[ CAS No. 149437-76-3 ] {[proInfo.proName]}

Name: 149437-76-3|5-(4-Fluorophenyl)-5-oxopentanoic acid|98%
Brand: Ambeed
SKU: A269940
Price: 8.0 USD
Availability: InStock
Rating: 96 (32 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 149437-76-3

Structure of 149437-76-3 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 149437-76-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 149437-76-3 ]

SDS Specification

Alternatived Products of [ 149437-76-3 ]

Product Details of [ 149437-76-3 ]

CAS No. :	149437-76-3	MDL No. :	MFCD00667222
Formula :	C₁₁H₁₁FO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZBQROUOOMAMCQW-UHFFFAOYSA-N
M.W :	210.20	Pubchem ID :	689096
Synonyms :

Calculated chemistry of [ 149437-76-3 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.27
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.79
TPSA :	54.37 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) :	-6.33 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.74
Log Po/w (XLOGP3) :	1.76
Log Po/w (WLOGP) :	2.68
Log Po/w (MLOGP) :	2.02
Log Po/w (SILICOS-IT) :	2.59
Consensus Log Po/w :	2.16

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.22
Solubility :	1.27 mg/ml ; 0.00605 mol/l
Class :	Soluble
Log S (Ali) :	-2.52
Solubility :	0.636 mg/ml ; 0.00302 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.22
Solubility :	0.127 mg/ml ; 0.000603 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.51

Safety of [ 149437-76-3 ]

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 [ 149437-76-3 ]

* 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 [ 149437-76-3 ]
Downstream synthetic route of [ 149437-76-3 ]

[ 149437-76-3 ] Synthesis Path-Upstream 1~5

1
[ 108-55-4 ]
[ 462-06-6 ]
[ 149437-76-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 0℃; for 0.5 h;	To a stirred suspension of aluminum chloride (205.85g, 1. 54MOL) in dichloromethane(500ML) was added a solution of glutaric anhydride (80g, 0. 7MOL) indichloromethane (125ML) at 0C. The reaction mass was stirred for30minutes and fluorobenzene (67.36g, 0. 7MOL) was added to the reactionmass slowly. The reaction was monitored for completion by TLC and thenpoured into ice cold water (2000ML) under stirring and the separatedsolids were collected by filtration. The solids were dissolved in 3percentaqueous sodium hydroxide solution (1100ML) and washed withdichloromethane (300ML). The aqueous layer was acidified to give aprecipitate. The solids were filtered and washed with water andvacuum-dried to yield the title product (125g, yield: 85percent). LHNMR(CDC13) 8 : 8.027-7. 98 (M, 2H), 7.17-7. 11 (M, 2H), 3.067 (t, 2H), 2.52(t, 2H), 2.14-2. 04 (M, 2H).
82%	Stage #1: at 15 - 30℃; for 5 h; Stage #2: at 0 - 20℃;	In a milliliter three-necked flask, 200 ml of fluorobenzene was added, Then aluminum trichloride (59.4 g, 0.45 mol) was added,And cooled to 15 ° C with an ice bath, Then, the solution of glutaric anhydride (30 g, 0.3 mol) in fluorobenzene (100 ml) was added dropwise at 15 ° C, After completion of the dropwise reaction at 30 ° C for 5 hours,Cold to about 0 deg C, Dropping 200 ml of 1 M hydrochloric acid, Note that the temperature during the dropwise process does not exceed 20 ° C. After completion of the dropwise addition, the reaction solution was added to a large amount of ice water, Precipitation of solids, filter, Wash the filter cake with steamed water, The filter cake was then added to 800 ml of saturated sodium bicarbonate solution and stirred at room temperature for 1 h, filter, The filtrate was added with activated carbon decolorization. Concentrated hydrochloric acid to adjust the PH value to 1, Solid precipitation, Filter and wash the filter cake with water, After drying, 51.7 g of white solid compound I, Yield 82percent.
79.3%	at 5 - 20℃; for 2.25 h;	EXAMPLES; Starting materials useful in the processes of the present invention can be made by the following procedures: Preparation of 4-(4-fluorobenzoyl)butyric acid; Charged 250 g of anhydrous AlCl₃(1.87 moles) to a 2 L 3-neck round bottom flask, added 300 mL fluorobenzene (307.5 g; 3.2 moles) and cooled the mixture in an ice bath to 5° C. Added a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintained the temperature below 12° C. The reaction mixture was warmed to ambient temperature gradually and agitated at r.t. for about 90 min.; checked for completion by NMR. Cooled the reaction mixture to 0 to 5° C., then added a cold aqueous solution (700 mL) of 1N HCl carefully to the mixture to destroy any unreacted AlCl₃, keeping the temperature of the mixture below 20° C. during the early part of the acid addition, and below 40° C. for the rest of the time. Poured the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filtered the white suspension and washed well with water. Added the white residue to 3 L of aqueous saturated solution (5percent) of NaHCO₃, heated the basic mixture on a steam bath for one hour and filtered the batch while hot through a thin pad of celite. Cooled the filtrate to r.t., added about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitated the white suspension in an ice bath for 30 min. Filtered the batch, washed the wet cake with ice cold water and dried in a vacuum oven at 50° C. for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142° C., isolated yield: 79.3percent.

79.3%	at 5 - 20℃; for 2.25 h;	Charge 250 g of anhydrous AlCl₃ (1.87 moles) to a 2 L 3-neck round bottom flask, add 300 mL fluorobenzene (307.5 g; 3.2 moles) and cool the mixture in an ice bath to 5°C. Add a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintain the temperature below 12°C. Warm the reaction mixture to ambient temperature gradually and agitate at r.t. for about 90 min.; check for completion by NMR. Cool the reaction mixture to 0 to 5°C, then add a cold aqueous solution (700 mL) of 1 N HCl carefully to the mixture to destroy any unreacted AlCl₃, keeping the temperature of the mixture below 20°C during the early part of the acid addition, and below 40°C for the rest of the time. Pour the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filter the white suspension and wash well with water. Add the white residue to 3 L of aqueous saturated solution (~5percent) of NaHCO₃, heat the basic mixture on a steam bath for one hour and filter the batch while hot through a thin pad of celite. Cool the filtrate to r.t., add about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitate the white suspension in an ice bath for 30 min. Filter the batch, wash the wet cake with ice cold water and dry in a vacuum oven at 50°C for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142°C, isolated yield: 79.3percent.
51%	Stage #1: With aluminum (III) chloride In dichloromethane at 8℃; for 0.5 h; Stage #2: at 20℃; for 19 h;	A flask was charged with AlCl3 (77.17 mmol, 10.29 g, 2.15 equiv) and dry CH2Cl2 (25 ml) under calcium chloride guard tube and the formed suspension was stirred on ice bath. Subsequently, a solution of glutaric anhydride 10 (35.8 mmol, 4.08 g) in dry CH2Cl2 (12 ml) was added dropwise (t < 8 °C). The resulting mixture was stirred on ice bath for 30 minutes and fluorobenzene 11c (35.1 mmol, 3.37 g, 1.0 equiv) was carefully added afterwards. The cooling bath was removed and the mixture was stirred at room temperature for 19 hours, then it was carefully quenched with ice water (20 ml), conc. H2SO4 (10 ml) and again with ice water (60 ml), the aqueous layer was extracted with ethyl acetate (1 x 200 ml, 1 x 100 ml, 1 x 70 ml), the combined organics were washed with half-saturated brine (200 ml), dried over Na2SO4, filtered and concentrated. The crude product was crystallized from ethyl acetate to provide 5-(4-fluorophenyl)-5-oxopentanoic acid (3.80 g, 51percent) as a yellow-brown powder;3 mp 141-142 °C; 1H NMR (300 MHz, CDCl3): δ = 2.08 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 7.13 (m, 2H), 7.99 (m, 2H). 5-(4-Fluorophenyl)-5-oxopentanoic acid (16.7 mmol, 3.50 g), paraformaldehyde (50.0 mmol, 1.50 g, 3.0 equiv) and piperidine (0.32 ml, 0.2 equiv) were dissolved/suspended in pyridine (15 ml) and stirred at 70 °C for 21 hours. Afterwards, the mixture was poured into 1M H2SO4 (340 ml), the aqueous layer was extracted with ethyl acetate (4 x 100 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EA/hexanes = 1/1 + 0.5percent AcOH). The obtained product was repeatedly coevaporated with toluene (4 x 25 ml) under reduced pressure to remove the residual AcOH, yielding 4-(4-fluorobenzoyl)pent-4-enoic acid 9c (3.33 g, 90percent) as an orange solid; mp 81-82 °C; 1H NMR (300 MHz, CDCl3): δ = 2.62 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 5.65 (s, 1H), 5.92 (s, 1H), 7.12 (dd, J = 8.7, 8.7 Hz, 2H), 7.78 (dd, J = 5.7, 8.7 Hz, 2H), 10.74 (bs, 1H); 13C NMR (75 MHz, CDCl3): δ = 27.3, 32.5, 115.3 (d, JCF = 21.8 Hz), 126.7, 132.0 (d, JCF = 9.0 Hz), 133.7, 145.9, 165.3 (d, JCF = 252.5 Hz), 178.9, 196.2
125 g	Stage #1: With aluminum (III) chloride In dichloromethane at 0℃; for 0.5 h;	To a suspension of aluminum chloride (205.85 g, 1.54 mol) in dichloromethane (500 mL) was added a solution of glutaric anhydride (80 g, 0.7 mol) in dichloromethane (125 mL) at 0° C. The reaction mixture was stirred for 30 minutes. Fluorobenzene (67.36 g, 0.7 mol) was then added slowly. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was poured into ice water (2000 mL) to precipitate a crude solid product, which was collected by filtration. The crude was re-dissolved in a 3percent aqueous sodium hydroxide solution (1100 mL). After being washed with dichloromethane (300 mL), the aqueous solution was acidified to obtain a solid product. The product was filtered, washed with water, and vacuum dried to yield compound 3 (125 g). H NMR of compound 3 (CDCl₃, 300M Hz): δ=2.10 (q, J=7.2 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 3.65 (t, J=7.2 Hz, 2H), 7.13 (t, J=7.4 Hz, 2H), 7.98 (q, J=5.4 Hz, 2H)
10 g	With aluminum (III) chloride In dichloromethane at 20℃;	25 gms of Aluminium chloride was added to 50 ml of dichloromethane and 4.5 ml of fluorobenzene. To this a solution of 50 ml of dichloromethane containing 10 gms of glutaric anhydride and 4.5 ml of fluorobenzene was added. Reaction mass was stirred at room temperature. After completion of reaction, reaction mass was quenched with ice& HCl solution at 0-10° C. Filtered the reaction mass. The obtained wet solid was dissolved in eq NaHCO₃solution at 60-70° C. and insoluable material was filtered. Cooled the filtrate and adjust pH to 2.0 by adding hydrochioric acid. Obtained solid was filtered and dried at 60-70° C. under vacuum to get 10 gm of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid.

Reference： [1] Patent: WO2004/99132, 2004, A2, . Location in patent: Page 7-8
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 15, p. 4424 - 4426
[3] Patent: CN106397292, 2017, A, . Location in patent: Paragraph 0053; 0083; 0084
[4] Patent: US2006/135755, 2006, A1, . Location in patent: Page/Page column 15
[5] Patent: EP1137634, 2005, B1, . Location in patent: Page/Page column 9
[6] Tetrahedron, 1993, vol. 49, # 15, p. 3193 - 3202
[7] Tetrahedron Letters, 2016, vol. 57, # 10, p. 1079 - 1082
[8] Patent: WO2003/104180, 2003, A1, . Location in patent: Page 6-8
[9] Patent: WO2003/104180, 2003, A1, . Location in patent: Page 9
[10] Patent: WO2007/17705, 2007, A1, . Location in patent: Page/Page column 12
[11] Patent: US2015/18565, 2015, A1, . Location in patent: Paragraph 0035; 0036; 0037
[12] Patent: US2016/280642, 2016, A1, . Location in patent: Paragraph 0056
[13] Patent: CN103694111, 2016, B, . Location in patent: Paragraph 0032-0035; 0042
[14] Chirality, 2018, vol. 30, # 5, p. 642 - 651

2
[ 53715-97-2 ]
[ 149437-76-3 ]

Yield	Reaction Conditions	Operation in experiment
79.3%	With hydrogenchloride; sodium hydrogencarbonate In fluorobenzene; water	Preparation of 4-(4-fluorobenzoyl)butyric acid: Charge 250 g of anhydrous AlCl₃ (1.87 moles) to a 2 L 3-neck round bottom flask, add 300 mL fluorobenzene (307.5 g; 3.2 moles) and cool the mixture in an ice bath to 5° C. Add a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintain the temperature below 12° C. Warm the reaction mixture to ambient temperature gradually and agitate at r.t. for about 90 min.; check for completion by NMR. Cool the reaction mixture to 0 to 5° C., then add a cold aqueous solution (700 mL) of 1N HCl carefully to the mixture to destroy any unreacted AlCl₃, keeping the temperature of the mixture below 20° C. during the early part of the acid addition, and below 40° C. for the rest of the time. Pour the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filter the white suspension and wash well with water. Add the white residue to 3 L of aqueous saturated solution (~5percent) of NaHCO₃, heat the basic mixture on a steam bath for one hour and filter the batch while hot through a thin pad of celite. Cool the filtrate to r.t., add about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitate the white suspension in an ice bath for 30 min. Filter the batch, wash the wet cake with ice cold water and dry in a vacuum oven at 50° C. for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142° C., isolated yield: 79.3percent.

Reference： [1] Patent: US6207822, 2001, B1,

3
[ 108-55-4 ]
[ 352-13-6 ]
[ 149437-76-3 ]

Reference： [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 9, p. 2723 - 2730

4
[ 99395-88-7 ]
[ 149437-76-3 ]
[ 189028-93-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; dicyclohexyl-carbodiimide In dichloromethane	Example 1: Preparation of ezetimibe; (1-1) Preparation of 3-[5-(fluorophenyl)-l,5-dioxapentyl]-4(S)- phenyl-2-oxazolidinone (Formula 7); 200 g of 5-(4-fluorophenyl)-5-oxopentanoic acid of formula 8, 16O g of (S)-4-phenyloxazolidine-2-one of formula 9, and 11.6 g of 4-dimethylaminopyridine were dissolved in 600 m.pound. of dichloromethane to prepare a reaction mixture. A solution which was prepared by dissolving 157 g of N,N'-dicyclohexylcarboimide in 200 ml of dichloromethane was added to the reaction mixture and stirred for 2 hours. After completion of the reaction, the resulting reaction mixture was filtered to remove by-products. The filtrate thus obtained was washed successively with 1 I of 6N HCl, 1 .euro. of water, and 1 .euro. of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 2 I of methanol by heating and cooled to induce crystallization. 2 .pound. of water was added thereto and stirred for 30 min. The solid thus obtained was isolated by filtering to obtain 289 g of the title compound as a white solid (yield: 86percent).¹H NMR(300MHz, CDCl₃) : δ 7.92 (2H, M), 7.35-7.13 (5H, m), 7.04 (2H, m), 5.43 (IH, q), 4.75(1H, t), 4.22 (IH, q), 3.05-2.93 (4H, m), 2.03 (2H, m)
85.7%	Stage #1: With dmap; pivaloyl chloride In N,N-dimethyl-formamide at 2 - 20℃; for 1.5 h; Stage #2: at 30 - 35℃; for 2 h;	5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino- pyridine (16.25 g, 133.0 mmol) were dissolved in N,N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2 ⁰C (ice/water bath), and trimethylacetyl chloride (16.40 mL, 16.04 g, 133.0 mmol) was added drop-wise to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature at or below 5 ⁰C. A heavy white precipitate was formed and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was charged with (6)-(+)-4-phenyl-2- oxazolidinone (16.32 g, 100.0 mmol) and 4-dimethylaminopyridine (12.22 g, 100.0 mmol) both as solids to afford a yellow colored suspension. The reaction was stirred at 30 °C - 35 ⁰C for 2 h. An aliquot was removed for analysis by TLC and HPLC. The pale olive colored suspension was poured into water (400 mL) while stirring vigorously and cooling the mixture in an ice-brine bath, transferred with water (150 mL) and stirred with ice-cooling for 1.5 h to afford a solution with an off-white precipitate. The compound was filtered, transferred with water (2 x 25 mL), washed with water (50 mL) and air dried for 15 min to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (58.0 mL; 1.6 mL/g theoretical yield) by heating to near reflux to afford a golden yellow colored solution. The solution was cooled slowly to room temperature over 12 h, a seed crystal was added and crystals began to precipitate. The mixture was cooled in an ice/water bath and stirred for 1 h. The crystals were filtered, transferred with cold isopropanol (2 x 10 mL), washed with cold isopropanol (25 mL), air dried and vacuum dried to constant weight to afford (45)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-l,3- oxazolidin-2-one (30.46 g, 85.7 percent yield) as a white crystalline solid; m.p. 91.0 ⁰C; EPO <DP n="43"/>R/ 0.40 (1:2 ethyl acetate-hexane); HPLC R_r7.02 min; HPLC purity 94 percent. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (dd, J= 5.4, 9.0 Hz, 2H), 7.28-7.42 (m, 5H), 7.10 (dd, J= 8.5, 9.0 Hz, 2H), 5.43 (dd, J= 3.7, 8.7 Hz, IH), 4.70 (t, J= 8.9 Hz, IH), 4.28 (dd, J= 3.7, 8.7 Hz, IH), 3.05 (dt, J= 1.2, 7.3 Hz, 2H), 2.97 (t, J= 7.3, 2H), 2.05 (p, J= 7.3 Hz, 2H), ppm.
85%	Stage #1: With pivaloyl chloride; triethylamine In tetrahydrofuran at -10℃; for 4 h; Inert atmosphere Stage #2: With lithium chloride In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere	To the soulution of compound 2 (700 g, 3.33 mol, 1.1 eq) dissolved in THF (5 L) was added triethylamine (1.2 L, 7.87 mol, 2.6 eq) at room temperature under N₂ atmosphere. Then the solution of pivalic acid chloride (400 g, 3.33 mol, 1.1 eq) in THF (700 mL) was added dropwise to the reaction mixture cooled to -10 °C for about 2 h. After addition, the mixture was stirred for 2 h at this temperature. TLC showed the compound 2 was consumed up, then the Evans auxiliary (493.5 g, 3 mol, 1 eq) and anhydrous LiCl (150.5 g, 3.5 mol,1.17 eq) were added sequencely. The mixture was warmed to room temperature and stirred for 2 h till the anhydride intermediate was consumed up. Then ethylacetate (2 L) and NH₄Cl aq (1 L) were added, stirred for 15 min, stayed and separated, the aqueous layer was extracted with ethyl acetate (500 mL×2), combined the organic phase, washed with water (250 mL ×2), concentrated.The residue was recrystallized from isopropanol (7 L) to afforded compound 4 as a white solid (913.6 g, 85.0percent yield). HPLC purity: 99.2percent, mp: 94-95 °C [lit.^9(b) 91°C]. ¹H-NMR (CDCl₃,400 MHz): δ 7.94-7.93 (m, 2H, J=2), 7.40-7.29 (m, 5H), 7.10-7.01 (m, 2H), 5.45-5.41 (m, 1H), 4.72-4.63 (m, 1H), 4.30-4.27 (m, 1H), 3.06 (t, 2H, J=8), 2.97 (t, 2H, J=12), 2.10-2.03 (m, 2H). ¹³C-NMR (CDCl₃, 100MHz): δ 197.7, 172.2, 167.0, 164.4, 153.8, 139.2, 133.3, 130.7, 130.6, 129.2, 128.7, 126.0, 115.7, 115.5, 70.1, 57.6, 37.3, 34.8, 18.5. MS (ESI) m/z calcd. for C₂₀H₁₈FNO₄: 355.12, calcd. for C₂₀H₁₈FNO₄Na (M+Na)=378.12, found 378.04 (M+Na).

70%	Stage #1: With pivaloyl chloride; triethylamine In dichloromethane Stage #2: With dmap In dichloromethane; N,N-dimethyl-formamide for 13 h; Reflux	Compound I (21 g, 0.1 mol) was added to a 500 ml three-necked flask, Triethylamine 20 ml and dichloromethane 250 ml, Stuttgart dropwise pivaloyl chloride (14.4g, 0.12mol), (4S) -4-phenyl-2-oxazolidinone (24.5 g, 0.15 mol), DMF 5 ml, 4,4-dimethylaminopyridine (1.22 g, 0.01 mol) was added after refluxing for 3 h, After refluxing for 10 h, Ice bath cooling, Then, 200 ml of 5 M hydrochloric acid was added dropwise at 0 ° C, Static stratification, The lower methylene chloride layer was washed successively with saturated sodium bicarbonate solution and water, Dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, To give 24.9 g of a white solid compound II, Yield 70percent.
68%	Stage #1: With pivaloyl chloride; triethylamine In dichloromethane at 5 - 10℃; for 2.5 h; Stage #2: With dmap In dichloromethane; N,N-dimethyl-formamide at 15 - 45℃; for 3 h;	The compound (4) (30 g, 142.72 mmol) Triethylamine (26 g, 256.91 mmol) was dissolved in dichloromethane (150 ml)Cooling to 5 to 10 ° C, dropwise addition of pivaloyl chloride (17.3g, 142.62mmol), System has exothermic, 30min drop finished,5 to 10 deg C insulation reaction 2h, To the reaction system was added (S) -4-phenyl-2-oxazolidinone (23.3 g, 142.76 mmol) DMAP (2.4 g, 19.63 mmol), DMF (15 ml),Exothermic The temperature rose to 15 ° C, Heated to 45 reflux reaction 3h, Down to room temperature, Plus dichloromethane (150 ml), The organic phase was washed with water (60 ml) 1N hydrochloric acid (120 ml) Water (60ml) 2.5percent aqueous sodium hydroxide solution (180 ml) Add water (50ml) wash, Organic phase concentrated dry, Plus isopropyl alcohol (60 ml), Stirring for 24 h, Filter, Add isopropyl alcohol (10ml) leaching, To give a white solid, I.e. compound (5) (34.4 g, 68percent yield).

Reference： [1] Patent: WO2010/71358, 2010, A2, . Location in patent: Page/Page column 14-15
[2] Patent: WO2006/122216, 2006, A2, . Location in patent: Page/Page column 41-42
[3] Synthetic Communications, 2016, vol. 46, # 20, p. 1687 - 1693
[4] Patent: CN106397292, 2017, A, . Location in patent: Paragraph 0053; 0086; 0087
[5] Patent: CN104513187, 2017, B, . Location in patent: Paragraph 0063; 0064; 0065; 0066

5
[ 3282-30-2 ]
[ 149437-76-3 ]
[ 186343-35-1 ]
[ 189028-93-1 ]

Yield	Reaction Conditions	Operation in experiment
85.7%	Stage #1: With dmap In N,N-dimethyl-formamide at 2 - 20℃; for 1.5 h; Stage #2: With dmap In N,N-dimethyl-formamide at 30 - 35℃; for 2 h;	Step 1A. Preparation of (4S)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3 -oxazolidin-2-one (A1 R⁶=phenyl); 5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino-pyridine (16.25 g, 133.0 mmol) were dissolved in N,N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2° C. (ice/water bath), and trimethylacetyl chloride (16.40 mL, 16.04 g, 133.0 mmol) was added drop-wise to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature at or below 5° C. A heavy white precipitate was formed and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was charged with (s)-(+)-4-phenyl-2-oxazolidinone (16.32 g, 100.0 mmol) and 4-dimethylaminopyridine (12.22 g, 100.0 mmol) both as solids to afford a yellow colored suspension. The reaction was stirred at 30° C. -35° C. for 2 h. An aliquot was removed for analysis by TLC and HPLC. The pale olive colored suspension was poured into water (400 mL) while stirring vigorously and cooling the mixture in an ice-brine bath, transferred with water (150 mL) and stirred with ice-cooling for 1.5 h to afford a solution with an off-white precipitate. The compound was filtered, transferred with water (2.x.25 mL), washed with water (50 mL) and air dried for 15 min to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (58.0 mL; 1.6 mL/g theoretical yield) by heating to near reflux to afford a golden yellow colored solution. The solution was cooled slowly to room temperature over 12 h, a seed crystal was added and crystals began to precipitate. The mixture was cooled in an ice/water bath and stirred for 1 h. The crystals were filtered, transferred with cold isopropanol (2.x.10 mL), washed with cold isopropanol (25 mL), air dried and vacuum dried to constant weight to afford (4S)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (30.46 g, 85.7percent yield) as a white crystalline solid; m.p. 91.0° C.; R_f0.40 (1:2 ethyl acetate-hexane); HPLC R_T7.02 min; HPLC purity 94percent. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (dd, J=5.4, 9.0 Hz, 2H), 7.28-7.42 (m, 5H), 7.10 (dd, J=8.5, 9.0 Hz, 2H), 5.43 (dd, J=3.7, 8.7 Hz, 1H), 4.70 (t, J=8.9 Hz, 1H), 4.28 (dd, J=3.7, 8.7 Hz, 1H), 3.05 (dt, J=1.2, 7.3 Hz, 2H), 2.97 (t, J=7.3, 2H), 2.05 (p, J=7.3 Hz, 2H), ppm.

Reference： [1] Patent: US2008/287663, 2008, A1, . Location in patent: Page/Page column 23

[ 149437-76-3 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 149437-76-3 ]
[ 149437-67-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; for 1h;Reflux;	To a flask were added 3 g of compound 3, 30 mL of methanol, and 0.25 mL of concentrated H2SO4. After the resultant solution was heated to reflux for 1 hour, it was cooled and then concentrated to 1/5 of its volume. Ethyl acetate (100 mL) was added. The mixture was washed with a saturated NaHCO3 aqueous solution and a brine solution. The ethyl acetate layer was separated and concentrated to dryness to give compound 4 in 100% yield. HNMR of compound 4 (CDCl3, 300M Hz): delta=2.01 (q, J=7.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H), 3.68 (s, 3H), 7.13 (t, J=8.7 Hz, 2H), 7.99 (q, J=5.4 Hz, 2H)
84%	sulfuric acid; for 16h;Heating / reflux;	Methyl 5- (4-fluorophenyl)-5-oxopentanoate To a solution of 5- (4-FLUOROPHENYL)-5-OXOPENTANOIC acid (3.0 g, 14.3 mmol) in dry MEOH (50 ml) was added concentrated sulfuric acid (50 mg) and the mixture refluxed under nitrogen for 16 H. THE bulk of the MeOH was removed by rotary evaporator and the residue treated with sodium bicarbonate solution (5%, 100 ml) and extracted with ethyl acetate (3X50 ml). The organic extract was washed with water (1X100 ml), brine (1X100 ml), dried (NA2SO4) and evaporated to give methyl 5- (4-FLUOROPHENYL)-5-OXOPENTANOATE (2. 69 g, 84%) as a white crystalline solid.
80%	With hydrogenchloride;	The 4-fluoro-(4-benzoyl) butyric acid (100G, 0. 476MOL) obtained inexample 1 was dissolved in 1050ML OF METHANOL and 100ml of 16% methanolhydrochloric acid was added. The reaction was monitored to completion byTLC and the solvent was evaporated under vacuum. The residue wastaken-up in 400ML dichloromethane and washed twice with 250ML of 5%sodium bicarbonate solution and then with 500ML of saturated brinesolution. The organic layer was dried over sodium sulfate and evaporatedto dryness under reduced pressure. The residue was crystallized fromethyl acetate and hexane to yield the pure product (85. 7g, yield: 80%).1H-NMR (CDC13) B : 8.01-7. 97 (M, 2H), 7.15-7. 10 (M, 2H), 3.66 (s, 3H),3.03 (t, 2H), 2.45 (t, 2H), 2.11-2. 02 (M, 2H).

Reference： [1]Patent: US2015/18565,2015,A1 .Location in patent: Paragraph 0038; 0039; 0040
[2]Tetrahedron,1993,vol. 49,p. 3193 - 3202
[3]Advanced Synthesis and Catalysis,2018,vol. 360,p. 686 - 695
[4]Patent: WO2004/89927,2004,A1 .Location in patent: Page 60
[5]Patent: WO2004/99132,2004,A2 .Location in patent: Page 8
[6]Organic Letters,2012,vol. 14,p. 5884 - 5887

2
[ 108-55-4 ]
[ 462-06-6 ]
[ 149437-76-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	aluminum (III) chloride; In dichloromethane; at 0℃; for 0.5h;	To a stirred suspension of aluminum chloride (205.85g, 1. 54MOL) in dichloromethane(500ML) was added a solution of glutaric anhydride (80g, 0. 7MOL) indichloromethane (125ML) at 0C. The reaction mass was stirred for30minutes and fluorobenzene (67.36g, 0. 7MOL) was added to the reactionmass slowly. The reaction was monitored for completion by TLC and thenpoured into ice cold water (2000ML) under stirring and the separatedsolids were collected by filtration. The solids were dissolved in 3%aqueous sodium hydroxide solution (1100ML) and washed withdichloromethane (300ML). The aqueous layer was acidified to give aprecipitate. The solids were filtered and washed with water andvacuum-dried to yield the title product (125g, yield: 85%). LHNMR(CDC13) 8 : 8.027-7. 98 (M, 2H), 7.17-7. 11 (M, 2H), 3.067 (t, 2H), 2.52(t, 2H), 2.14-2. 04 (M, 2H).
82%		In a milliliter three-necked flask, 200 ml of fluorobenzene was added, Then aluminum trichloride (59.4 g, 0.45 mol) was added,And cooled to 15 C with an ice bath, Then, the solution of glutaric anhydride (30 g, 0.3 mol) in fluorobenzene (100 ml) was added dropwise at 15 C, After completion of the dropwise reaction at 30 C for 5 hours,Cold to about 0 deg C, Dropping 200 ml of 1 M hydrochloric acid, Note that the temperature during the dropwise process does not exceed 20 C. After completion of the dropwise addition, the reaction solution was added to a large amount of ice water, Precipitation of solids, filter, Wash the filter cake with steamed water, The filter cake was then added to 800 ml of saturated sodium bicarbonate solution and stirred at room temperature for 1 h, filter, The filtrate was added with activated carbon decolorization. Concentrated hydrochloric acid to adjust the PH value to 1, Solid precipitation, Filter and wash the filter cake with water, After drying, 51.7 g of white solid compound I, Yield 82%.
79.3%	aluminum (III) chloride; at 5 - 20℃; for 2.25h;	EXAMPLES; Starting materials useful in the processes of the present invention can be made by the following procedures: Preparation of 4-(4-fluorobenzoyl)butyric acid; Charged 250 g of anhydrous AlCl3 (1.87 moles) to a 2 L 3-neck round bottom flask, added 300 mL fluorobenzene (307.5 g; 3.2 moles) and cooled the mixture in an ice bath to 5 C. Added a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintained the temperature below 12 C. The reaction mixture was warmed to ambient temperature gradually and agitated at r.t. for about 90 min.; checked for completion by NMR. Cooled the reaction mixture to 0 to 5 C., then added a cold aqueous solution (700 mL) of 1N HCl carefully to the mixture to destroy any unreacted AlCl3, keeping the temperature of the mixture below 20 C. during the early part of the acid addition, and below 40 C. for the rest of the time. Poured the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filtered the white suspension and washed well with water. Added the white residue to 3 L of aqueous saturated solution (5%) of NaHCO3, heated the basic mixture on a steam bath for one hour and filtered the batch while hot through a thin pad of celite. Cooled the filtrate to r.t., added about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitated the white suspension in an ice bath for 30 min. Filtered the batch, washed the wet cake with ice cold water and dried in a vacuum oven at 50 C. for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142 C., isolated yield: 79.3%.

79.3%	aluminum (III) chloride; at 5 - 20℃; for 2.25h;	Charge 250 g of anhydrous AlCl3 (1.87 moles) to a 2 L 3-neck round bottom flask, add 300 mL fluorobenzene (307.5 g; 3.2 moles) and cool the mixture in an ice bath to 5C. Add a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintain the temperature below 12C. Warm the reaction mixture to ambient temperature gradually and agitate at r.t. for about 90 min.; check for completion by NMR. Cool the reaction mixture to 0 to 5C, then add a cold aqueous solution (700 mL) of 1 N HCl carefully to the mixture to destroy any unreacted AlCl3, keeping the temperature of the mixture below 20C during the early part of the acid addition, and below 40C for the rest of the time. Pour the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filter the white suspension and wash well with water. Add the white residue to 3 L of aqueous saturated solution (~5%) of NaHCO3, heat the basic mixture on a steam bath for one hour and filter the batch while hot through a thin pad of celite. Cool the filtrate to r.t., add about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitate the white suspension in an ice bath for 30 min. Filter the batch, wash the wet cake with ice cold water and dry in a vacuum oven at 50C for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142C, isolated yield: 79.3%.
51%		A flask was charged with AlCl3 (77.17 mmol, 10.29 g, 2.15 equiv) and dry CH2Cl2 (25 ml) under calcium chloride guard tube and the formed suspension was stirred on ice bath. Subsequently, a solution of glutaric anhydride 10 (35.8 mmol, 4.08 g) in dry CH2Cl2 (12 ml) was added dropwise (t < 8 C). The resulting mixture was stirred on ice bath for 30 minutes and fluorobenzene 11c (35.1 mmol, 3.37 g, 1.0 equiv) was carefully added afterwards. The cooling bath was removed and the mixture was stirred at room temperature for 19 hours, then it was carefully quenched with ice water (20 ml), conc. H2SO4 (10 ml) and again with ice water (60 ml), the aqueous layer was extracted with ethyl acetate (1 x 200 ml, 1 x 100 ml, 1 x 70 ml), the combined organics were washed with half-saturated brine (200 ml), dried over Na2SO4, filtered and concentrated. The crude product was crystallized from ethyl acetate to provide 5-(4-fluorophenyl)-5-oxopentanoic acid (3.80 g, 51%) as a yellow-brown powder;3 mp 141-142 C; 1H NMR (300 MHz, CDCl3): delta = 2.08 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 7.13 (m, 2H), 7.99 (m, 2H). 5-(4-Fluorophenyl)-5-oxopentanoic acid (16.7 mmol, 3.50 g), paraformaldehyde (50.0 mmol, 1.50 g, 3.0 equiv) and piperidine (0.32 ml, 0.2 equiv) were dissolved/suspended in pyridine (15 ml) and stirred at 70 C for 21 hours. Afterwards, the mixture was poured into 1M H2SO4 (340 ml), the aqueous layer was extracted with ethyl acetate (4 x 100 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EA/hexanes = 1/1 + 0.5% AcOH). The obtained product was repeatedly coevaporated with toluene (4 x 25 ml) under reduced pressure to remove the residual AcOH, yielding 4-(4-fluorobenzoyl)pent-4-enoic acid 9c (3.33 g, 90%) as an orange solid; mp 81-82 C; 1H NMR (300 MHz, CDCl3): delta = 2.62 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 5.65 (s, 1H), 5.92 (s, 1H), 7.12 (dd, J = 8.7, 8.7 Hz, 2H), 7.78 (dd, J = 5.7, 8.7 Hz, 2H), 10.74 (bs, 1H); 13C NMR (75 MHz, CDCl3): delta = 27.3, 32.5, 115.3 (d, JCF = 21.8 Hz), 126.7, 132.0 (d, JCF = 9.0 Hz), 133.7, 145.9, 165.3 (d, JCF = 252.5 Hz), 178.9, 196.2
	aluminum (III) chloride; In dichloromethane; at 10 - 15℃; for 4h;	Into a 3L three-necked RB flask were charged [500ML] of methylene chloride, 250gr of aluminum chloride and 45gr of fluorobenzene (benzene content 300ppm) under nitrogen atmosphere. 'The reaction mixture was cooled to [10C] and a solution of [LOOGR] of glutaric anhydride, 45gr of fluorobenzene (benzene content 300ppm) and [500ML] of methylene chloride was added slowly over a period of 3hrs between [10-15C.] The reaction mixture was maintained for another one hour at the same temperature. The reaction mixture was slowly poured onto a mixture of crushed ice (700gr) and conc. HCI [(300ML)] below [10C.] The reaction mass temperature was allowed to reach [25C] and methylene chloride distilled off from the reaction mixture below [50C.] After cooling the reaction mixture to [20C,] solids were filtered off and washed with [500ML] of water. The wet cake thus obtained was suspended in [250-300ML] of methylene chloride and filtered. The solid compound was dissolved in [600ML] of 4% sodium hydroxide, treated with [LOGR] of activated charcoal and filtered. The filtrate was acidified with conc. HCI and the precipitated acid was filtered. After washing the wet cake with [500ML] of water, it was dissolved in [500ML] of acetone. The acetone solution was slowly cooled to [15-20C] and the solid filtered, washed with chilled acetone (50ml) and dried at [50-70C] to get 122gr of white crystalline solid, m. p. [143C.] Purity by [HPLC] is 99.65%. Desfluoro impurity is less than 0.05%. Example 2 Preparation of [4- (4-FLUOROBENZOY) LBUTYRIC ACID] of formula-I using fluorobenzene (benzene content [500PPM)] with methylene chloride as solvent: Into a 3L three-necked RB flask were charged [500MI] of methylene chloride, 250gr of aluminum chloride and 45gr of fluorobenzene (benzene content 500ppm) under nitrogen atmosphere. The reaction mixture was cooled to [10C] and a solution of [LOOGR] of glutaric anhydride, 45gr of fluorobenzene (benzene content [500PPM)] and [500ML] of methylene chloride was added slowly over a period of 3hrs between [10-15C.] The reaction mixture was maintained for another one hour at the same temperature. The reaction mixture was slowly poured onto a mixture of crushed ice (700gr) and conc. [HCL] [(300ML)] below [10C.] The reaction mass temperature was allowed to reach [25C] and methylene chloride distilled off from the reaction mixture below [50C.] After cooling the reaction-mixture to [20OC-1 SOLIDS :] were filtered off and washed with [500ML] of water. The wet cake thus obtained was suspended in [250-300ML OF] methylene chloride and filtered. The solid compound was dissolved in [600ML] of [4%] sodium hydroxide, treated with [10GR] of activated charcoal and filtered. The filtrate pH was adjusted'to 1.0-2. 0 with conc. [HCL] and the precipitated acid of formula-I was filtered. After washing the wet cake with [500ML] of water, it was dissolved in [500ML] of acetone. The acetone solution was slowly cooled to [15-20C,] maintained for 2h, and the solid filtered, washed with chilled acetone [(50ML)] and dried at [50-70C] to get 120gr of white crystalline solid of [FORMULA-1,] m. p. 143-143. [5C.] Purity by [HPLC] is 99. [7%.] Desfluoro impurity is less than 0.05%. Example 3 Preparation of [4- (4-FLUOROBENZOY)] lbutyric acid of formula-I using fluorobenzene (benzene content 700ppm) with methylene chloride as solvent: Tnto a 3L three-necked RB flask were charged 500ml of methylene chloride, 250gr of aluminum chloride and 45gr of fluorobenzene (benzene content [700PPM)] under nitrogen atmosphere. The reaction mixture was cooled to [10C] and a solution of [LOOGR] of glutaric anhydride, 45gr of fluorobenzene (benzene content 700ppm) and [500ML] of methylene chloride was added slowly over a period of 3hrs between [10-15C.] The reaction mixture was maintained for another one hour at the same temperature. The reaction mixture was slowly poured onto a mixture of crushed ice (700gr) [AND CONC. HCI (300ML)] below [10C.] The reaction mass temperature was allowed to reach [25C] and methylene chloride distilled off from the reaction mixture below [50C.] After cooling the reaction mixture to [20C,] solids were filtered off and washed with [500ML] of water. The wet cake thus obtained was suspended in [250-300ML] of methylene chloride and filtered. The solid compound was dissolved in [600ML] of 4% sodium hydroxide, treated with [LOGR] of activated charcoal and filtered. The filtrate pH was adjusted to 1.0-2. 0 with conc. [HCL] and the precipitated acid of formula-I was filtered. After washing the wet cake with [500ML] of water, it was dissolved in 500ml of acetone. The acetone solution was slowly cooled to [15-20C,] maintained for 2h, and the solid filtered, washed with chilled acetone [(50ML)] and dried at [50-70C] to get 123gr of white crystalline solid [OF FORMULA-1,] m. p. [143C.] Purity by [HPLC] is 99.6%. Desfluoro impurity is less than 0.05%.
	aluminum (III) chloride; In 1,2-dichloro-ethane; at 10 - 15℃; for 4h;	Into a 3L three-necked RB flask was charged ethylene dichloride [(500ML),] aluminum chloride [(250GR)] and fluorobenzene [(45GR)] under nitrogen atmosphere. The reaction mixture was cooled to [10C] and a solution of glutaric anhydride [(LOOGR),] fluorobenzene (45gr) and ethylene dichloride [(500ML)] was added slowly over a period of 3hrs between [10-15C.] After maintaining for one hour at [15-18C] the reaction mixture was slowly poured onto a mixture of crushed ice (700gr) and conc. HCI [(300ML)] below [10C.] The reaction mass temperature was raised to reach [25C] and distilled off ethylene dichloride from the reaction mixture below [100C.] After cooling the reaction mixture to [20C,] crude solid was filtered off and washed with [500ML] of water. The wet cake-thus obtained was suspended in 300ml of ethylene dichloride and filtered. The solid compound was dissolved in [600ML] of 4% sodium hydroxide, treated with [15GR] of activated charcoal and filtered. The filtrate was acidified to pH 1. [5-2.] 0 with conc. [HCI] and the precipitated acid was filtered. After washing the wet cake with [500ML] of water, it was dried at [60-70C] to get 130gr of white solid, rn. p. [140-142C.] This solid was dissolved in [500ML] of acetone. The acetone solution was slowly cooled to [15-20C] and the solid filtered, washed with chilled acetone [(50ML)] and dried at [50-70C] to get 120gr of white crystalline solid, m. p. [143C.] Purity by [HPLC] is 99.65%. Desfluoro impurity is less than 0. [05%.]
		[0030] To anhydrous AlCl3 (250.Og, 1.87 mol) kept in a dry flask fluorobenzene(307.5 g:3.2 moles) was added. The reaction mass was cooled to a temperature of about 5C and a suspension of glutaric anhydride (0.86 mol) in fluorobenzene (400.0 ml, 4.3 mol) was added dropwise. After completion of the addition, the reaction mass was brought to room temperature and maintained for 2 hours. On completion of the reaction as determined by NMR, the reaction mass was cooled to a temperature ranging from about 0C to about 30C and IN HCl (715.0 ml) was added below a temperature of about 20C. The reaction mixture was poured into 2.3 L of ice- water suspension under stirring and the precipitated solids were filtered out. The solids were washed with water (500.0 ml) and treated with 5% NaHCO3 (3.2L) and filtered through a hy-flo bed. The solids were acidified with concentrated HCl (pH of about 1.0) at a temperature ranging from about O0C to about 5C. The solids were precipitated out and the product was filtered and dried to yield 4-(4-fluorobenzoyl)-butyric acid (150.Og). Mp: 142-143C. IR(Cm'1): 3073, 2967, 1698, 1672, 1597, 1509, 1414, 1258, 1241, 1165, 1075, 989, 839. 1H NMR (CDCl3) (delta ppm): 1.8(2H), 2.3(2H), 3.1(2H), 7.3(2H), 8.0(2H), 12.1(1H).
125 g		To a suspension of aluminum chloride (205.85 g, 1.54 mol) in dichloromethane (500 mL) was added a solution of glutaric anhydride (80 g, 0.7 mol) in dichloromethane (125 mL) at 0 C. The reaction mixture was stirred for 30 minutes. Fluorobenzene (67.36 g, 0.7 mol) was then added slowly. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was poured into ice water (2000 mL) to precipitate a crude solid product, which was collected by filtration. The crude was re-dissolved in a 3% aqueous sodium hydroxide solution (1100 mL). After being washed with dichloromethane (300 mL), the aqueous solution was acidified to obtain a solid product. The product was filtered, washed with water, and vacuum dried to yield compound 3 (125 g). H NMR of compound 3 (CDCl3, 300M Hz): delta=2.10 (q, J=7.2 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 3.65 (t, J=7.2 Hz, 2H), 7.13 (t, J=7.4 Hz, 2H), 7.98 (q, J=5.4 Hz, 2H)
10 g	With aluminum (III) chloride; In dichloromethane; at 20℃;	25 gms of Aluminium chloride was added to 50 ml of dichloromethane and 4.5 ml of fluorobenzene. To this a solution of 50 ml of dichloromethane containing 10 gms of glutaric anhydride and 4.5 ml of fluorobenzene was added. Reaction mass was stirred at room temperature. After completion of reaction, reaction mass was quenched with ice& HCl solution at 0-10 C. Filtered the reaction mass. The obtained wet solid was dissolved in eq NaHCO3 solution at 60-70 C. and insoluable material was filtered. Cooled the filtrate and adjust pH to 2.0 by adding hydrochioric acid. Obtained solid was filtered and dried at 60-70 C. under vacuum to get 10 gm of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid.
	With aluminum (III) chloride; In dichloromethane; nitrobenzene; for 8h;	Treatment of aluminum trichloride:Anhydrous aluminum trichloride (purchased from Sinopharm Group Chemical Reagent Co., Ltd.,Product number 10000862). The aluminum trichloride was pulverized in a mortar,The aluminum trichloride fine particles were obtained by sieving with a 40 mesh sieve,The fine particles were then placed at 110 C C bake lh to a large number of white smoke smoke,And the mixture was cooled to room temperature under a nitrogen atmosphere.Preparation of 4- (4-fluorobenzoyl) butanoic acid:Under the protection of nitrogen, the treated aluminum chloride was added to the 500 mL three-necked flask according to the raw material ratio of Table 1,Fluorobenzene and organic solvent 100mL, stirring and evenly, the three-necked flask placed in the ice bath, to which dropping glutaric anhydride solution, which, glutaric anhydride solution used in the same solvent and dissolved fluoride, the amount of 48mL, Lh. After dropping, the ice bath was withdrawn, the room temperature was recovered, and the reaction was carried out according to the reaction conditions in Table 2. After completion of the reaction,The reaction was poured into a 2 L beaker and ice was added. The pH was adjusted to 1 by the addition of dilute hydrochloric acid (2N)Filtration gave the crude product, in which the brown red viscous material was aluminum complex;The crude product was redissolved twice in 600 mL of saturated aqueous NaHC03 solution ( & 110) 3 in an appropriate excess)Heated in boiling water bath for 2 hours to have a large number of red sticky material floating on the surface,While filtering the pale yellow solution,And adding concentrated hydrochloric acid to adjust pH to 1,A large number of bubbles emerge,A white solid precipitation,Filtering, washing with cold water, drying,To give 4- (4-fluorobenzoyl) butanoic acid.

Reference： [1]Patent: WO2004/99132,2004,A2 .Location in patent: Page 7-8
[2]Organic Letters,2020,vol. 22,p. 818 - 822
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4424 - 4426
[4]Patent: CN106397292,2017,A .Location in patent: Paragraph 0053; 0083; 0084
[5]Patent: US2006/135755,2006,A1 .Location in patent: Page/Page column 15
[6]Patent: EP1137634,2005,B1 .Location in patent: Page/Page column 9
[7]Tetrahedron,1993,vol. 49,p. 3193 - 3202
[8]Tetrahedron Letters,2016,vol. 57,p. 1079 - 1082
[9]Patent: WO2003/104180,2003,A1 .Location in patent: Page 6-8
[10]Patent: WO2003/104180,2003,A1 .Location in patent: Page 9
[11]Patent: WO2007/17705,2007,A1 .Location in patent: Page/Page column 12
[12]Patent: US2015/18565,2015,A1 .Location in patent: Paragraph 0035; 0036; 0037
[13]Patent: US2016/280642,2016,A1 .Location in patent: Paragraph 0056
[14]Patent: CN103694111,2016,B .Location in patent: Paragraph 0032-0035; 0042
[15]Chirality,2018,vol. 30,p. 642 - 651
[16]Advanced Synthesis and Catalysis,2018,vol. 360,p. 4319 - 4324
[17]Chemical Communications,2019,vol. 55,p. 933 - 936

3
[ 149437-76-3 ]
[ 149437-68-3 ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 3193 - 3202

4
[ 149437-76-3 ]
[ 149437-69-4 ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 3193 - 3202

5
[ 149437-76-3 ]
trans 3-chloro-6-p-fluorophenyl-1-methyl-2-piperidinone [ No CAS ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 3193 - 3202

6
[ 149437-76-3 ]
cis 3-chloro-6-p-fluorophenyl-1-methyl-2-piperidinone [ No CAS ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 3193 - 3202

7
[ 149437-76-3 ]
cis 1-benzyl-3-chloro-6-p-fluorophenyl-2-piperidinone [ No CAS ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 3193 - 3202

8
[ 149437-76-3 ]
trans 1-benzyl-3-chloro-6-p-fluorophenyl-2-piperidinone [ No CAS ]

Reference： [1]Tetrahedron,1993,vol. 49,p. 3193 - 3202

9
[ 107-21-1 ]
[ 149437-76-3 ]
methyl 4-[2-(4-fluorophenyl)-1,3-dioxolane-2-yl]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	toluene-4-sulfonic acid; In toluene; for 17h;Heating / reflux; Dean-Stark apparatus;	Methyl 5- (4-fluorophenyl)-5-oxopentanoate To a solution of 5- (4-FLUOROPHENYL)-5-OXOPENTANOIC acid (3.0 g, 14.3 mmol) in dry MEOH (50 ml) was added concentrated sulfuric acid (50 mg) and the mixture refluxed under nitrogen for 16 H. THE bulk of the MeOH was removed by rotary evaporator and the residue treated with sodium bicarbonate solution (5%, 100 ml) and extracted with ethyl acetate (3X50 ml). The organic extract was washed with water (1X100 ml), brine (1X100 ml), dried (NA2SO4) and evaporated to give methyl 5- (4-FLUOROPHENYL)-5-OXOPENTANOATE (2. 69 g, 84%) as a white crystalline solid. METHYL 4-[2-(4-FLUOROPHENYL)-1, 3-DIOXOLAN-2-VLLBUTANOATE (9) To a solution of 5- (4-FLUOROPHENYL)-5-OXOPENTANOATE (2.26 g, 10 mmol) in toluene (60 ML) was added ethylene glycol (1.95 ml, 35 mmol) and P-TOLUENESULFONIC acid monohydrate (60 mg, 0.32 mmol) and the mixture refluxed in a Dean-Stark apparatus under nitrogen for 17 h. The toluene was removed by rotary evaporator and the residue treated with sodium bicarbonate solution (5%, 50 ml) and extracted with ether (2X50 ml). The ether extract was washed with brine (1X50 ml), dried (Na2SO4) and evaporated to give methyl 4- [2- (4-FLUOROPHENYL)-1, 3-dioxolan-2-yl] butanoate (9) as a pale yellow oil (2.47 g, 91%). 1H nmr (CDCl3, 300 MHz) 1.6-1. 7, m, H3; 1.9, m, H4; 2.30, t (7.5 Hz), H2; 3.64, s, OMe; 3.7-3. 8, m, CH2O ; 3.95-4. 05, m, CH2O ; 7.01, m, H3, 5 ; 7.41, m, H2 , 6 . ESI (+ve) MS m/z 269 (M+H, 45%).

Reference： [1]Patent: WO2004/89927,2004,A1 .Location in patent: Page 60

10
[ 3282-30-2 ]
[ 149437-76-3 ]
[ 1056188-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In N,N-dimethyl-formamide;	Commercially available <strong>[149437-76-3]4-(4-fluorobenzoyl)butyric acid</strong> (5A) is converted to the corresponding mixed anhydride by treatment with pivaloyl chloride and DMAP in DMF EPO <DP n="247"/>and then coupled to (iota_>)-4-benzyl-2-oxazolidmone to afford the imide (6A). Treatment of 6A with borane dimethylsulfide complex in the presence of a catalytic amount of (R)-I - methyl-3,3-diphenyltetrahydro-3H-Pyrrolo[l,2-c][l,3,2]oxazaborole produces the desired (4.S}-4-benzyl-3-[(5)5)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-l,3-oxazolidm-2-one (7aA) in good yield. Protection of the benzylic alcohol as the TBS ether is effected by reaction with tert-butyldimethylsilyl chloride in the presence of imidazole as a base to provide 7bA in good yield.; Commercially available <strong>[149437-76-3]4-(4-fluorobenzoyl)butyric acid</strong> (IB) was converted to the corresponding mixed anhydride by treatment with pivaloyl chloride and DMAP in DMF and then coupled to (5)-4-benzyl-2-oxazolidinone to afford the imide (2B). Treatment of 2B with borane dimethylsulfide complex in the presence of a catalytic amount of (i?)-l-methyl-3,3- diphenyltetrahydro-3H-PyrroIo[l,2-c][l,3,2]oxazaborole produced the desired (4S)-4- benzyl-3-[(5JS)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-l ,3-oxazolidin-2-one (3aB) in good yield. Protection of the benzylic alcohol as the TBS ether was effected by reaction with tert-butyldimethylsilyl chloride in the presence of imidazole as a base to provide 3bB in good yield. EPO <DP n="290"/>
		Equip a 3-necked 500 mL round bottom flask with a thermometer, an addition funnel and a nitrogen inlet. Add p-fluoro-benzoylbutyric acid (20 g, 95.15 mmol), CH2Cl2 (100 mL) and TEA (23 mL, 165 mmol) and agitate the mixture at room temperature for 5 min. Add trimethylacetyl chloride (11.3 mL, 91.75 mmol) slowly over a period of 30 min. Check for complete formation of mixed anhydride by NMR. Add the compound of formula III (10 g, 61.3 mmol), DMAP (1.6 g, 13 mmol) and dry DMF (10 mL) and heat the mixture at reflux for about 7 h or until the reaction is complete (<3% compound III) by NMR. Cool to room temperature, transfer the batch to a flask containing 2N H2SO4 (80 mL) slowly with agitation and continue agitation for about 30 min. Separate the layers and wash the organic layer with 5% NaHCO3 (80 mL). Concentrate the organic layer and crystallize the product from isopropyl alcohol (100 mL), filter and dry. Yield: 20 g (92% molar); mp: 92-94C.
	With dmap; In N,N-dimethyl-formamide;	Commercially available <strong>[149437-76-3]4-(4-fluorobenzoyl)butyric acid</strong> (52) was converted to the corresponding mixed anhydride by treatment with pivaloyl chloride and DMAP in DMF and then coupled to (5)-4-benzyl-2-oxazolidinone to afford the imide (53). Treatment of 53 with borane dimethylsulfde complex in the presence of a catalytic amount of (R)-I -methyl- 3,3-diphenyltetrahydro-3H-pyrrolo[l,2-c][l,3,2]oxazaborole produced the desired (4S)-4- benzyl-3-[(55)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-l,3-oxazolidin-2-one (54a) in good yield. Protection of the benzylic alcohol as the TBS ether was effected by reaction with tert-butyldimethylsilyl chloride in the presence of imidazole as a base to provide 54b in good yield.; Commercially available <strong>[149437-76-3]4-(4-fluorobenzoyl)butyric acid</strong> (306) was converted to the corresponding mixed anhydride by treatment with pivaloyl chloride and DMAP in DMF and then coupled to (jS)-4-benzyl-2-oxazolidinone to afford the imide (307). Treatment of 307 with borane dimethylsulfide complex in the presence of a catalytic amount of (R)-I- methyl-3,3-diphenyltetrahydro-3H-pyrrolo[l,2-c][l,3,2]oxazaborole produced the desired (4S)-4-benzyl-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-l,3-oxazolidin-2-one (308a) in good yield. Protection of the benzylic alcohol as the TBS ether was effected by reaction with tert-butyldimethylsilyl chloride in the presence of imidazole as a base to provide 308b in good yield.

Reference： [1]Patent: WO2006/86562,2006,A2 .Location in patent: Page/Page column 245-246; 288-289
[2]Patent: EP1137634,2005,B1 .Location in patent: Page/Page column 7
[3]Patent: WO2006/102674,2006,A2 .Location in patent: Page/Page column 258; 303-304

11
[ 149437-76-3 ]
[ 793673-93-5 ]

Yield	Reaction Conditions	Operation in experiment
		Referring to Scheme 1, <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> 100 was dissolved in dichloromethane and cooled to - 4 C in an ice/brine bath, stirred for 40 min, and then treated with 1.0 M (i?)-l-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[l,2- c][l,3,2]oxazaborole in toluene. After 10 min, a borane-methyl sulfide complex was added drop- wise. The reaction was quenched by slow addition of methanol, 6% aqueous hydrogen peroxide, and 1.0 M aqueous sulfuric acid. The reaction was stirred at room temperature for 60 min. and poured into a separatory funnel. The organic layer then was separated and the aqueous layer extracted with dichloromethane. The dichloromethane extract was dried and concentrated to give (65)-6-(4-fluorophenyl)tetrahydro-2H-pyran- 2-one 101.
	With dimethylsulfide borane complex;(3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole;	Commercially available <strong>[149437-76-3]4-(4-fluorobenzoyl)butyric acid</strong> (69) is reduced with borane dimethylsulfide complex in the presence of a catalytic amount of (i?)-l-methyl-3,3- diphenyltetrahydro-3H-pyrrolo[l,2-c][l,3,2]oxazaborole to produce lactone 70 after acidification. Treatment of 70 with 2-benzyloxy-4-bromophenyl lithium (generated from 1- benzyloxy-2,5-dibromobenzene with one equivalent of n-butyllithium) followed by protection of the benzylic alcohol as the TBS ether (tert-butyldimethylsilyl chloride and imidizole) gives ketone 71. Alkylation of the enolate of 71, generated with LDA, with methyl bromoacetate gives the keto ester 72. Careful saponification of 72 with lithium EPO <DP n="263"/>hydroxide in aqueous methanol gives the corresponding acid, which is treated with aniline in the presence of EDCI to give amide 73. Reduction of 73 with borane dimethylsulfide complex, in the presence of a catalytic amount of (5)-l-methyl-3,3-diphenyltetrahydro-3H- pyrrolo[l,2-c][l,3,2]oxazaborole gives 74 as a mixture of diastereomers. Mitsunobu Reaction of 74 (triphenylphosphine and diethyldiazodicarboxylate) produces the two diasteromeric gama-lactams 75 and 16 that are separable by chromatography. Suzuki coupling of 75 with 3-hydroxyphenylboronic acid gives the desired biphenyl derivative. Catalytic hydrogenation of the biphenyl derivative over palladium on carbon removes the benzyl protecting group, finally treatment with aqueous HF removes the silyl protecting group to provide 77. In a similar manner, compound 78 can be prepared from 76.

Reference： [1]Patent: WO2008/61238,2008,A2 .Location in patent: Page/Page column 40; 52
[2]Patent: US2015/18565,2015,A1
[3]Patent: WO2006/102674,2006,A2 .Location in patent: Page/Page column 261-263

12
[ 53715-97-2 ]
[ 149437-76-3 ]

Yield	Reaction Conditions	Operation in experiment
79.3%	With hydrogenchloride; sodium hydrogencarbonate;AlCl3; In fluorobenzene; water;	Preparation of 4-(4-fluorobenzoyl)butyric acid: Charge 250 g of anhydrous AlCl3 (1.87 moles) to a 2 L 3-neck round bottom flask, add 300 mL fluorobenzene (307.5 g; 3.2 moles) and cool the mixture in an ice bath to 5 C. Add a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintain the temperature below 12 C. Warm the reaction mixture to ambient temperature gradually and agitate at r.t. for about 90 min.; check for completion by NMR. Cool the reaction mixture to 0 to 5 C., then add a cold aqueous solution (700 mL) of 1N HCl carefully to the mixture to destroy any unreacted AlCl3, keeping the temperature of the mixture below 20 C. during the early part of the acid addition, and below 40 C. for the rest of the time. Pour the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filter the white suspension and wash well with water. Add the white residue to 3 L of aqueous saturated solution (~5%) of NaHCO3, heat the basic mixture on a steam bath for one hour and filter the batch while hot through a thin pad of celite. Cool the filtrate to r.t., add about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitate the white suspension in an ice bath for 30 min. Filter the batch, wash the wet cake with ice cold water and dry in a vacuum oven at 50 C. for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142 C., isolated yield: 79.3%.

Reference： [1]Patent: US6207822,2001,B1

13
[ 149437-76-3 ]
C₁₁H₁₀ClFO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pivaloyl chloride; triethylamine; In tetrahydrofuran; at -5 - 20℃; for 2h;	5-(4-Fluorophenyl)-5-oxopentanoic acid (10.08 g, 47.9 mmol) and triethylamine (6.8 mL, 4.94 g, 48.8 mmol) were dissolved in tetrahydrofuran (50 mL). The reaction was cooled to -5 0C (ice/brine bath), trimethylacetyl chloride (6.0 mL, 5.87 g, 48.7 mmol) was added quickly drop-wise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction was cooled to -5 C (ice/brine bath) again for 30 min, filtered through Celite, washed with cold 1 : 1 hexane-tetrahydrofuran (60 mL) and hexane (120 mL). The filtrate was concentrated, dissolved in N,N- dimethylformamide (16 mL) and to this mixture was added (S)-benzyl-2- oxazolidinone (8.47 g, 47.8 mmol) and 4-dimethylaminopyridine (8.57 g, 70.2 mmol) as solids. The reaction was stirred at room temperature for 20 h, poured into 1.0 N hydrochloric acid (400 mL) and extracted with ethyl acetate (2 x 300 mL). The organic layer was washed with water (400 mL), quarter saturated sodium bicarbonate solution (400 mL), brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from hot isopropyl alcohol (75 mL) with slow cooling to room temperature over 16 h. The crystals were filtered cold and washed with cold isopropyl alcohol (50 mL) to afford (4S)-4-benzyl-3-[5-(4- fluorophenyl)-5-oxopentanoyl]-l,3-oxazolidin-2-one (13.87 g, 78% yield) as a white crystalline solid; mp 114.5 0C; Rf 0.29 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) delta 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J = 8.7 Hz, 2H), 4.72- 4.64 (m, IH), 4.25-4.15 (m, 2H), 3.32 (dd, J = 13.3, 3.4 Hz, IH), 3.12-3.01 (m, 4H), 2.78 (dd, J = 13.3, 9.6 Hz, IH), 2.15 (quint., J = 7.2 Hz, 2H) ppm

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4336 - 4351
[2]Patent: WO2006/124713,2006,A2 .Location in patent: Page/Page column 240

14
[ 107-21-1 ]
[ 149437-76-3 ]
[ 942485-64-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trimethyl orthoformate;sulfuric acid; In dichloromethane; at 20 - 25℃; for 3 - 6h;	21.0 g (0.1 mol) 4-(4-fluor-benzoil)-butyric acid (II) was weighed into a 500 ml round- bottom flask and suspended in 210 ml dichloro methane. During continuous stirring 28 ml (31.2 g, 0.5 mol) ethylene-glycol, 32 ml (31.04 g, 0.3 mol) trimethyl-ortho-formiate, and 0.5 ml cone, sulphuric acid is added dropwise into the suspension. The reaction mixture was stirred at 20-25 C for 3-6 h. The reaction was analytically controlled by thin-layer chromatography. When the ketone came to an end, as its spot disappeared by thin-layer chromatography, the reaction was stopped with adding 5 g solid NaHCO3. The suspension was stirred for 05 min., then the solvent is removed by evaporation, and the residue is solved in 150 ml methanol. This solution was cooled in an icy water-bath, and during the cooling 100 ml 10% NaOH solution was added. The flask was closed and the turbid mixture was stirred at 20-25 0C for about 1 h. The hydrolysis was analytically controlled by thin-layer chromatography. When the ester came to an end, as its spot disappeared by thin-layer chromatography, the methanol was removed by vacuum evaporation, and during intensive cooling in an icy water-bath, 350 ml 10% citric acid solution was added to the residue to achieve an acidic pH-value between 3-4. The precipitated product was extracted with 200 ml ethyl acetate. The aqueous phase was extracted twice with 50-50 ml ethyl acetate, and then the united organic phase was washed to neutral with 5x50 ml water. The ethyl acetatic solution was dried on anhydrous Na2SO4, the desiccant was filtered out, and the filtrate was evaporated in vacuum. The evaporating residue is crytallized with addition of 50 ml n-hexane at 0 C. The crystalline material of (IV) is isolated by filtration, and is dried. Yield: 23 g, (90%) Melting point: 65-67C <n="18"/>1H NMR data: (500 MHz, OMSO-d6, 25 0C) delta 1.41-1.52 (m, 2H), 1.79-1.87 (m, 2H), 2.18 (t, / = 7.5 Hz, 2H), 3.63-3.73 (m, 2H), 3.91-4.01 (m, 2H), 7.13-7.22 (m, 2H), 7.37-7.45 (m, 2H), 11.97 (brs, IH) ppm.

Reference： [1]Patent: WO2007/72088,2007,A1 .Location in patent: Page/Page column 15-16

15
[ 3282-30-2 ]
[ 149437-76-3 ]
[ 186343-35-1 ]
[ 189028-93-1 ]

Yield	Reaction Conditions	Operation in experiment
85.7%		Step 1A. Preparation of (4S)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3 -oxazolidin-2-one (A1 R6=phenyl); 5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino-pyridine (16.25 g, 133.0 mmol) were dissolved in N,N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2 C. (ice/water bath), and trimethylacetyl chloride (16.40 mL, 16.04 g, 133.0 mmol) was added drop-wise to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature at or below 5 C. A heavy white precipitate was formed and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was charged with (s)-(+)-4-phenyl-2-oxazolidinone (16.32 g, 100.0 mmol) and 4-dimethylaminopyridine (12.22 g, 100.0 mmol) both as solids to afford a yellow colored suspension. The reaction was stirred at 30 C. -35 C. for 2 h. An aliquot was removed for analysis by TLC and HPLC. The pale olive colored suspension was poured into water (400 mL) while stirring vigorously and cooling the mixture in an ice-brine bath, transferred with water (150 mL) and stirred with ice-cooling for 1.5 h to afford a solution with an off-white precipitate. The compound was filtered, transferred with water (2×25 mL), washed with water (50 mL) and air dried for 15 min to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (58.0 mL; 1.6 mL/g theoretical yield) by heating to near reflux to afford a golden yellow colored solution. The solution was cooled slowly to room temperature over 12 h, a seed crystal was added and crystals began to precipitate. The mixture was cooled in an ice/water bath and stirred for 1 h. The crystals were filtered, transferred with cold isopropanol (2×10 mL), washed with cold isopropanol (25 mL), air dried and vacuum dried to constant weight to afford (4S)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (30.46 g, 85.7% yield) as a white crystalline solid; m.p. 91.0 C.; Rf 0.40 (1:2 ethyl acetate-hexane); HPLC RT 7.02 min; HPLC purity 94%. 1H NMR (300 MHz, CDCl3) delta 7.93 (dd, J=5.4, 9.0 Hz, 2H), 7.28-7.42 (m, 5H), 7.10 (dd, J=8.5, 9.0 Hz, 2H), 5.43 (dd, J=3.7, 8.7 Hz, 1H), 4.70 (t, J=8.9 Hz, 1H), 4.28 (dd, J=3.7, 8.7 Hz, 1H), 3.05 (dt, J=1.2, 7.3 Hz, 2H), 2.97 (t, J=7.3, 2H), 2.05 (p, J=7.3 Hz, 2H), ppm.

Reference： [1]Patent: US2008/287663,2008,A1 .Location in patent: Page/Page column 23

16
[ 183072-04-0 ]
[ 3282-30-2 ]
[ 149437-76-3 ]
[ 852148-48-2 ]
[ 914777-32-5 ]
[ 914777-33-6 ]

Yield	Reaction Conditions	Operation in experiment
78%		Step 1. Preparation of (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (A1) 5-(4-Fluorophenyl)-5-oxopentanoic acid (372.0 g, 1.77 mol) and 4-dimethylamino-pyridine (286.9 g, 2.35 mol) were dissolved in N,N-dimethylformamide (1770 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 6 C. (ice/water bath), trimethylacetyl chloride (290 mL, 2.35 mol) was added quickly drop-wise over 17 min to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature below 8.5 C. The mixture was stirred for 1 h at 9 C. (ice/water bath) then for 2 h at 20 C. (colorless solution with copious white thick precipitate). The mixture was charged with (S)-benzyl-2-oxazolidinone (313.5 g, 1.77 mol) and 4-dimethylaminopyridine (216.4 g, 1.77 mol) both as solids to afford a bright yellow colored suspension. The reaction was stirred at 27 C. for 3.3 h. The pale olive colored solution was poured into water (4300 mL) while stirring vigorously (an exotherm was detected to 39 C.), transferred with water (1000 mL) and stirred at room temperature for 2 h to afford a pale orange-brown solution with an off-white precipitate. The compound was filtered, transferred with water (2×300 mL), washed with water (400 mL) and air dried for 1.5 h to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (2600 mL, 4.0 mL/g theoretical yield) by heating to near reflux to afford a dark golden yellow colored solution. The mixture was cooled slowly from 81 C. to 74 C. in 20 min, a seed crystal was added and crystals began to precipitate. The mixture was cooled slowly to room temperature over 11 h, cooled to 2 C. in an ice/water bath and stirred for 3 h. The crystals were filtered, transferred with cold mother liquor (350 mL), washed with cold isopropanol (2×350 mL), air dried and vacuum dried to constant weight to afford (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (A1) (510.6 g, 78 % yield) as a white crystalline solid; m.p. 113.4+/-1.2 C.; Rf 0.37 (1:2 ethyl acetate-hexane); HPLC purity 99.7 A % (96.4 A % by NMR); 1H NMR (300 MHz, CDCl3) delta 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J=8.7 Hz, 2H), 4.72-4.64 (m, 1H), 4.25-4.15 (m, 2H), 3.32 (dd, J=13.3, 3.4 Hz, 1H), 3.12-3.01 (m, 4H), 2.78 (dd, J=13.3, 9.6 Hz, 1H), 2.15 (quint., J=7.2 Hz, 2H), ppm.In the synthesis of (4S)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-1,3-oxazolidin-2-one (A1), two side products are formed: The first of these, AI1, can be reduced with hydrogen in the presence of a chiral catalyst to produce AI4 which can be utilized in the synthesis of D2 using the procedure described in PCT WO2004 099132. Although AI1 and AI2 were isolated by chromatography from the reaction described above, if one wishes to make AI1 directly, one can react <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> with oxalyl chloride. The second by-product, AI2, if not removed, is subsequently reduced to AI3 in the following step. It then co-crystallizes with A2 from toluene/alkane solvents and remains an impurity in A2. It can be removed from A2 by crystallization from isopropanol/alkane. The analytical assessment of the products is by TLC or HPLC with the following results: A0-Rf 0.08 (1:2 ethyl acetate-hexane); HPLC RT 3.7 min; A1-Rf 0.37 (1:2 ethyl acetate-hexane); HPLC RT 7.4 min; A2-Rf 0.14 (1:2 ethyl acetate-hexane); HPLC RT 6.5 min; AI1-Rf 0.50 (1:2 ethyl acetate-hexane); HPLC RT 5.5 min; AI2-Rf 0.38 (1:2 ethyl acetate-hexane); HPLC RT 7.6 min; AI3-Rf 0.43 (2:1 ethyl acetate-hexane); HPLC RT 5.4 min. HPLC on Waters Xterra MS C18 (3.0×150 mm), 5 mum at 35 C. Mobile Phase (A): 0.1% Formic Acid in Water (HPLC grade) Mobile Phase (B): Acetonitrile (HPLC grade) Gradient Program: 25% B-initial conditions 25% to 100% B-11 min 100% to 25% B-0.4 min 25% B-3.6 min (flow increase to 1.75 mL/min) Detection: 254 nm Flow Rate: 1.0 mL/min Run Time: 15 min AI1 6-(4-fluorophenyl)-3,4-dihydro-2H-pyran-2-one. 1H NMR (CDCl3/300 MHz) 7.54(dd, 2H, J=5.1, 9.0 Hz), 7.01(dd, 2H, J=9.0, 9.0 Hz), 5.72(t, 1H, J=4.8 Hz), 2.68-2.63(m, 2H), 2.51-2.47(m, 2H). Mass spectrum, M+H=193. AI2 1,9-bis(4-fluorophenyl)nonane-1,5,9-trione, mp 97.1+/-0.7 C. 1H NMR (CDCl3/300 MHz) 7.92(dd, 4H, J=5.4, 9.0 Hz), 7.06(dd, 4H, J=9.0, 9.0 Hz), 2.92(t, 4H, J=6.9 Hz), 2.49(t, 4H, J=6.9 Hz), 1.95(sept, 4H, J=6.9 Hz). Mass spectrum, M+H=359. AI3 (1S,9S)-1,9-bis(4-fluorophenyl)nonane-1,5,9-triol. 1H NMR (CDCl3/300 MHz) 7.24(dd, 4H, J=5.4, 8.4 Hz), 6.98(dd, 4H, J=8.4, 8.4 Hz), 4.60(m, 2H), 3.52(m, 1H), 3.20-2.60(m, 2H), 1.80-1.20(m, 10H). Mass spectrum, M+H=365.

Reference： [1]Patent: US2008/287663,2008,A1 .Location in patent: Page/Page column 19-20

17
[ 20989-17-7 ]
[ 149437-76-3 ]
[ 1187468-19-4 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 140℃; for 20h;Molecular sieve;	Synthesis 67; (S)-2-[(/?)-2-(4-Fluoro-phenyl)-piperidin-1-yl]-2-phenyl-ethanol hydrochloride <n="140"/>; 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid (1g, 5.10 mmol) and (S)-(+)-2-phenylglycinol (0.839 g, 6.12 mmol) in toluene (15 ml.) together with 4A molecular sieves was heated at 1400C under Dean-Stark conditions for 20 hours. The reaction mixture was filtered through Celite, evaporated and the residue dissolved in ethyl acetate then re- evaporated. The crude material was purified by column chromatography eluting with 20- 40% ethyl acetate in cyclohexane to afford (3S,8aS)-8a-(4-fluoro-phenyl)-3-phenyl- hexahydro-oxazolo[3,2-a]pyridin-5-one (1.08g).

Reference： [1]Patent: WO2009/112845,2009,A1 .Location in patent: Page/Page column 138-139

18
[ 90719-32-7 ]
[ 149437-76-3 ]
[ 852148-48-2 ]

Yield	Reaction Conditions	Operation in experiment
78%		Example 35. (4S)-4-Benzyl-3- [5- (4-fluorophenyl)-5-oxopentanoyl]-1, 3- oxazolidin-2-one 5- (4-Fluorophenyl)-5-oxopentanoic acid (10.08 g, 47.9 mmol) and triethylamine (6.8 mL, 4.94 g, 48.8 mmol) were dissolved in tetrahydrofuran (50 mL). The reaction was cooled to-5 C (ice/brine bath), trimethylacetyl chloride (6.0 mL, 5.87 g, 48.7 mmol) was added quickly drop-wise and the mixture was warmed to room temperature and stirred for 1.5 h. The reaction was cooled to-5 C (ice/brine bath) again for 30 min, filtered through Celte, washed with cold 1: 1 hexane-tetrahydrofuran (60 mL) and hexane (120 mL). The filtrate was concentrated, dissolved in N, N-dimethylformamide (16 mL) and to this mixture was added (S)-benzyl-2-oxazolidinone (8.47 g, 47.8 mmol) and 4- dimethylaminopyridine (8.57 g, 70.2 mmol) as solids. The reaction was stirred at room temperature for 20 h, poured into 1.0 N hydrochloric acid (400 mL) and extracted with ethyl acetate (2 x 300 mL). The organic layer was washed with water (400 mL), quarter saturated sodium bicarbonate solution (400 mL), brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by crystallization from hot isopropyl alcohol (75 mL) with slow cooling to room temperature over 16 h. The crystals were filtered cold and washed with cold isopropyl alcohol (50 mL) to afford (4S)-4- benzyl-3- [5- (4-fluorophenyl)-5-oxopentanoyl]-1, 3-oxazolidin-2-one (13. 87 g, 78% yield) as a white crystalline solid; mp 114. 5 C ; Rf 0.29 (1: 2 ethyl acetate-hexane) ;'H NMR (300 MHz, CDC13) b 8.03-7. 98 (m, 2H), 7. 37-7. 19 (m, 5H), 7.14 (t, J= 8.7 Hz, 2H), 4.72- 4.64 (m, 1H), 4.25-4. 15 (m, 2H), 3.32 (dd, J= 13.3, 3.4 Hz, 1H), 3.12-3. 01 (m, 4H), 2.78 (dd, J= 13.3, 9.6 Hz, 1H), 2.15 (quint. , J= 7.2 Hz, 2H) ppm

Reference： [1]Patent: WO2005/47248,2005,A1 .Location in patent: Page/Page column 68

19
[ 870-46-2 ]
[ 149437-76-3 ]
[ 1235493-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 50℃; for 16h;	A mixture of tert-butyl hydrazinecarboxylate (1.45 g, 11.0 mmol) and <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> (2.1 g, 10 mmol) in THF (20 mL) was stirred at 50 0C for 16 h. The reaction mixture was concentrated in vacuo to afford 5-(2-(tert-butoxycarbonyl)hydrazono)-5-(4-fluorophenyl)pentanoic acid (3.2 g, 9.87 mmol, 99 % yield). LC-MS (M+H)+ 325.24. The crude product was used for subsequent chemistry without purification.

Reference： [1]Patent: WO2010/83141,2010,A1 .Location in patent: Page/Page column 81

20
[ 99395-88-7 ]
[ 149437-76-3 ]
[ 189028-93-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane;	Example 1: Preparation of ezetimibe; (1-1) Preparation of 3-[5-(fluorophenyl)-l,5-dioxapentyl]-4(S)- phenyl-2-oxazolidinone (Formula 7); 200 g of <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> of formula 8, 16O g of (S)-4-phenyloxazolidine-2-one of formula 9, and 11.6 g of 4-dimethylaminopyridine were dissolved in 600 m£ of dichloromethane to prepare a reaction mixture. A solution which was prepared by dissolving 157 g of N,N'-dicyclohexylcarboimide in 200 ml of dichloromethane was added to the reaction mixture and stirred for 2 hours. After completion of the reaction, the resulting reaction mixture was filtered to remove by-products. The filtrate thus obtained was washed successively with 1 I of 6N HCl, 1 ? of water, and 1 ? of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 2 I of methanol by heating and cooled to induce crystallization. 2 £ of water was added thereto and stirred for 30 min. The solid thus obtained was isolated by filtering to obtain 289 g of the title compound as a white solid (yield: 86%).1H NMR(300MHz, CDCl3) : delta 7.92 (2H, M), 7.35-7.13 (5H, m), 7.04 (2H, m), 5.43 (IH, q), 4.75(1H, t), 4.22 (IH, q), 3.05-2.93 (4H, m), 2.03 (2H, m)
85.7%		5-(4-Fluorophenyl)-5-oxopentanoic acid (21.02 g, 100.0 mmol) and 4 dimethylamino- pyridine (16.25 g, 133.0 mmol) were dissolved in N,N-dimethylformamide (100 mL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 2 0C (ice/water bath), and trimethylacetyl chloride (16.40 mL, 16.04 g, 133.0 mmol) was added drop-wise to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature at or below 5 0C. A heavy white precipitate was formed and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The mixture was charged with (6)-(+)-4-phenyl-2- oxazolidinone (16.32 g, 100.0 mmol) and 4-dimethylaminopyridine (12.22 g, 100.0 mmol) both as solids to afford a yellow colored suspension. The reaction was stirred at 30 C - 35 0C for 2 h. An aliquot was removed for analysis by TLC and HPLC. The pale olive colored suspension was poured into water (400 mL) while stirring vigorously and cooling the mixture in an ice-brine bath, transferred with water (150 mL) and stirred with ice-cooling for 1.5 h to afford a solution with an off-white precipitate. The compound was filtered, transferred with water (2 x 25 mL), washed with water (50 mL) and air dried for 15 min to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (58.0 mL; 1.6 mL/g theoretical yield) by heating to near reflux to afford a golden yellow colored solution. The solution was cooled slowly to room temperature over 12 h, a seed crystal was added and crystals began to precipitate. The mixture was cooled in an ice/water bath and stirred for 1 h. The crystals were filtered, transferred with cold isopropanol (2 x 10 mL), washed with cold isopropanol (25 mL), air dried and vacuum dried to constant weight to afford (45)-4-phenyl-3-[5-(4-fluorophenyl)-5-oxopentanoyl]-l,3- oxazolidin-2-one (30.46 g, 85.7 % yield) as a white crystalline solid; m.p. 91.0 0C; EPO <DP n="43"/>R/ 0.40 (1:2 ethyl acetate-hexane); HPLC Rr7.02 min; HPLC purity 94 %. 1H NMR (300 MHz, CDCl3) delta 7.93 (dd, J= 5.4, 9.0 Hz, 2H), 7.28-7.42 (m, 5H), 7.10 (dd, J= 8.5, 9.0 Hz, 2H), 5.43 (dd, J= 3.7, 8.7 Hz, IH), 4.70 (t, J= 8.9 Hz, IH), 4.28 (dd, J= 3.7, 8.7 Hz, IH), 3.05 (dt, J= 1.2, 7.3 Hz, 2H), 2.97 (t, J= 7.3, 2H), 2.05 (p, J= 7.3 Hz, 2H), ppm.
85%		To the soulution of compound 2 (700 g, 3.33 mol, 1.1 eq) dissolved in THF (5 L) was added triethylamine (1.2 L, 7.87 mol, 2.6 eq) at room temperature under N2 atmosphere. Then the solution of pivalic acid chloride (400 g, 3.33 mol, 1.1 eq) in THF (700 mL) was added dropwise to the reaction mixture cooled to -10 C for about 2 h. After addition, the mixture was stirred for 2 h at this temperature. TLC showed the compound 2 was consumed up, then the Evans auxiliary (493.5 g, 3 mol, 1 eq) and anhydrous LiCl (150.5 g, 3.5 mol,1.17 eq) were added sequencely. The mixture was warmed to room temperature and stirred for 2 h till the anhydride intermediate was consumed up. Then ethylacetate (2 L) and NH4Cl aq (1 L) were added, stirred for 15 min, stayed and separated, the aqueous layer was extracted with ethyl acetate (500 mL×2), combined the organic phase, washed with water (250 mL ×2), concentrated.The residue was recrystallized from isopropanol (7 L) to afforded compound 4 as a white solid (913.6 g, 85.0% yield). HPLC purity: 99.2%, mp: 94-95 C [lit.9(b) 91C]. 1H-NMR (CDCl3,400 MHz): delta 7.94-7.93 (m, 2H, J=2), 7.40-7.29 (m, 5H), 7.10-7.01 (m, 2H), 5.45-5.41 (m, 1H), 4.72-4.63 (m, 1H), 4.30-4.27 (m, 1H), 3.06 (t, 2H, J=8), 2.97 (t, 2H, J=12), 2.10-2.03 (m, 2H). 13C-NMR (CDCl3, 100MHz): delta 197.7, 172.2, 167.0, 164.4, 153.8, 139.2, 133.3, 130.7, 130.6, 129.2, 128.7, 126.0, 115.7, 115.5, 70.1, 57.6, 37.3, 34.8, 18.5. MS (ESI) m/z calcd. for C20H18FNO4: 355.12, calcd. for C20H18FNO4Na (M+Na)=378.12, found 378.04 (M+Na).

70%		Compound I (21 g, 0.1 mol) was added to a 500 ml three-necked flask, Triethylamine 20 ml and dichloromethane 250 ml, Stuttgart dropwise pivaloyl chloride (14.4g, 0.12mol), (4S) -4-phenyl-2-oxazolidinone (24.5 g, 0.15 mol), DMF 5 ml, 4,4-dimethylaminopyridine (1.22 g, 0.01 mol) was added after refluxing for 3 h, After refluxing for 10 h, Ice bath cooling, Then, 200 ml of 5 M hydrochloric acid was added dropwise at 0 C, Static stratification, The lower methylene chloride layer was washed successively with saturated sodium bicarbonate solution and water, Dried over anhydrous sodium sulfate. The filtrate was concentrated to dryness, To give 24.9 g of a white solid compound II, Yield 70%.
68%		The compound (4) (30 g, 142.72 mmol) Triethylamine (26 g, 256.91 mmol) was dissolved in dichloromethane (150 ml)Cooling to 5 to 10 C, dropwise addition of pivaloyl chloride (17.3g, 142.62mmol), System has exothermic, 30min drop finished,5 to 10 deg C insulation reaction 2h, To the reaction system was added (S) -4-phenyl-2-oxazolidinone (23.3 g, 142.76 mmol) DMAP (2.4 g, 19.63 mmol), DMF (15 ml),Exothermic The temperature rose to 15 C, Heated to 45 reflux reaction 3h, Down to room temperature, Plus dichloromethane (150 ml), The organic phase was washed with water (60 ml) 1N hydrochloric acid (120 ml) Water (60ml) 2.5% aqueous sodium hydroxide solution (180 ml) Add water (50ml) wash, Organic phase concentrated dry, Plus isopropyl alcohol (60 ml), Stirring for 24 h, Filter, Add isopropyl alcohol (10ml) leaching, To give a white solid, I.e. compound (5) (34.4 g, 68% yield).

Reference： [1]Patent: WO2010/71358,2010,A2 .Location in patent: Page/Page column 14-15
[2]Patent: WO2006/122216,2006,A2 .Location in patent: Page/Page column 41-42
[3]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[4]Patent: CN106397292,2017,A .Location in patent: Paragraph 0053; 0086; 0087
[5]Patent: CN104513187,2017,B .Location in patent: Paragraph 0063; 0064; 0065; 0066

21
[ 98-01-1 ]
[ 17356-08-0 ]
[ 149437-76-3 ]
[ 1242183-65-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4424 - 4426

22
[ 90719-32-7 ]
[ 149437-76-3 ]
[ 852148-48-2 ]
[ 914777-32-5 ]
[ 914777-33-6 ]

Yield	Reaction Conditions	Operation in experiment
78%		5-(4-Fluorophenyl)-5-oxopentanoic acid (372.0 g, 1.77 mol) and 4-dimethylamino- pyridine (286.9 g, 2.35 mol) were dissolved in LambdazetaN-dimethylformamide (1770 rnL, 1.0 M) to afford a copious white precipitate suspended in solution. The reaction was cooled to 6 0C (ice/water bath), trimethylacetyl chloride (290 mL, 2.35 mol) was added quickly drop-wise over 17 min to afford a pale yellow mixture. The rate of addition was controlled in order to keep the temperature below 8.5 C. The mixture was stirred for 1 h at 9 C (ice/water bath) then for 2 h at 20 C (colorless solution with copious white thick precipitate). The mixture was charged with (S)-benzyl-2- oxazolidinone (313.5 g, 1.77 mol) and 4-dimethylaminopyridine (216.4 g, 1.77 mol) both as solids to afford a bright yellow colored suspension. The reaction was stirred at 27 C for 3.3 h. The pale olive colored solution was poured into water (4300 mL) while stirring vigorously (an exotherm was detected to 39 C), transferred with water (1000 mL) and stirred at room temperature for 2 h to afford a pale orange-brown solution with an off-white precipitate. The compound was filtered, transferred with water (2 x 300 mL), washed with water (400 mL) and air dried for 1.5 h to afford an off-white moist clumpy powder. The material was crystallized from isopropanol (2600 mL, 4.0 mL/g theoretical yield) by heating to near reflux to afford a dark golden yellow colored solution. The mixture was cooled slowly from 81 C to 74 C in 20 min, a seed crystal was added and crystals began to precipitate. The mixture was cooled slowly to room temperature over H h, cooled to 2 C in an ice/water bath and stirred for 3 h. The crystals were filtered, transferred with cold mother liquor (350 mL), washed with cold isopropanol (2 x 350 mL), air dried and vacuum dried to constant weight to afford (4iotaS)-4-benzyl-3-[5-(4-fluorophenyl)-5-oxopentanoylj-l,3- oxazolidin-2-one (Al) (510.6 g, 78 % yield) as a white crystalline solid; m.p. 113.4 + EPO <DP n="33"/>1.2 C; R/ 0.37 (1 :2 ethyl acetate-hexane); HPLC purity 99.7 A% (96.4 A% by NMR); 1H NMR (300 MHz, CDCl3) delta 8.03-7.98 (m, 2H), 7.37-7.19 (m, 5H), 7.14 (t, J= 8.7 Hz, 2H), 4.72-4.64 (m, IH), 4.25-4.15 (m, 2H), 3.32 (dd, J= 13.3, 3.4 Hz, IH), 3.12-3.01 (m, 4H), 2.78 (dd, J= 13.3, 9.6 Hz, IH), 2.15 (quint, J= 7.2 Hz, 2H) ppm.

Reference： [1]Patent: WO2006/122216,2006,A2 .Location in patent: Page/Page column 31-32

23
[ 110-91-8 ]
[ 149437-76-3 ]
[ 924909-70-6 ]

Yield	Reaction Conditions	Operation in experiment
		[0017] A solution of p-fluorobenzoyl butyric acid (50.Og, 0.24 mol) in DMF(500.0 ml) and N,N'-Carbonyl diimidazole (50.Og, 0.31 mol) was stirred under nitrogen at about room temperature (from about 25C to about 30C) for three hours. Morpholine (40.0 ml, 0.46 mol) was added to the reaction mass dropwise. The reaction mass was stirred at a temperature ranging from about 4O0C to about 45 C for about 10 hours. After completion of the reaction as determined by TLC, the reaction mass was cooled to a temperature ranging from about O0C to about 5C and adjusted to a pH of about 2.0 with 2N HCl and extracted with ethyl acetate (2 X 500.0 ml). The ethyl acetate layer was washed with saturated sodium bicarbonate solution (200.0 ml), water (200.0 ml) and brine (200.0 ml). The ethyl acetate layer on evaporation gave a residue. The residue on crystallization from ethyl acetate/hexane yielded 55.Og of the keto amide III. [0018] Mp: 54-55C. IR(Cm'1) :3044, 3061, 1636, 1677, 1599, 1441, 1278, 1241,1114, 1030, 988, 960. 1H NMR (CDCl3) (delta ppm): 2.1(2H), 2.4(2H), 3.1(2H), 3.5(2H), 3.7(6H), 7.1(2H), 8.0(2H). (M+l):280.2
10 g		10 gms of 5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid and 5.6 gms of triethyl amine was added to 25 ml of toluene. 5.1 gms of Pivollyl chloride was added and stirred the reaction mass at room temperature for about 2 hours. 4 ml of Morpholine in 25 ml of toluene was added to the reaction mass at 0 C. Stirred the reaction mass for about 30 minutes at 0-5 C. and 20 ml of water was added. To the reaction mass 30 ml of brine solution was added and organic layer was separated. Dried the separated organic layer over sodium sulfate. Distill off the solvent completely under reduced pressure at 50-55 C. The resulted oily mass was dissolved in 12 ml of toluene and 60 ml of hexane. Cooled the reaction mass and 12 ml of toluene was added. Stirred the reaction mass for about 1-2 hours at 0-5 C., filtered, washed with 5 ml of hexane and dried at 40-45 C. to get 10 gms of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1, 5-dione

Reference： [1]Organic Letters,2020,vol. 22,p. 818 - 822
[2]Patent: WO2007/17705,2007,A1 .Location in patent: Page/Page column 6; 8
[3]Patent: US2016/280642,2016,A1 .Location in patent: Paragraph 0057

Yield	Reaction Conditions	Operation in experiment
83%	With aluminum (III) chloride; at 0℃; for 1h;Reflux;	General procedure: Stirred benzene (Aa) (60 mL) and glutaric anhydride (B) (44 mmol) at 0 CTo this was added powdery anhydrous aluminum chloride (96.5 mmol), and the resulting mixture was refluxed for 1 hour.The reaction mixture was then cooled to 0 C and slowly cooled with water at the same temperature.Neutralize and extract with saturated sodium carbonate solution.Acidified with hydrochloric acid to pH 1 and the aqueous solution was concentrated,Extracted with ethyl acetate (100 mL 3). The extract was dried over anhydrous MgSO4,Concentrated in vacuo to give crude 4-benzoylbutanoic acid (1a),It was recrystallized from petroleum ether and ethyl acetate with a yield of 85%.

25
[ 149437-76-3 ]
[ 521073-83-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4336 - 4351

26
BF₄^(1-)*C₁₇H₂₅N₄O₂⁽¹⁺⁾ [ No CAS ]
[ 149437-76-3 ]
BF₄^(1-)*C₂₈H₃₂FN₄O₃⁽¹⁺⁾ [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2011,vol. 6,p. 2471 - 2480

27
[ 1779-49-3 ]
[ 149437-76-3 ]
[ 1258204-06-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1562 - 1565
[2]Journal of Organic Chemistry,2016,vol. 81,p. 8287 - 8295
[3]Angewandte Chemie - International Edition,2012,vol. 51,p. 7771 - 7775

28
[ 149437-76-3 ]
(S)-6-(bromomethyl)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 7771 - 7775
[2]Journal of Organic Chemistry,2016,vol. 81,p. 8287 - 8295

29
[ 149437-76-3 ]
[ 1268103-05-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With oxygen; potassium carbonate; calcium iodide; In tetrahydrofuran; at 20 - 50℃; for 10h;Irradiation;	General procedure: Table 1, entry10: A solution of substrate (0.3 mmol), CaI2 (0.2 equiv) and K2CO3 (0.1 equiv) in dry THF (5 mL) in a Pyrex test tube with O2 balloon is stirred and irradiated externally with 400 W high pressure mercury lamp at room temperature for indicated time. The temperature of the reaction mixture at the final stage of this reaction was about 50 C. The product is quenched with 0.5 M aq Na2S2O3. Then the solution is acidified with 0.5 N aq HCl and extracted with EtOAc. The product is purified by PTLC.

Reference： [1]Organic Letters,2017,vol. 19,p. 6622 - 6625
[2]Tetrahedron Letters,2013,vol. 54,p. 256 - 258
[3]Green Chemistry,2012,vol. 14,p. 3007 - 3009,3

30
[ 149437-76-3 ]
[ 1258204-06-6 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 5884 - 5887

31
[ 149437-76-3 ]
[ 1258203-99-4 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 5884 - 5887

32
[ 149437-76-3 ]
[ 1261280-42-5 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 5884 - 5887

33
[ 123-75-1 ]
[ 149437-76-3 ]
[ 1215651-45-8 ]

Reference： [1]Chemistry - A European Journal,2013,vol. 19,p. 2606 - 2610

34
[ 149437-76-3 ]
[ 1267235-40-4 ]

Reference： [1]Chemistry - A European Journal,2013,vol. 19,p. 2606 - 2610

35
[ 149437-76-3 ]
[ 1453172-01-4 ]

Reference： [1]Chemistry - A European Journal,2013,vol. 19,p. 2606 - 2610

36
[ 149437-76-3 ]
[ 1260675-05-5 ]

Reference： [1]Chemistry - A European Journal,2013,vol. 19,p. 2606 - 2610
[2]Chemistry - A European Journal,2013,vol. 19,p. 2606 - 2610
[3]Chirality,2018,vol. 30,p. 642 - 651
[4]Chemical Communications,2019,vol. 55,p. 933 - 936

37
[ 149437-76-3 ]
[ 1574316-84-9 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1562 - 1565

38
[ 149437-76-3 ]
C₁₂H₁₄FN₃O [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1562 - 1565

39
[ 149437-76-3 ]
[ 3068-32-4 ]
(2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(5-(4-fluorophenyl)-5-oxopentanoyl)tetrahydro-2H-pyran-3, 4, 5-triyl triacetate [ No CAS ]
(2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-(5-(4-fluorophenyl)-5-oxopentanoyl)tetrahydro-2H-pyran-3, 4, 5-triyl triacetate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 17645 - 17651

40
[ 149437-76-3 ]
(5S)-5-(4-fluorophenyl)-5-hydroxy-N-((S)-2-hydroxy-1-phenylethyl)pentanamide [ No CAS ]

Reference： [1]Patent: US2015/18565,2015,A1

41
[ 149437-76-3 ]
tert-butyl (S)-5-(4-fluorophenyl)-5-hydroxypentanoyl((S)-2-hydroxy-1-phenylethyl)carbamate [ No CAS ]

Reference： [1]Patent: US2015/18565,2015,A1

42
[ 149437-76-3 ]
[ 189028-95-3 ]

Reference： [1]Patent: US2015/18565,2015,A1
[2]Patent: CN104513187,2017,B

43
[ 149437-76-3 ]
[ 163222-33-1 ]

Reference： [1]Patent: US2015/18565,2015,A1
[2]Patent: CN106397292,2017,A
[3]Patent: CN104513187,2017,B
[4]Patent: CN104230978,2016,B

44
[ 149437-76-3 ]
(S)-3-((2R,5S)-5-(4-fluorophenyl)-2-((4-fluorophenylamino)(4-(trimethylsilyloxy)phenyl)methyl)-5-(trimethylsilyloxy)pentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Reference： [1]Patent: US2015/18565,2015,A1

45
[ 108-55-4 ]
[ 352-13-6 ]
[ 149437-76-3 ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 2723 - 2730

46
[ 149437-76-3 ]
5-hydroxy-N-methoxy-N-methyl-5-(4-fluorophenyl)pentanamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 2723 - 2730

47
[ 149437-76-3 ]
1-(4-fluorophenyl)pentane-1,5-diol [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 2723 - 2730

48
[ 6638-79-5 ]
[ 149437-76-3 ]
N-methoxy-N-methyl-5-oxo-5-(4-fluorophenyl)pentanamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 2723 - 2730

49
[ 149437-76-3 ]
[ 1187468-22-9 ]

Reference： [1]ACS Catalysis,2016,vol. 6,p. 3753 - 3759
[2]ACS Catalysis,2017,vol. 7,p. 2920 - 2925

50
[ 149437-76-3 ]
[ 1187468-21-8 ]

Reference： [1]ACS Catalysis,2016,vol. 6,p. 3753 - 3759
[2]Patent: WO2009/112845,2009,A1

51
[ 149437-76-3 ]
[ 163380-16-3 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[2]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

52
[ 149437-76-3 ]
(3S,4R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

53
[ 149437-76-3 ]
[ 1376614-99-1 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

54
[ 149437-76-3 ]
[ 1376615-01-8 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

55
[ 149437-76-3 ]
[ 163222-33-1 ]
[ 163380-16-3 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[2]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

56
[ 149437-76-3 ]
(S)-3-((R)-2-((R)-(4-((tert-butyldimethylsilyl)oxy)phenyl)((4-fluorophenyl)amino)methyl)-5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

57
[ 149437-76-3 ]
(R)-3-(5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

58
[ 149437-76-3 ]
(R)-3-((R)-2-((S)-(4-((tert-butyldimethylsilyl)oxy)phenyl)((4-fluorophenyl)amino)methyl)-5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

59
[ 149437-76-3 ]
(3S,4R)-4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3,3-dimethoxypropyl)azetidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

60
[ 149437-76-3 ]
[ 1185883-41-3 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

61
[ 149437-76-3 ]
(S)-3-((R)-2-((S)-(4-((tert-butyldimethylsilyl)oxy)phenyl)((4-fluorophenyl)amino)methyl)-5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[2]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

62
[ 149437-76-3 ]
(3R,4S)-4-(4-((tert-butyldimethylsilyl)oxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3,3-dimethoxypropyl)azetidin-2-one [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[2]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

63
[ 149437-76-3 ]
[ 191330-56-0 ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[2]Synthetic Communications,2016,vol. 46,p. 1687 - 1693
[3]Patent: CN107488173,2017,A
[4]Patent: CN107488165,2017,A

64
[ 90319-52-1 ]
[ 149437-76-3 ]
(R)-1-(4-fluorophenyl)-5-(2-oxo-4-phenyloxazolidin-3-yl)pentane-1,5-dione [ No CAS ]

Reference： [1]Synthetic Communications,2016,vol. 46,p. 1687 - 1693

65
[ 149437-76-3 ]
(S)-5-(4-fluoro-phenyl)-5-hydroxy-1-morpholin-4-yl-pentan-1-one [ No CAS ]

Reference： [1]Patent: US2016/280642,2016,A1

66
[ 99395-88-7 ]
[ 149437-76-3 ]
[ 189028-95-3 ]

Yield	Reaction Conditions	Operation in experiment
		This invention adopts the "one-pot synthesis" according to bookletmai Bu intermediates for the synthesis of (4S)-3-[ (5S)-5-(4-fluoro phenyl)-5-hydroxy- fifth heavenly stem acyl group ]-4-phenyl -1, 3-oxygen nitrogen heterocyclic pentane-2-one (II), has the advantage of short synthetic route. One-pot synthesis (one-potreaction) is a high-efficiency organic synthetic method. "One-pot synthesis" in the reaction step from the reaction can be a plurality of relatively simple proceeding easily available raw materials, without intermediate separation, direct access to the molecules of the complex structure, thus having the advantage of the cost of synthesizing, and friendly to the environment.Firstly the 42g compound (I) dissolved in 420 ml in the reaction solution. The reaction solution includes: tetrahydrofuran, chloroform, dioxane or dichloromethane, and most preferably dichloromethane. In this embodiment, the reaction solution is dichloromethane, then added into the 1L three-necked bottle , will three-necked bottle is placed over the magnetic stirring device to mix uniformly to perform mechanical stirring. Compound (I) shown in the chemical structural formula as follows:In three-necked bottle is placed in the ice bath, ice-bath temperature is kept at 0 C three-necked bottle in until the oven is not higher than 10 C. Successive adds by drops Fu Suanji 30 ml and pivalyl chloride 75 ml. In this embodiment, the fu Suanji in particular to triethylamine. three-necked bottle is maintained during the dropping of the oven is not higher than 15 C. fu Suanji can absorb the acid generated in the reaction, a weakly alkaline substance with an acid salt, avoid acid influence the reaction or reaction balance. fu Suanji including triethylamine, pyridine, sodium methoxide or potassium hydroxide, and most preferably triethylamine. pivalyl chloride is an acylation reagent, pivaloyl chloride in organic synthesis in organic molecules can be oxygen, nitrogen, carbon, sulfur atom is introduced to the acyl.Triethylamine and pivalylchlorine instillment to room temperature reaction after 4 hours. Adding ice-bath to the oven is not higher than 10 C, dropwise S-4-phenyl-2-oxazolidinone 20g and N, N-dimethyl formamide 200 ml of the mixed solution, keep three-necked bottle the oven is not higher than 20 C, dropping temperature to reflux temperature of the reaction 2 hours. S-4-phenyl-2-oxazolidinone is an important pharmaceutical intermediates, is mainly used for asymmetric chiral organic synthesis.Salt bath to the oven is not higher than 0 C, successive instillment borane dimethyl sulfide 15 ml and (R)-2-methyl-CBS-oxazole borane 7.5 ml, maintain the oven is not higher than in three-necked bottle 5 C, after dropping temperature to stirring the mixture at room temperature for 30 minutes, add 150 ml dichloromethane, the reaction continued at room temperature for 3 hours. Borane dimethyl sulfide with synthesizing chiral the positioning function.Dropwise 300 ml quenching reaction of methanol, is added to the system again 100ml5% hydrogen peroxide and 20ml2N sulfuric acid, stirring 30 minutes, the organic layer is separated. Using 200ml2N sulfuric acid and 500ml5% wash once all sodium bisulfite solution, concentrating the organic layer to dry. Wherein F is fluoro, Ph is phenyl.Then using 200 ml isopropanol to dissolve residue, dripping 40 ml deionized water. Solid precipitated gradually during the dropping, the stirring at room temperature dropwise 2-3h, filtered, the filter cake drying to obtain 45g white solid.Detection method: high performance liquid chromatography (China Pharmacopoeia 2015 year version of the two-section appendix VD).Octadecyl silane bonds and silica gel as a filler, with cheap acetonitrile mobile phase, column temperature is 40 C, detection wavelength of 245 nm, flow rate is 0.5 ml/min. Isomer and weighed amount of product, respectively, using the mobile phase containing the dissolved and diluted into 0.01 mg/ml, diastereoisomer 0.01 mg/ml, isomer 0.01 mg/ml solution, as the system application solution. Applicability of system solution precision measuring 20ul, into the liquid chromatograph, and record chroatogram, diastereoisomer, vigiv, isomer peak in turn, non-enantiomer of the retention time of about 20 min, the main peak of the retention time of about 15 min, isomer produces the peak about 25 min, the main peak and the degree of separation of the isomer should be more than 2.0.The product weighed for proper amount of mobile phase containing the dissolved and diluted to 1.0 mg/ml solution is used for the solution of the sample. Sample solution taking precise quantity 20ul, into the liquid chromatograph, calculated normalization according to the area, such as in the chromatogram of the sample corresponding to isomer chromatographic peaks, the peak area of the isomer should not be more than the main peak and the sum of the peak area of 0.1%.Chromatographic conditions and system suitability test: with octadecyl silane bo...

Reference： [1]Patent: CN105237492,2016,A .Location in patent: Paragraph 0021-0034

67
cis-2-(4-fluorophenyl)cyclohexylamine [ No CAS ]
[ 149437-76-3 ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 17566 - 17570

68
(1S,2R)-trans-2-(4-fluorophenyl)-1-cyclohexanol [ No CAS ]
[ 149437-76-3 ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 17566 - 17570

69
[ 149437-76-3 ]
[ 953805-20-4 ]

Reference： [1]Patent: CN106397292,2017,A

70
[ 149437-76-3 ]
[ 953805-22-6 ]

Reference： [1]Patent: CN106397292,2017,A

71
[ 149437-76-3 ]
[ 953805-24-8 ]

Reference： [1]Patent: CN106397292,2017,A

72
[ 149437-76-3 ]
[ 190595-65-4 ]

Reference： [1]Patent: CN106397292,2017,A

73
[ 149437-76-3 ]
[ 163222-32-0 ]

Reference： [1]Patent: CN106397292,2017,A

74
[ 149437-76-3 ]
[ 937798-07-7 ]

Reference： [1]Patent: CN104513187,2017,B
[2]Organic Letters,2020,vol. 22,p. 818 - 822

75
[ 149437-76-3 ]
C₄₅H₅₈F₂N₂O₅Si₂ [ No CAS ]

Reference： [1]Patent: CN104513187,2017,B

76
[ 149437-76-3 ]
C₄₁H₄₆F₂N₂O₆Si [ No CAS ]

Reference： [1]Patent: CN104513187,2017,B

77
[ 149437-76-3 ]
[ 795306-57-9 ]

Reference： [1]Patent: CN104513187,2017,B

78
[ 108-48-5 ]
[ 149437-76-3 ]
(±)-5-(4-fluorophenyl)-5-hydroxy-6-(6-methylpyridin-2-yl)hexanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		General procedure: In a 50 mL dry three-neck round-bottom flask was introduced asolution of 2,6-lutidine (2 equiv, 0.09 mmol) in THF underargon. The solution was cooled to -78 C and a solution of s-BuLi(1.4 M in cyclohexane, 2.3 equiv) was added dropwise to thereaction mixture, which was then stirred for 15-30 min at -78 C.A solution of the electrophile of choice (1 equiv) in THF wasthen added dropwise and stirred for 15-60 min at -78 C.The crude reaction was quenched with a sat. aq NH4Cl solution at -78 C and allowed to warm up to r.t. The aqueous phase wasthen extracted three times with EtOAc. The combined organiclayers were washed with a sat. solution of NaCl, dried overanhydrous MgSO4, and concentrated under reduced pressure.The crude residue was purified by flash chromatography (gradientof eluent from 100% heptane to 100% EtOAc) to afford thedesired products (6a,b, 9 and 9? series, and 12; for 15 see theSupporting Information).

Reference： [1]Synlett,2017,vol. 28,p. 1219 - 1223

79
[ 108-48-5 ]
[ 149437-76-3 ]
(±)-6-(4-fluorophenyl)-6-((6-methylpyridin-2-yl)-methyl)tetrahydro-2H-pyran-2-one [ No CAS ]

Reference： [1]Synlett,2017,vol. 28,p. 1219 - 1223

80
[ 149437-76-3 ]
C₂₀H₁₉ClFNO₄ [ No CAS ]

Reference： [1]Patent: CN104230978,2016,B

81
[ 149437-76-3 ]
C₃₉H₄₅ClF₂N₂O₅Si₂ [ No CAS ]

Reference： [1]Patent: CN104230978,2016,B

82
(S)-4-(2-chlorophenyl)-1,3-oxazolidin-2-one [ No CAS ]
[ 149437-76-3 ]
C₂₀H₁₇ClFNO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.7%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 12h;	A 500ml three-neck flask was added 5- (4-fluorophenyl) 5-carbonyl acid (20g, 95mmol), (S ) -4- (2-chlorophenyl) -2-oxazolone (19g, 96mmol ), N, N'- dicyclohexyl carbodiimide (19.8g, 96mmol) and dichloromethane 200ml, stirred at room temperature for 12 hours.Filtration, the organic layer was washed with 3% diluted hydrochloric acid (80ml) with.The organic layer was concentrated and from isopropanol (150ml) crystallized product was filtered and dried.To give the product 31g, yield 83.7%.

Reference： [1]Patent: CN104230978,2016,B .Location in patent: Paragraph 0032-0034

83
[ 149437-76-3 ]
6-(4-fluorophenyl)piperidin-2-one [ No CAS ]

Reference： [1]ChemSusChem,2019,vol. 12,p. 3778 - 3784
[2]Advanced Synthesis and Catalysis,2018,vol. 360,p. 686 - 695

84
[ 149437-76-3 ]
(R)-6-(4-fluorophenyl)piperidin-2-one [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 686 - 695
[2]Organic Letters,2020,vol. 22,p. 2707 - 2713

85
[ 149437-76-3 ]
[ 1394905-64-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2018,vol. 360,p. 686 - 695

86
[ 149437-76-3 ]
(S)-5-(4-fluorobenzoyl)-1-((R)-2-hydroxy-1-phenylethyl)piperidin-2-one [ No CAS ]
(R)-5-(4-fluorobenzoyl)-1-((R)-2-hydroxy-1-phenylethyl)piperidin-2-one [ No CAS ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 1079 - 1082

87
[ 50-00-0 ]
[ 149437-76-3 ]
4-(4-fluorobenzoyl)pent-4-enoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With piperidine; In pyridine; at 70℃; for 21h;	A flask was charged with AlCl3 (77.17 mmol, 10.29 g, 2.15 equiv) and dry CH2Cl2 (25 ml) under calcium chloride guard tube and the formed suspension was stirred on ice bath. Subsequently, a solution of glutaric anhydride 10 (35.8 mmol, 4.08 g) in dry CH2Cl2 (12 ml) was added dropwise (t < 8 C). The resulting mixture was stirred on ice bath for 30 minutes and fluorobenzene 11c (35.1 mmol, 3.37 g, 1.0 equiv) was carefully added afterwards. The cooling bath was removed and the mixture was stirred at room temperature for 19 hours, then it was carefully quenched with ice water (20 ml), conc. H2SO4 (10 ml) and again with ice water (60 ml), the aqueous layer was extracted with ethyl acetate (1 x 200 ml, 1 x 100 ml, 1 x 70 ml), the combined organics were washed with half-saturated brine (200 ml), dried over Na2SO4, filtered and concentrated. The crude product was crystallized from ethyl acetate to provide <strong>[149437-76-3]5-(4-fluorophenyl)-5-oxopentanoic acid</strong> (3.80 g, 51%) as a yellow-brown powder;3 mp 141-142 C; 1H NMR (300 MHz, CDCl3): delta = 2.08 (m, 2H), 2.51 (t, J = 7.2 Hz, 2H), 3.05 (t, J = 7.2 Hz, 2H), 7.13 (m, 2H), 7.99 (m, 2H). 5-(4-Fluorophenyl)-5-oxopentanoic acid (16.7 mmol, 3.50 g), paraformaldehyde (50.0 mmol, 1.50 g, 3.0 equiv) and piperidine (0.32 ml, 0.2 equiv) were dissolved/suspended in pyridine (15 ml) and stirred at 70 C for 21 hours. Afterwards, the mixture was poured into 1M H2SO4 (340 ml), the aqueous layer was extracted with ethyl acetate (4 x 100 ml), the combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EA/hexanes = 1/1 + 0.5% AcOH). The obtained product was repeatedly coevaporated with toluene (4 x 25 ml) under reduced pressure to remove the residual AcOH, yielding 4-(4-fluorobenzoyl)pent-4-enoic acid 9c (3.33 g, 90%) as an orange solid; mp 81-82 C; 1H NMR (300 MHz, CDCl3): delta = 2.62 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 5.65 (s, 1H), 5.92 (s, 1H), 7.12 (dd, J = 8.7, 8.7 Hz, 2H), 7.78 (dd, J = 5.7, 8.7 Hz, 2H), 10.74 (bs, 1H); 13C NMR (75 MHz, CDCl3): delta = 27.3, 32.5, 115.3 (d, JCF = 21.8 Hz), 126.7, 132.0 (d, JCF = 9.0 Hz), 133.7, 145.9, 165.3 (d, JCF = 252.5 Hz), 178.9, 196.2

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 1079 - 1082
[2]Organic Letters,2018,vol. 20,p. 3259 - 3262

88
[ 149437-76-3 ]
[ 1017158-54-1 ]

Reference： [1]Chirality,2018,vol. 30,p. 642 - 651

Same Skeleton Products

Related Products

Historical Records

Related Functional Groups of
[ 149437-76-3 ]

Fluorinated Building Blocks

[ 582-83-2 ]

1-(4-Fluorophenyl)butan-1-one

Similarity: 0.87

[ 2251-76-5 ]

2-(4-Fluorophenyl)-2-oxoacetic acid

Similarity: 0.86

[ 1999-00-4 ]

Ethyl 3-(4-fluorophenyl)-3-oxopropanoate

Similarity: 0.85

[ 407640-40-8 ]

2-(4-Fluoro-2-methylphenyl)acetic acid

Similarity: 0.85

[ 2840-44-0 ]

7-Fluoro-3,4-dihydronaphthalen-1(2H)-one

Similarity: 0.85

Aryls

[ 582-83-2 ]

1-(4-Fluorophenyl)butan-1-one

Similarity: 0.87

[ 2251-76-5 ]

2-(4-Fluorophenyl)-2-oxoacetic acid

Similarity: 0.86

[ 1999-00-4 ]

Ethyl 3-(4-fluorophenyl)-3-oxopropanoate

Similarity: 0.85

[ 407640-40-8 ]

2-(4-Fluoro-2-methylphenyl)acetic acid

Similarity: 0.85

[ 2840-44-0 ]

7-Fluoro-3,4-dihydronaphthalen-1(2H)-one

Similarity: 0.85

Ketones

[ 582-83-2 ]

1-(4-Fluorophenyl)butan-1-one

Similarity: 0.87

[ 2251-76-5 ]

2-(4-Fluorophenyl)-2-oxoacetic acid

Similarity: 0.86

[ 1999-00-4 ]

Ethyl 3-(4-fluorophenyl)-3-oxopropanoate

Similarity: 0.85

[ 2840-44-0 ]

7-Fluoro-3,4-dihydronaphthalen-1(2H)-one

Similarity: 0.85

[ 456-03-1 ]

1-(4-Fluorophenyl)propan-1-one

Similarity: 0.84

Carboxylic Acids

[ 2251-76-5 ]

2-(4-Fluorophenyl)-2-oxoacetic acid

Similarity: 0.86

[ 407640-40-8 ]

2-(4-Fluoro-2-methylphenyl)acetic acid

Similarity: 0.85

[ 459-31-4 ]

3-(4-Fluorophenyl)propanoic acid

Similarity: 0.84

[ 589-06-0 ]

4-(4-Fluorophenyl)butyric Acid

Similarity: 0.84

[ 583880-95-9 ]

2-(Carboxymethyl)-5-fluorobenzoic acid

Similarity: 0.84

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
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. 149437-76-3 ] {[proInfo.proName]}

Quality Control of [ 149437-76-3 ]

Related Doc. of [ 149437-76-3 ]

Product Details of [ 149437-76-3 ]

Calculated chemistry of [ 149437-76-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 149437-76-3 ]

Application In Synthesis of [ 149437-76-3 ]

[ 149437-76-3 ] Synthesis Path-Upstream 1~5

[ 149437-76-3 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 149437-76-3 ]

Fluorinated Building Blocks

Aryls

Ketones

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 149437-76-3 ]