mixture of ethyl para-fluorophenoxyacetate, the product of Example 1, (approximately 22.0 g (0.1 mole) and 20.0 g (0.3 mole) potassium hydroxide in 100 ml absolute ethanol was heated at reflux for three hours, cooled to room temperature and then stripped. The residue was taken up in 300 ml water. The aqueous solution was washed with 200 ml ether, acidified to give a pH of about 1 with concentrated hydrochloric acid and extracted a second time with ether. The second ethereal extract was washed with 200 ml water, dried with anhydrous magnesium sulfate and then concentrated to give 16.4 g of the product.
	With sodium hydroxide; In methanol; at 20℃; for 1h;	General procedure: To a stirred solution of 4j (2.5 g, 9.8 mmol) in MeOH (30 mL) was added 3N NaOH solution (13.1 mL, 39.3 mmol). After being stirred at room temperature for 1 h, the mixture was diluted with water (100 mL), acidified with 3N HCl, and extracted with dichloromethane (100 mL × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (2.12 g, 97% yield) . 1H NMR (300MHz, DMSO-d6) delta 7.49(d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H),4.73 (s, 2H).

Reference： [1]Biomedicine and Pharmacotherapy,2017,vol. 95,p. 375 - 386
[2]European Journal of Medicinal Chemistry,2018,vol. 143,p. 1826 - 1839
[3]Tetrahedron,2004,vol. 60,p. 12231 - 12237
[4]Journal of Medicinal Chemistry,2007,vol. 50,p. 1675 - 1684
[5]Patent: US4620867,1986,A
[6]Bulletin of the Korean Chemical Society,2010,vol. 31,p. 3826 - 3829
[7]Journal of Fluorine Chemistry,2012,vol. 142,p. 24 - 28
[8]Phosphorus, Sulfur and Silicon and the Related Elements,2013,vol. 188,p. 663 - 671
[9]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 3180 - 3186
[10]Journal of Medicinal Chemistry,2014,vol. 57,p. 7523 - 7535
[11]Journal of Heterocyclic Chemistry,2015,vol. 52,p. 173 - 179
[12]European Journal of Organic Chemistry,2015,vol. 2015,p. 2197 - 2204
[13]Bulletin of the Korean Chemical Society,2015,vol. 36,p. 2549 - 2552

38
C₄₆H₆₅NO₁₄ [ No CAS ]
[ 405-79-8 ]
C₅₄H₇₀FNO₁₆ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 9022 - 9023

39
[ 371-41-5 ]
[ 105-36-2 ]
[ 405-79-8 ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2006,vol. 181,p. 2135 - 2145

40
[ 4518-10-9 ]
[ 405-79-8 ]
[ 934593-99-4 ]

Yield	Reaction Conditions	Operation in experiment
88.5%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	To 4-Fluoro-acetic acid (150.1 mg, 0.88 mmol), the amine 5 (199.6 mg, 1.32 mmol), EDCHCl (253.1 mg, 1.32 mmol) and HOBt (179.7 mg, 1.32 mmol) in DMF (8 mL) was added DIPEA (0.23 mL, 1.32 mmol). The mixture was stirred overnight, and then partitioned between Ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (anhydrous MgSO4), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(4-Fluoro-phenoxy)acetylamino]-benzoic acid methyl ester as a white solid (236.1 mg, 88.5% yield). 1H-NMR (CDCl3) 8.37 (1H, s, NH), 8.07 (1H, nm, aromatic-H), 7.99 8.02 (1H, m, aromatic-H), 7.83 (1H, d, J=7.8 Hz, aromatic-H), 7.44 (1H, ps-t, J=7.8, aromatic-H), 7.02 7.08 (2H, m, aromatic-H), 6.93 6.97 (2H, m, aromatic-H), 4.59 (2H, s, CH2), 3.92 (3H, s, CH3).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1675 - 1684
[2]Patent: US2009/306078,2009,A1 .Location in patent: Page/Page column 24

41
4-amino-3-(2,4-dichloro-5-fluorophenyl)-5-mercapto-1,2,4-triazol-5-thiol [ No CAS ]
[ 405-79-8 ]
3-(2,4-dichloro-5-fluorophenyl)-6-[(4-fluorophenoxy)methyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2007,vol. 138,p. 1309 - 1316

42
[ 371-41-5 ]
[ 405-79-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1675 - 1684
[2]Tetrahedron,2004,vol. 60,p. 12231 - 12237
[3]Bulletin of the Korean Chemical Society,2010,vol. 31,p. 3826 - 3829
[4]Journal of Fluorine Chemistry,2012,vol. 142,p. 24 - 28
[5]Phosphorus, Sulfur and Silicon and the Related Elements,2013,vol. 188,p. 663 - 671
[6]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 3180 - 3186
[7]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3732 - 3735
[8]Journal of Medicinal Chemistry,2014,vol. 57,p. 7523 - 7535
[9]Journal of Heterocyclic Chemistry,2015,vol. 52,p. 173 - 179
[10]European Journal of Organic Chemistry,2015,vol. 2015,p. 2197 - 2204
[11]Bulletin of the Korean Chemical Society,2015,vol. 36,p. 2549 - 2552
[12]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5601 - 5603
[13]Biomedicine and Pharmacotherapy,2017,vol. 95,p. 375 - 386
[14]European Journal of Medicinal Chemistry,2018,vol. 143,p. 1826 - 1839

43
[ 405-79-8 ]
3-[2-(4-fluoro-phenoxy)-acetylamino]-benzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1675 - 1684

44
[ 405-79-8 ]
O,O-dimethyl α-(4-fluorophenoxyacetoxy)benzylphosphonate [ No CAS ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2006,vol. 181,p. 2135 - 2145

45
[ 405-79-8 ]
O,O-dimethyl α-(4-fluorophenoxyacetoxy)-3-nitrobenzylphosphonate [ No CAS ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2006,vol. 181,p. 2135 - 2145

46
[ 405-79-8 ]
4-(4'-fluorophenoxy)-but-2-ynenitrile [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 12231 - 12237

47
[ 405-79-8 ]
3-cyano-5-fluoro-2-methyl-benzofuran [ No CAS ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 12231 - 12237

48
[ 405-79-8 ]
[ 826990-48-1 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 12231 - 12237

49
[ 405-79-8 ]
[ 826990-54-9 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 12231 - 12237

50
[ 405-79-8 ]
[ 524713-99-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2157 - 2165

51
[ 405-79-8 ]
[ 524714-02-1 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2157 - 2165

52
[ 405-79-8 ]
(3R)-4-(4-fluorophenoxy)-3-hydroxy-1-butyne [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2157 - 2165

53
[ 405-79-8 ]
[ 524714-03-2 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2157 - 2165

54
[ 405-79-8 ]
2-fluoro-6H-naphtho[2,3-c]chromene-7,12-dione [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 5941 - 5946

55
[ 405-79-8 ]
2-fluoro-8-methoxy-6H-naphtho[2,3-c]chromene-7,12-dione [ No CAS ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 5941 - 5946

56
[ 405-79-8 ]
(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-1-[2-(4-fluoro-phenoxy)-acetyl]-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 1039 - 1048

57
[ 405-79-8 ]
(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-1-[2-(4-fluoro-phenoxy)-acetyl]-2-(4-methoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 1039 - 1048

58
[ 405-79-8 ]
[ 81293-30-3 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1981,vol. 20,p. 1013 - 1015

59
[ 405-79-8 ]
[ 345930-28-1 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1981,vol. 20,p. 1013 - 1015

60
[ 405-79-8 ]
[ 332-50-3 ]

Reference： [1]Journal of the American Chemical Society,1955,vol. 77,p. 3924

61
[ 405-79-8 ]
[ 588-57-8 ]

Reference： [1]Journal of the American Chemical Society,1955,vol. 77,p. 3924

62
[ 405-79-8 ]
[ 398-63-0 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

63
[ 459-60-9 ]
[ 405-79-8 ]

Reference： [1]Journal of the American Chemical Society,1939,vol. 61,p. 161,164

64
[ 459-26-7 ]
[ 405-79-8 ]

Reference： [1]Journal of the American Chemical Society,1939,vol. 61,p. 161,164

65
[ 405-79-8 ]
[ 7689-03-4 ]
[ 401478-41-9 ]

Yield	Reaction Conditions	Operation in experiment
76.7%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;	The mixture of camptothecin (30 mg, 0.086 mmol), 4-fluorophenoxyacetic acid (30 mg, 0.18 mmol), EDCI (60 mg, 0.31 mmol), DMAP (5 mg, 0.047 mmol) and dichloromethane (5 ml) was stirred at room temperature for 20 hours (h), then dichloromethane (20 ml) was added to the solution. The organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was separated by column chromatography (eluent: CHCl3:CH3OH 9:1) to afford 33 mg camptothecin-20-O-4-fluorophenoxyacetate, yield: 76.7%, mp 227-229 C. (dec.). The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz): delta 8.41 (s, 1H, Ar-H), 8.25 (d, 1H, Ar-H), 7.96 (d, 1H, Ar-H), 7.86 (t, 1H, Ar-H), 7.69 (t, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 6.97 (s, 2H, Ar-H), 6.88 (m, 2H, Ar-H), 5.68 (d, 1H, H17), 5.40 (d, 1H, H17), 5.29 (s, 2H, H5), 4.80 (q, 2H, OCH2CO), 2.25 (d, 2H, CH2), 0.97 (t, 3H, CH3).

Reference： [1]Patent: US6350756,2002,B1 .Location in patent: Page column 22-23

66
[ 405-79-8 ]
[ 518-28-5 ]
8-oxo-9-(3,4,5-trimethoxyphenyl)-5,5a,7,8,8a,9-hexahydrofuro[2′,3′:6,7]naphtho[2,3-d][1,3]dioxol-5-yl 2-(4-fluorophenoxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;	General procedure: Fibiric acids derivatives L1-L16 (0.015 mol), podophyllotoxin(0.01 mol), 4-dimethyaminopyridine (DMAP) (0.001mol) and N,N-dicyclohexylcarbodiimide (DCC) (0.02 mol)were dissolved in dichloromethane (30 mL) and stirred for12 h at room temperature. Then, a proper amount of silicagel were added and the solvent was condensed by vacuumconcentration. Finally, the target compounds were collectedby column chromatography (V(acetone): V(dichloromethane)= 1: 50). Chemical structures of the targetcompounds (M1-M16) were shown in Fig. 2. All the targetcompounds were reported for the first time.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;	Example 1; A. Podophyllotoxin-4-O-ester of 4-fluorophenoxyacetic acid (000615); The mixture of podophyllotoxin (20 mg, 0.048 mmol), 4-fluorophenoxyacetic acid (17 mg, 0.1 mmol), EDCI (40 mg, 0.21 mmol), DMAP (2 mg, 0.02 mmol) and dichloromethane (3 ml) were stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting liquid was separated by column chromatography (eluent: ethyl acetate and petroleum ether) to afford 12 mg podophyllotoxin-4-O-4-fluorophenoxyacetate, mp. [0154] The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz); delta 7.01 (t, 2H, Ar-H), 6.88 (q, 2H, Ar-H), 6.62 (s, 1H, Ar-H), 6.54 (s, 1H, Ar-H), 6.37 (s, 2H, Ar-H), 5.99 (d, 3H, OCH2O), 4.73 (q, 2H, COCH2O), 4.60 (d, 1H, H4), 4.34 (t, 1H, H11), 4.20 (t, 1H, H11), 3.81 (s, 3H, OCH3), 3.74 (s, 6H, OCH3), 2.95 (d, 1H, H2), 2.85 (m, 1H, H3).

Reference： [1]Medicinal Chemistry Research,2018,vol. 27,p. 351 - 365
[2]Patent: US2005/4169,2005,A1 .Location in patent: Page 9

67
[ 405-79-8 ]
[ 2731-16-0 ]
N-deacetyl-N-(4-fluorophenoxyacetyl)thiocolchicine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 10h;	The reaction mixture of N-deacetylthiocolchicine (24 mg, 0.053 mmol), 4-fluorophenoxyacetic acid (25.5 mg, 0.15 mmol), EDCI (25 mg, 0.13 mmol), DMAP (2 mg, 0.2 mmol) and dichloromethane (3 ml) was stirred at room temperature for 10 h. Then dichloromethane (20 ml) was added. Organic layer was washed with H2O, 5% Na2CO3 and brine, and then dried over MgSO4. After the solvent was removed under vaccum, the residue was separated by column chromatography (eluent: ethyl acetate and petroleum ether) to afford 21 mg N-Deacetyl-N-(4-fluorophenoxyacetyl)thiocolchicine, mp 200-203(dec.). [0221] The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz); delta 7.28 (d, 11H, Ar-H), 7.19 (s, 11H, H7), 7.05 (m, 4H, NH, Ar-H and H11), 6.90 (d, 11H, Ar-H), 6.54 (s, 111, H4), 4.70 (m, 1H, H7), 4.39 (q, 2H, COCH2O, 3.95 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 2.44 (s, 3H, SCH3), 2.60-1.80 (m, 4H, H5, 6).

Reference： [1]Patent: US2004/204370,2004,A1 .Location in patent: Page/Page column 10-11

68
[ 186581-53-3 ]
[ 405-79-8 ]
[ 55444-93-4 ]

Yield	Reaction Conditions	Operation in experiment
		Treatment of vinyl iodide 10 with sodium hydride in THF generates the corresponding sodium carboxylate, which is treated with t-butyllithium in diethyl ether at -78 C. generates a vinyllithium species that is trapped with N,N-dimethylformamide (DMF) to provide cis-enal 21 after workup. Horner-Emmons condensation of 21 with phosphonate 22 [prepared as follows: 1. 2-(p-fluorophenoxy)acetic acid, diazomethane (to form methyl 2-(p-fluorophenoxy)acetate); 2. (MeO)2P(O)CH3, n-butyllithium] using NEt3/LiCl in THF provides dienone 23, which is reduced to R alcohol acid 4 (R=H) using (-)-B-chlorodiisopinocampheylborane [(-)-Ipc2BCl] in THF at 0 C. Treatment of 4 (R=H) with either diazomethane or ethyl iodide/DBU provides 4 (R=CH3) and 4 (R=C2H5), respectively

Reference： [1]Patent: US2006/128803,2006,A1 .Location in patent: Page/Page column 4; 5

69
[ 189955-95-1 ]
[ 405-79-8 ]
[ 189955-02-0 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 163 (5R)-3-(4-Fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl) phenyl-5H-furan-2-one Following the procedure described in Example 1, Step 4, the title compound was prepared using (2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one (Example 117, Step 3) and 4-fluorophenoxy acetic acid. M.P.: 96.8-97.4 C. 1 H NMR (CD3 COCD3) delta 0.92 (3H, t), 1.77 (3H, s), 2.11 (2H, q), 3.14 (3H, s), 7.08-7.11 (4H, m), 7.9 (2H, d), 8.02 (2H, d).
		EXAMPLE 163 (5R)-3-(4Fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one Following the procedure described in Example 1, Step 4, the title compound was prepared using (2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one (Example 117, Step 3) and 4-fluorophenoxy acetic acid. M.P.: 96.8-97.4 C. 1 H NMR (CD3 COCD3) delta 0.92 (3H, t), 1.77 (3H, s), 2.11 (2H, q), 3.14 (3H, s), 7.08-7.11 (4H, m), 7.9 (2H, d), 8.02 (2H, d).
		EXAMPLE 163 (5R)-3-(4-Fluorophenoxy)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl-5H-furan-2-one Following the procedure described in Example 1, Step 4, the title compound was prepared using (2R)-2-hydroxy-2-methyl-1-(4-methylsulfonyl)phenylbutan-1-one (Example 117, Step 3) and 4-fluorophenoxy acetic acid. M.P.: 96.8-97.4 C. 1 H NMR (CD3 COCD3) delta 0.92 (3H, t), 1.77 (3H, s), 2.11 (2H, q), 3.14 (3H, s), 7.08-7.11 (4H, m), 7.9 (2H, d), 8.02 (2H, d).

Reference： [1]Patent: US5981576,1999,A
[2]Patent: US6020343,2000,A
[3]Patent: US5698584,1997,A

70
[ 405-79-8 ]
[ 189956-01-2 ]
[ 189955-05-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 166 (5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one Following the procedure described in Example 1, Step 4, the title compound was prepared using 2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone (Example 130, Step 2) and 4-fluorophenoxyacetic acid. M.P.: 104.7-107.0 C. 1 H NMR (CD3 COCD3) delta 1.94 (3H, s), 3.15 (3H, s), 3.27 (2H, m), 7.07-7.13 (4H, m), 7.98-8.04 (4H, m), M.S.: (CI, CH4) m/z 463 (M+H)+
		EXAMPLE 166 (5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one Following the procedure described in Example 1, Step 4, tie title compound was prepared using 2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone (Example 130, Step 2) and 4-fluorophenoxyacetic acid. M.P.: 104.7-107.0 C. 1 H NMR (CD3 COCD3) delta 1.94 (3H, s), 3.15 (3H, s), 3.27 (2H, m), 7.07-7.13 (4H, m), 7.98-8.04 (4H, m), M.S.: (CI, CH4) m/z 463 (M+H)+
		EXAMPLE 166 (5R)-3-(4-fluorophenoxy)-5-methyl-4-(4-methylsulfonyl)phenyl-5-(2,2,2-trifluoroethyl)-5H-furan-2-one Following the procedure described in Example 1, Step 4, the title compound was prepared using 2-(R)-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)-4,4,4-trifluoro-1-butanone (Example 130, Step 2) and 4-fluorophenoxyacetic acid. M.P.: 104.7-107.0 C. 1 H NMR (CD3 COCD3) delta 1.94 (3H, s), 3.15 (3H, s), 3.27 (2H, m), 7.07-7.13 (4H, m), 7.98-8.04 (4H, m), M.S.: (CI, CH4) m/z 463 (M+H)+

Reference： [1]Patent: US5981576,1999,A
[2]Patent: US6020343,2000,A
[3]Patent: US5698584,1997,A

71
[ 79-37-8 ]
[ 405-79-8 ]
[ 405-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	EXAMPLE 283 Preparation of 4-fluorophenoxyacetyl chloride A solution of 13.0 g. of 4-fluorophenoxyacetic acid and 15 ml. of oxalyl chloride in 80 ml. benzene-15 ml. tetrahydrofuran is stirred 19 hours. The solvent is removed and the residue is distilled (71-74 C., 0.2 mm) to give 13.1 g. of 4-fluorophenoxyacetyl chloride.

Reference： [1]Patent: US4039574,1977,A

72
[ 405-79-8 ]
[ 2924-66-5 ]

Yield	Reaction Conditions	Operation in experiment
	With diborane; In tetrahydrofuran; chloroform;	EXAMPLE 51 2-(4-fluorophenoxy)ethanol To 200 ml of 1 M diborane in tetrahydrofuran was added dropwise 17.0 L g of 4-fluorophenoxyacetic acid in 100 ml of tetrahydrofuran at 5-10 C. The reaction was stirred at room temperature overnight and poured into a mixture of 100 ml of ice and 750 ml of chloroform. The water phase was extracted twice more with 250 ml each of chloroform and the combined organic phase dried. This solution was concentrated to a light yellow oil. This material was placed on the Kugelrohr (vacuum distillation) giving 14.8 g on distillation.

Reference： [1]Patent: US4182776,1980,A

73
[ 79-37-8 ]
[ 405-79-8 ]
[ 90719-32-7 ]
[ 406701-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In hexane;	[Reference example 22 (a)] (S)-4-Benzyl-3-[(4-fluorophenoxy)acetyl]oxazolidin-2-one The target compound (2.76 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(a) using 4-fluorophenoxyacetic acid (1.70 g), oxalyl chloride (2.18 ml), (S)-4-benzyl-2-oxazolidinone (1.77 g) and a solution of n-butyl lithium in hexane (1.61N, 7.14 ml). mp: 113-115ØC 1H-NMR (270 MHz, CDCl3): delta (ppm) 2.85 (1H, dd, J=9.5, 13.5Hz), 3.36 (1H, dd, J=3.0, 13.5Hz), 4.26-4.38 (2H, m), 4.68-4.77 (1H, m), 5.21 (2H, s), 6.90-7.04 (4H, m), 7.20-7.38 (5H, m).

Reference： [1]Patent: EP1354602,2003,A1

74
[ 2759-28-6 ]
[ 405-79-8 ]
[ 255847-33-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With hydrogenchloride; thionyl chloride; triethylamine;palladium/carbon catalyst; In tetrahydrofuran; ethanol;	Example 61 Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)acetyl]piperazine Thionyl chloride (4 ml) was added to 4-fluorophenoxy acetic acid (3.52 g) and heated under reflux for 1 hour. The reaction mixture was evaporated, and the residual tetrahydrofuran (5 ml) solution was added under ice-cooling to a solution of 1-benzyl piperazine (3.65 g) and triethylamine (2.9 ml) in tetrahydrofuran (15 ml), followed by stirring for 1 hour at room temperature. The reaction mixture was dilutedwith ethyl acetate, washed with water, dried, and evaporated. The residue was dissolved in ethanol (60 ml), then conc. hydrochloric acid (3 ml) and 10% palladium/carbon catalyst (1.3 g) were added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was evaporated, basified with 2 N aqueous NaOH, and extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (4.09 g, 83 %) as a pale brown oil.

Reference： [1]Patent: EP1099692,2001,A1

75
[ 1023699-54-8 ]
[ 405-79-8 ]
[ 1023698-91-0 ]