[ CAS No. 70627-52-0 ] {[proInfo.proName]}

Name: 70627-52-0|N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline|95%
Brand: Ambeed
SKU: A130033
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Quality Control of [ 70627-52-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 70627-52-0 ]

SDS Specification

Alternatived Products of [ 70627-52-0 ]

Product Details of [ 70627-52-0 ]

CAS No. :	70627-52-0	MDL No. :	MFCD00017951
Formula :	C₂₀H₁₆FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IWNBEFDVKWCBFY-UHFFFAOYSA-N
M.W :	305.35	Pubchem ID :	791783
Synonyms :

Calculated chemistry of [ 70627-52-0 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.05
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	91.07
TPSA :	21.59 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.6
Log Po/w (XLOGP3) :	4.79
Log Po/w (WLOGP) :	5.42
Log Po/w (MLOGP) :	4.47
Log Po/w (SILICOS-IT) :	5.77
Consensus Log Po/w :	4.81

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-5.0
Solubility :	0.00305 mg/ml ; 0.00001 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.98
Solubility :	0.00323 mg/ml ; 0.0000106 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-7.93
Solubility :	0.00000355 mg/ml ; 0.0000000116 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.55

Safety of [ 70627-52-0 ]

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 [ 70627-52-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 70627-52-0 ]
Downstream synthetic route of [ 70627-52-0 ]

[ 70627-52-0 ] Synthesis Path-Upstream 1~5

1
[ 4397-53-9 ]
[ 371-40-4 ]
[ 70627-52-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 40℃;	P-Fluoroaniline (100 g, 1.1 eq) and isopropanol (1730 ml, 10 V) were added and heated to 40 ° C. with mechanical stirring to precipitate a large amount of a pale yellow crystalline solid gradually, Stir over time and monitor until reaction is complete. The heating was stopped, the temperature was naturally lowered to room temperature while stirring, extraction and filtration were carried out, the filter cake was washed off with cold isopropanol, and after drying, a pale yellow crystalline substance SM 2 was obtained, the mass was 238 g , The yield is 95percent, and the purity is 99percent.
93.6%	Reflux; Large scale	The p-fluoroaniline (1.11kg, 10mol) and 4-benzyloxybenzaldehyde (2.12kg, 10mol) were added to 10L of toluene and refluxed. After the reaction was completed, the solvent was evaporated and the solvent was normal. n-hexane and ethyl acetate 10:1 Crystallization gave Compound 4 (2.85 kg) in 93.6percent yield.

Reference： [1] Patent: JP2016/147843, 2016, A, . Location in patent: Paragraph 0016
[2] Patent: CN107793339, 2018, A, . Location in patent: Paragraph 0021; 0023; 0031; 0038
[3] Pharmacy and Pharmacology Communications, 2000, vol. 6, # 1, p. 25 - 29
[4] Journal of Organic Chemistry, 2018,

2
[ 100-39-0 ]
[ 123-08-0 ]
[ 371-40-4 ]
[ 70627-52-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: at 20℃; for 12 h; Stage #2: for 4 h; Reflux	100 ml of DMF, p-hydroxybenzaldehyde (12.2 g, 0.1 mol), potassium carbonate (16.6 g, 0.12 mol) were successively added to a 250 ml three-necked flask, Benzyl bromide (20.4 g, 0.12 mol) was added dropwise, Room temperature reaction for 12 hours, The reaction solution was poured into ice water, Solid precipitation,filter, Washed cake, The filter cake is dry. To give benzyl-protected p-hydroxybenzaldehyde (26.2 g)Yield 91percent. And then take another 250ml single neck round bottom flask, Followed by adding 100 ml of acetone, benzyl-protected p-hydroxybenzaldehyde (14.4 g, 0.05 mol), p-fluoroaniline (5.55 g, 0.05 mol) After the reaction was refluxed for 4 h, the reaction solution was cooled to 5 ° C to precipitate a solid, filter, The solid was washed with cold acetone, The solid was dried to give N-(4-fluorophenyl)-4-benzyloxybenzylideneamine (Compound IV) 14g, Yield 92percent.

Reference： [1] Patent: CN106397292, 2017, A, . Location in patent: Paragraph 0092; 0093
[2] Patent: WO2008/96372, 2008, A2, . Location in patent: Page/Page column 17

3
[ 123-08-0 ]
[ 70627-52-0 ]

Reference： [1] Patent: JP2016/147843, 2016, A,

4
[ 100-44-7 ]
[ 70627-52-0 ]

Reference： [1] Patent: JP2016/147843, 2016, A,

5
[ 99395-88-7 ]
[ 70627-52-0 ]

Reference： [1] Patent: CN105439929, 2016, A, . Location in patent: Paragraph 0029

[ 70627-52-0 ] Synthesis Path-Downstream 1~58

1
[ 5469-16-9 ]
[ 70627-52-0 ]
[ 221349-56-0 ]
(3S,4R)-4-(4-Benzyloxy-phenyl)-3-((S)-1,2-dihydroxy-ethyl)-1-(4-fluoro-phenyl)-azetidin-2-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718

2
[ 591-80-0 ]
[ 352-34-1 ]
[ 70627-52-0 ]
1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-1-E-propenyl)-4-(4-benzyloxyphenyl)-2-azetidinone [ No CAS ]
1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-2-E-propenyl)-4-(4-benzyloxyphenyl)-2-azetidinone [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 5735 - 5742

3
[ 4397-53-9 ]
[ 371-40-4 ]
[ 70627-52-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	In isopropyl alcohol; at 40℃;	P-Fluoroaniline (100 g, 1.1 eq) and isopropanol (1730 ml, 10 V) were added and heated to 40 C. with mechanical stirring to precipitate a large amount of a pale yellow crystalline solid gradually, Stir over time and monitor until reaction is complete. The heating was stopped, the temperature was naturally lowered to room temperature while stirring, extraction and filtration were carried out, the filter cake was washed off with cold isopropanol, and after drying, a pale yellow crystalline substance SM 2 was obtained, the mass was 238 g , The yield is 95%, and the purity is 99%.
93.6%	In toluene;Reflux; Large scale;	The p-fluoroaniline (1.11kg, 10mol) and 4-benzyloxybenzaldehyde (2.12kg, 10mol) were added to 10L of toluene and refluxed. After the reaction was completed, the solvent was evaporated and the solvent was normal. n-hexane and ethyl acetate 10:1 Crystallization gave Compound 4 (2.85 kg) in 93.6% yield.

Reference： [1]Patent: JP2016/147843,2016,A .Location in patent: Paragraph 0016
[2]Patent: CN107793339,2018,A .Location in patent: Paragraph 0021; 0023; 0031; 0038
[3]Pharmacy and Pharmacology Communications,2000,vol. 6,p. 25 - 29
[4]Journal of Organic Chemistry,2018,vol. 83,p. 11886 - 11895

4
[ 204589-92-4 ]
[ 70627-52-0 ]
4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-[3-(4-fluorophenyl)propyl]-2-azetidinone [ No CAS ]

Reference： [1]Pharmacy and Pharmacology Communications,2000,vol. 6,p. 25 - 29

5
[ 70627-52-0 ]
1-(4-fluorophenyl)-[3-(4-fluorophenyl)propyl]-4-(4-hydroxyphenyl)-2-azetidinone [ No CAS ]

Reference： [1]Pharmacy and Pharmacology Communications,2000,vol. 6,p. 25 - 29
[2]Tetrahedron,2000,vol. 56,p. 5735 - 5742

6
[ 70627-52-0 ]
N-(4-fluorophenyl)-5-(4-fluorophenyl)-2-(4-hydroxybenzyl)pentanamide [ No CAS ]

Reference： [1]Pharmacy and Pharmacology Communications,2000,vol. 6,p. 25 - 29

7
[ 70627-52-0 ]
1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-2-E-propenyl]-4-(4-hydroxyphenyl)-2-azetidinone [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 5735 - 5742

8
[ 70627-52-0 ]
4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-[3-(4-fluorophenyl)propyl]-2-azetidinone [ No CAS ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 5735 - 5742
[2]Tetrahedron,2000,vol. 56,p. 5735 - 5742

9
[ 70627-52-0 ]
[ 191330-56-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718

10
[ 70627-52-0 ]
[ 190595-65-4 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718
[2]Patent: CN106397292,2017,A

11
[ 70627-52-0 ]
[ 163222-33-1 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718
[2]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718
[3]Patent: CN106397292,2017,A
[4]Patent: CN102850390,2017,B
[5]Patent: CN107793339,2018,A

12
[ 70627-52-0 ]
[ 163222-32-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718
[2]Patent: CN106397292,2017,A
[3]Patent: CN107793339,2018,A

13
[ 70627-52-0 ]
[ 221349-58-2 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718
[2]Patent: CN105439929,2016,A

14
[ 70627-52-0 ]
[ 221349-60-6 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718

15
[ 70627-52-0 ]
[ 231301-00-1 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 3714 - 3718

16
[ 1501-26-4 ]
[ 99395-88-7 ]
[ 133472-27-2 ]
[ 70627-52-0 ]
[ 191330-56-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1): To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2Cl2 (200 mL), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 mL, 0.61 mol) and the reaction mixture was cooled to 0 C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2Cl2 (375 mL) dropwise over 1 h, and the reaction was allowed to warm to 22 C. After 17 h, water and H2SO4 (2N, 100 mL), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCl (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product. Step 2): To a solution of TiCl4 (18.2 mL, 0.165 mol) in CH2Cl2 (600 mL) at 0 C., was added titanium isopropoxide (16.5 mL, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2Cl2 (100 mL). After 5 min., diisopropylethylamine (DIPEA) (65.2 mL, 0.37 mol) was added and the reaction mixture was stirred at 0 C. for 1 h, the reaction mixture was cooled to -20 C., and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20 C., then acetic acid was added as a solution in CH2Cl2 dropwise over 15 min, the reaction mixture was allowed to warm to 0 C., and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate. Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 mL) at 50 C., was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 mL, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 50 C. for an additional 3 h. The reaction mixture was cooled to 22 C., CH3OH (10 mL), was added. The reaction mixture was washed with HCl (1 N), NaHCO3 (1 N) and NaCl (sat'd.), and the organic layer was dried over MgSO4. Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 mL), was added water (1 mL) and LiOH.H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22 C. for 1 h and then additional LiOH.H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCl (1 N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2Cl2 at 22 C., was added ClCOCOCl (0.29 mL, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo. Step 5): To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1 M in THF, 4.4 mL, 4.4 mmol) and ZnCl2 (0.6 g, 4.4 mmol) at 4 C., was added tetrakis(triphenyl-phosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 mL). The reaction was stirred for 1 h at 0 C. and then for 0.5 h at 22 C. HCl (1 N, 5 mL) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone: HRMS calc'd for C24H19F2NO3=408.1429, found 408.1411.

Reference： [1]Patent: US2006/69080,2006,A1 .Location in patent: Page/Page column 26-27

17
[ 1501-26-4 ]
[ 99395-88-7 ]
[ 133472-27-2 ]
[ 70627-52-0 ]
[ 163222-31-9 ]

Yield	Reaction Conditions	Operation in experiment
		Compound of Formula (II); Step 1):; To a solution of (S)-4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH2CI2 (200 mL), was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) and triethylamine (84.7 mL, 0.61 mol) and the reaction mixture was cooled to 0C. Methyl-4-(chloroformyl)butyrate (50 g, 0.3 mol) was added as a solution in CH2CI2 (375 mL) dropwise over 1 h, and the reaction was allowed to warm to 22C. After 17 h, water and H2SO4 (2N, 100 mL), was added the layers were separated, and the organic layer was washed sequentially with NaOH (10%), NaCI (sat'd) and water. The organic layer was dried over MgSO4 and concentrated to obtain a semicrystalline product.; Step 2):; To a solution of TiCI4 (18.2 mL, 0.165 mol) in CH2CI2 (600 mL) at0C, was added titanium isopropoxide (16.5 mL, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2CI2 (100 mL). After 5 min., diisopropylethylamine (DIPEA) (65.2 mL, 0.37 mol) was added and the reaction mixture was stirred at 0C for 1 h, the reaction mixture was cooled to -20C, and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20C, then acetic acid was added as a solution in CH2CI2 dropwise over 15 min, the reaction mixture was allowed to warm to 0C, and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate.; Step 3):; To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 mL) at 50C, was added N,O-bis(trimethylsilyl)acetamide (BSA) (7.50 mL, 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture stirred at 50C for an additional 3 h. The reaction mixture was cooled to 22C, CH3OH (10 mL), was added. The reaction mixture was washed with HCI (1N), NaHCOe (1 N) and NaCI (sat'd.), and the organic layer was dried over MgSO4.; Step 4):; To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 mL), was added water (1 mL) and LiOH-H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22C for 1 h and then additional LiOH-H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCI (1 N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2CI2 at EPO <DP n="306"/>22C, was added CIC(O)C(O)CI (0.29 ml_, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.; Step 5):; To an efficiently stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1 M in THF, 4.4 mL, 4.4 mmol) and ZnCI2 (0.6 g, 4.4 mmol) at 4C, was added tetrakis(triphenyl- phosphine)palladium (0.25 g, 0.21 mmol) followed by the product of Step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 mL). The reaction was stirred for 1 h at 0C and then for 0.5 h at 22C. HCI (1N, 5 mL) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to obtain 1 -(4-f luorophenyl)-4(S)-(4-hydroxyphenyl)- 3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone: HRMS calc'd for C24Hi9F2NO3 = 408.1429, found 408.1411.

Reference： [1]Patent: WO2006/60461,2006,A1 .Location in patent: Page/Page column 303-305

18
[ 70627-52-0 ]
[ 917392-16-6 ]

Yield	Reaction Conditions	Operation in experiment
		Step-c: Preparation of compound of formula- VII.; Titanium tetrachloride (18 ml) and dichloromethane (600ml) were taken into a clean RBF, cooled the reaction mixture to 0C and added titanium isopropoxide (16 ml) at 0-5C. Dissolved the Formula-V material (50 gm) in dichloromethane and added to the reaction mass at 0-5C and maintained the reaction mass for 15 minutes. Diisopropyl ethyl amine (65 ml) is added to the reaction mixture and maintained for 45 minutes and cooled to -20 to -10C and charged the benzylated imine (92 gm) of formula- VI to the reaction mixture, maintained for 4 hrs at -20 to -1O0C. Quenched the reaction with acetic acid and washed the organic layer with sulfuric acid solution , distilled the solvent completely and material is recrystalised in methanol. Yield: 65 gm.

Reference： [1]Patent: WO2006/137080,2006,A1 .Location in patent: Page/Page column 12

19
[ 100-39-0 ]
[ 123-08-0 ]
[ 371-40-4 ]
[ 70627-52-0 ]

Yield	Reaction Conditions	Operation in experiment
92%		100 ml of DMF, p-hydroxybenzaldehyde (12.2 g, 0.1 mol), potassium carbonate (16.6 g, 0.12 mol) were successively added to a 250 ml three-necked flask, Benzyl bromide (20.4 g, 0.12 mol) was added dropwise, Room temperature reaction for 12 hours, The reaction solution was poured into ice water, Solid precipitation,filter, Washed cake, The filter cake is dry. To give benzyl-protected p-hydroxybenzaldehyde (26.2 g)Yield 91%. And then take another 250ml single neck round bottom flask, Followed by adding 100 ml of acetone, benzyl-protected p-hydroxybenzaldehyde (14.4 g, 0.05 mol), p-fluoroaniline (5.55 g, 0.05 mol) After the reaction was refluxed for 4 h, the reaction solution was cooled to 5 C to precipitate a solid, filter, The solid was washed with cold acetone, The solid was dried to give N-(4-fluorophenyl)-4-benzyloxybenzylideneamine (Compound IV) 14g, Yield 92%.
		Example 3: Preparation of Benzylated Schiff Base p-Hydroxy benzaldehyde (100 g) was taken along with demineralized water (1.0 L), sodium hydroxide (34.40 g) and stirred at ambient temperature for 5 minutes. Dichloromethane (750 ml) and tetrabutylammonium bromide (26.40 g) were added and stirred for 10 minutes. Benzyl bromide (107 ml) was added and then the reaction mass was stirred at 25-3O0C for 90 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (200 ml) and the extraction was added to the main organic layer. The combined organic layer was washed with 10% aqueous sodium hydroxide solution (2x500 ml), demineralized water (500 ml) and finally with 10% brine (1.0 L). Solvent was distilled out completely at atmospheric pressure. Isopropyl alcohol (1.20 L) was added and the reaction mass was heated to 600C to get a clear solution. 4-Fluoroaniline (156 g) was added dropwise and then the reaction mass was maintained at 600C for 2 hours. After 2 hours the reaction mass was cooled to ambient temperature and stirred for 30 minutes. The solid was filtered and washed with isopropyl alcohol (100 ml) and then with hexane (100 ml). Finally the solid was dried under vacuum at 50-600C to get 230 g of benzylated Schiff base having purity of 95.97% by HPLC.

Reference： [1]Patent: CN106397292,2017,A .Location in patent: Paragraph 0092; 0093
[2]Patent: WO2008/96372,2008,A2 .Location in patent: Page/Page column 17

20
[ 1046809-83-9 ]
[ 70627-52-0 ]
[ 1046809-84-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4: Preparation of 44(4-benzyloxy-phenyl)-(4-fluoro-phenylaniino)-methyri-5-oxo- 5-(2-oxo-4-phenyl-oxazolidin-3-yl)pentanoic acid benzyl esterDichloromethane (1.532 L) was cooled to O0C under nitrogen atmosphere. Titanium tetrachloride (37.53 ml) and Titanium isopropoxide (32.40 ml) were added and the reaction mass was stirred at 0 to -5C for 15 minutes. A solution of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester (125 g) in methylene chloride (375 ml) was added slowly at 0 to -5C. The reaction mass was stirred at 0 to -5C for 30 minutes. Diisopropylethylamine (166.8 ml) was <n="19"/>added dropwise at O to -50C and then the reaction mass was stirred at 0 to -50C for 60 minutes. The reaction mass was cooled to -25C and benzylated schiff base (115 g) was added. The reaction mass was maintained at -15 to -2O0C for 6 hours. After 6 hours the reaction mass was cooled to -3O0C and then a solution of acetic acid (100 ml) and dichloromethane (100 ml) was added slowly at -30 to -250C. The reaction mass was poured into 7% aqueous tartaric acid solution (1.75 L) precooled to 00C. The temperature of reaction mass was raised to 25C and then maintained for 30 minutes. 20% aqueous sodium bisulfite solution (625.50 ml) was added and then the reaction mass was stirred at 25-3O0C for 30 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (250 ml) and added to the main organic layer. The combined organic layer was washed with demineralized water (2x800 ml). Solvent was removed by distillation at atmospheric pressure and finally degassed under^-vacuum. Ethyl acetate (375 ml) was added and the reaction mass was heated to reflux temperature to get a clear solution. The reaction mass was cooled to 6O0C and then hexane (750 ml) was added slowly. The reaction mass was cooled to ambient temperature and maintained for 2 hours. The reaction mass was cooled to 0-50C and maintained at this temperature for 2 hours. The solid was filtered and washed with hexane (250 ml). Finally the solid was dried under vacuum at 50-550C to get 186 g of the title compound having purity of 99.48 % by HPLC.

Reference： [1]Patent: WO2008/96372,2008,A2 .Location in patent: Page/Page column 17-18

21
[ 477558-79-5 ]
[ 70627-52-0 ]
[ 934245-17-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2): To a solution of TiCl4 (18.2 ml, 0.165 mol) in CH2Cl2 (600 ml) at 0 C., was added titanium isopropoxide (16.5 ml, 0.055 mol). After 15 min, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH2Cl2 (100 ml). After 5 min., diisopropylethylamine (DIPEA) (65.2 ml, 0.37 mol) was added and the reaction mixture was stirred at 0 C. for 1 h, the reaction mixture was cooled to -20 C., and 4-benzyloxybenzylidine(4-fluoro)aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was stirred vigorously for 4 h at -20 C., then acetic acid was added as a solution in CH2Cl2 dropwise over 15 min, the reaction mixture was allowed to warm to 0 C., and H2SO4 (2N) was added. The reaction mixture was stirred an additional 1 h, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol/water to obtain the pure intermediate.

Reference： [1]Organic Process Research and Development,2009,vol. 13,p. 907 - 910
[2]Patent: US2005/96307,2005,A1 .Location in patent: Page/Page column 23

22
[ 942485-56-5 ]
[ 70627-52-0 ]
[ 954109-20-7 ]

Yield	Reaction Conditions	Operation in experiment
58%		Example 3 Preparation (S)-3-{(R)-2-[(S)-(4-(benzyloxyphenyl))-(4-fluoro phenylamino)methyl]-4-[2-(4-fluorophenyl)-[1,3]-dioxolan-2-yl]butyryl}-4-phenyloxazolidin-2-one (Compound VIa) in a 2.0 L flask, titanium tetraisopropoxide (9.31 g, 32.8 mmol) was added dropwise to a 1M solution of TiCl4 (136.5 g, 0.10 mol), which was cooled previously at 0 C. under N2. The mixture was stirred during 30 min. Next, a solution of (S)-3-{4-[2-(4-fluorophenyl)-[1,3]-dioxolan-2-yl]butyryl}-4-phenyloxazolidin-2-one (52.4 g, 0.13 mol) in dichloromethane (476 mL) was added, and the reaction mixture was stirred for 10 min at 0 C. Diisopropylethylamine (36.8 g, 0.28 mol) was then added, and the mixture was further stirred for 1 h at 0 C. The solution was then cooled to -15 C., and 4-benzyloxybenzylidine(4-fluoro)aniline (73.3 g, 0.24 mol) was added. The suspension was stirred at -15 C. for 4 h. The reaction was quenched by adding dropwise at -15 C. acetic acid (45.4 mL). Then the reaction mixture was allowed to warm at 0 C., and sulfuric acid 1M (47.6 mL) was added. The reaction mixture was stirred at 0 C. for 30 min and then allowed to warm at room temperature. Dichloromethane (300 mL) was added, the phases were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic solutions were washed with aqueous sodium hydrogencarbonate (300 mL), dried over sodium sulfate and concentrated under vacuum. Ethanol (350 mL) was added to the reaction mixture, and the resulting suspension was heated under reflux for 1 h. The mixture was cooled to 5 C. and filtered while cold. The solid was washed with cold ethanol (3*10 mL) yielding (S)-3-{(R)-2-[(S)-(4-(benzyloxyphenyl))-(4-fluorophenylamino)methyl]-4-[2-(4-fluorophenyl)-[1,3]-dioxolan-2-yl]butyryl}-4-phenyloxazolidin-2-one as a solid (54.2 g; Yield: 58%; 92% purity). The purity was increased to 97% with one recrystallization with acetonitrile.

Reference： [1]Patent: US2009/227786,2009,A1 .Location in patent: Page/Page column 15

23
[ 793673-93-5 ]
[ 70627-52-0 ]
trans-1-(4-fluorophenyl)-3-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		To a stirred solution of diisopropylamine (5.72g, 56.6mmol) intetrahydrofuran (13. 5ml) was added 2. 5M solution of n-butyl lithium(22. 64ML, 56.6mmol) in hexane slowly at-50C and stirred for 30minutes. A solution of (6S)-6- (4- fluorophenyl)tetrahydro-2H-pyran-2-one (5. 5g, 28.3 mmol) in tetrahydrofuran (37 ml)was added to the reaction mixture at-50C in 5 minutes. After about 15minutes of stirring at- 50C, DMPU (6ML) was added followed by theaddition of a solution of <strong>[70627-52-0]4-benzyloxybenzylidene-4-fluoroaniline</strong> (8.63g, 28. 3MMOL) in 68. 75ML of DMF in about 30 minutes. Stirring wascontinued for lhr at-50C and the reaction was quenched with 5.5 mlacetic acid. After 15 minutes stirring, the reaction mass was pouredinto a chilled mixture of 1M hydrochloric acid (250ML) and ethyl acetate(110ml) under vigorous stirring. The layers were separated and theaqueous layer was extracted with 100ml ethyl acetate. The combinedorganic layers were washed twice with 100ml of 10% sodium chloridesolution and dried over sodium sulphate. The organic layer wasevaporated to dryness under reduced pressure. The residue waschromatographed over silica gel (eluant : Hexane: Ethyl acetate 85: 15)to yield 9. 5g (yield: 67%) of the title product.'H NMR (CDC13) 8 : 7.40-7. 21 (M, 11H), 7.02-6. 87 (M, 6H), 5.04 (s,2H), 4.69 (M, 1H), 4. 55 (d, 1H), 3. 11-3. 04 (M, 1H), 2. 36 (brs, 1H),2.02-1. 77 (M, 4H)

Reference： [1]Patent: WO2004/99132,2004,A2 .Location in patent: Page 9-10

24
[ 1246611-03-9 ]
[ 70627-52-0 ]
C₄₁H₃₇F₂N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		6Og of the oxime (product of Example 1) was dissolved in dichloromethane (12OmL). To this solution was added TiCl4 (18.OmL) and titanium isopropoxide (15.OmL) in dichloromethane (78OmL) in an atmosphere of nitrogen. The reaction mixture was stirred for 30 - 40 min. at - 5 to O0C, diisopropylethylamine (58.5mL) was added and stirring was continued for 1 hr at the same temperature. This was then cooled further to about -25C and 4- benzyloxyben2ylidine-(4-fluoro)aniline (103.4g) was added to it. The reaction mixture was stirred for another 5 - 6 hrs at the same temperature after which a mixture of acetic acid (6OmL) and dichloromethane (12OmL) was added dropwise over 20 - 25min. This mixture was warmed to 0C and 2N H2SO4 (300ml) was added dropwise over 20 - 25min. The mixture was then warmed to 20 - 250C and stirring was continued for 1 hr, the layers were separated and the organic layer was washed with water (300ml) and brine (20% soln., 300ml). The solvent was distilled off u.v. to leave an oil which was crystallized from a mixture of ethyl acetate (240ml) and n-heptane (1200ml) to give a solid product (7Og). m.p.: 135 - 137C.1H NMR (DMSO-de, 200MHz) delta 7.54-7.11 (m, 16H)5 6.95-6.70 (m, 4H)5 6.68-6.50(m, 2H)5 5.97(d5 IH), 5.60 (dd, J= 4.45 &;3.63, IH), 5.02 (s, 2H)5 4.78 (t, J= 8.73, IH)5 4.48-4.30 (m, 2H)5 4.20-4.08 (?i, IH), 3.83 (s,3H), 2.85-2.52 (m, 3H)5 1.67 (bs, IH).MS = 690.94 (M+l)IR (KBr): 3388, 1755, 1697, 1608, 1509, 1386cm"1

Reference： [1]Patent: WO2010/113182,2010,A1 .Location in patent: Page/Page column 10

25
(S)-3-(5-(4-fluorophenyl)-5-(hydroxyimino)pentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]
[ 70627-52-0 ]
[ 1380431-22-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4: Preparation of(S)-3-((S)-2-((S)-(4-(benzyloxy)phenyl)(4- fluorophenylamino)methyl)-5-(4-fluorophenyl)-5-(hydroxyimino)pentanoyl)-4^2-oneIn a heatgun-dried round bottom flask containing 6.0mL methylene chloride, 0.65mL TiCl4 are added at 0C, followed by 0.5 lmL Ti(0'Pr)4 and the resulting creamy suspension is stirred at temperature of about 0C for 30 minutes. 2.0g of free oxime Ilia are dissolved in 7.8mL methylene chloride and added dropwise at 0C to the above mixture, stirring continues for 10 minutes then 2.35mL diisopropylethylamine are slowly added at 0C and the resulting red enolate mixture is further stirred for 1 hour at this temperature then cooled to temperature about -15C. A solution of 3.3g fluoroaniline IV in 22mL methylene chloride is added through an addition funnel at -15C. Stirring continues at this temperature for 5 hours, then the mixture is quenched at this temperature using 5mL acetic acid, left to reach 0C and lOmL HCl 1M and 30mL methylene chloride are added. After stirring at room temperature for 20 minutes, the organic layer is washed with lOmL HCl 1M, lOmL water and lOmL brine then dried over sodium sulfate and evaporated under reduced pressure to afford crude Va as a 16: 1 mixture of diastereomers. The residue is purified through column chromatography eluting with 1% methanohmethylene chloride affording 512mg of pure Va.Analytical data for Va (major isomer):mp: 198.0-198.8C;LC-MS (CI+) m/z: 676 (M+), 677 (MH+), 678 (M+2H+);IR (KBr) cm 1:3440, 3352, 3060, 3033, 2920 ,1759, 1688, 1609, 1509, 1456, 1390, 1323, 1271, 1241, 1223, 1115, 1107, 1043, 1021, 920, 836, 825, 759, 752, 719, 698, 586;1H NMR (300 MHz, CDC13) delta 7.54 - 7.29 (m, H), 7.21 - 6.94 (m, 1H), 6.85 - 6.64 (m, 1H), 6.44 (d, J = 5.0 Hz, 1H), 5.42 (d, J = 6.5 Hz, 1H), 4.96 (s, 1H), 4.61 (t, J = 8.5 Hz, 1H), 4.48 - 4.36 (m, 1H), 4.30 (d, J = 9.0 Hz, 1H), 4.17 (dd, J = 8.5, 2.3 Hz, 1H), 3.05 - 2.83 (m, 1H), 2.72 - 2.53 (m, 1H), 2.10 - 1.90 (m, 1H), 1.66 - 1.41 (m, 1H), 1.25 (s, 1H);13C NMR (75 MHz, CDC13) delta 174.49, 165.31, 162.00, 158.58, 158.34, 154.64, 141.75, 138.49,136.94, 130.66, 129.09, 128.76, 128.40, 128.20, 127.72, 125.44, 115.87, 115.84, 115.59, 115.54,114.95, 77.16, 70.38, 70.07, 60.31, 58.21, 47.63, 29.86, 26.27.

Reference： [1]Patent: WO2012/76030,2012,A1 .Location in patent: Page/Page column 10

26
[ 1380431-20-8 ]
[ 70627-52-0 ]
(S)-3-((S)-2-((S)-(4-(benzyloxy)phenyl)(4-fluorophenylamino)methyl)-5-(tert-butyldimethylsilyloxyimino)-5-(4-fluorophenyl)pentanoyl)-4-phenyloxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 5: Preparation of(S)-3-((S)-2-((S)-(4-(benzyloxy)phenyl)(4- fluorophenylamino)methyl)-5-(tert-butyldimethylsilyloxyimino)-5-(4-flwphenyloxazolidin-2-one In a heatgun-dried round bottom flask containing 21mL methylene chloride, 2.3mL TiCl4 are added at 0C, followed by 1.9mL Ti(0'Pr)4 and the resulting creamy suspension is stirred at 0C for 30 minutes. lO.Og of protected oxime IHb are dissolved in 30mL methylene chloride and added dropwise at 0C to the above mixture, stirring continues for 10 minutes then 8.0mL diisopropylethylamine are slowly added at 0C and the resulting red enolate mixture is further stirred for 1 hour at this temperature. It is then cooled to -15C (internal temperature) and a solution of 12.6g fluoroaniline IV in lOOmL methylene chloride is added through an addition funnel during 1 hour at -15C. Stirring continues at this temperature for 2 hours, then the mixture is quenched using lOmL acetic acid at this temperature and left to reach 0C. 30mL HCl 1M are added and the mixture is stirred at this temperature for 10 mins, then left to reach 25C. The layers are separated and the aqueous phase is washed with 30mL methylene chloride. The combined organic phases are washed with 20mL water and 20mL brine then dried over sodium sulfate and evaporated under reduced pressure. 120mL EtOH are added to the residue and the mixture is heated to 80C for 1 hour then cooled to 0C under stirring. 10.2g of pure compound Vb are collected as white flakes through filtration and a lOmL wash of cold EtOH.Analytical data for Vb:LC-MS (CI+) m/z: 789 (M+);IR (KBr) cm"1: 3360, 3033, 2952, 2930, 2856, 1773, 1689, 1608, 1510, 1453, 1384, 1320, 1250, 1218, 1108, 950, 929, 840, 825, 801, 785, 700, 533, 528;1H NMR (300 MHz, CDC13) delta 7.54 (dd, J = 8.8, 5.4 Hz, 2H), 7.45 - 7.29 (m, 6H), 7.16 - 6.95 (m, 8H), 6.89 - 6.79 (m, 2H), 6.78 - 6.66 (m, 2H), 6.41 - 6.32 (m, 2H), 5.36 (dd, J = 8.5, 3.2 Hz, 1H), 4.99 (s, 2H), 4.66 - 4.43 (m, 2H), 4.32 (d, J = 8.9 Hz, 1H), 4.16 (dd, J = 8.7, 3.2 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.65 - 2.50 (m, 1H), 2.04 - 1.86 (m, 1H), 1.71 - 1.54 (m, 1H), 0.89 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H);13C NMR (75 MHz, CDC13) delta 175.26, 164.27, 161.01, 159.46, 159.44, 158.36, 157.68, 154.57, 143.05, 143.03, 138.60, 138.12, 138.08, 137.23, 133.28, 129.07, 128.74, 128.36, 128.24, 128.13, 127.66, 127.57, 125.49, 115.70, 115.40, 115.27, 115.18, 115.12, 114.91, 109.91, 77.16, 70.25, 64.78, 64.44, 64.37, 61.68, 58.26, 48.00, 37.60, 24.91, 18.58.

Reference： [1]Patent: WO2012/76030,2012,A1 .Location in patent: Page/Page column 10-11

27
[ 70627-52-0 ]
C₂₄H₂₀FNO₃ [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 298 - 300

28
[ 70627-52-0 ]
C₃₁H₂₈FNO₆S [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 298 - 300

29
[ 70627-52-0 ]
(3S,4S)-4-(4-Benzyloxy-phenyl)-3-[(S)-2-(4-fluoro-phenoxy)-1-hydroxy-ethyl]-1-(4-fluoro-phenyl)-azetidin-2-one [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 298 - 300

30
[ 70627-52-0 ]
⁽⁵⁷⁹⁾Sch₃₉ [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 298 - 300

31
[ 5469-16-9 ]
[ 70627-52-0 ]
[ 221349-56-0 ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 298 - 300

32
ethyl 3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propanoate [ No CAS ]
[ 70627-52-0 ]
ethyl-3-(4-(benzyloxy)benzyl)-3-((4-fluorophenyl)amino)-2-((S)-2-oxo-4-phenyloxazolidin-3-carbonyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		2 - ((S) -2-oxo-4-phenyloxazoline-3-carbonyl) -3- (4- (benzyloxy) Ethyl propionate,The structure is as follows:In a 250 ml three-necked flask,2.5 g of the compound prepared in Example 1 was added(S) -3-oxo-3- (2-oxo-4-phenyloxazolin-3-yl) propanoate (9 mmol, 1 eq)3.3 gN- (4-fluorophenyl) -4-benzyloxybenzylideneamine(11 mmol, 1.2 eq) and 100 ml of methylene chloride,Cooled to -30 & lt; 0 & gt; C under nitrogen blanket,1.75 g of diisopropylethylamine (13 mmol, 1.5 eq)After stirring for 10 minutes,2.1 g of titanium tetrachloride (11 mmol, 1.2 eq) was added,The reaction solution was reddish brown,Stirring was continued at -30 to -20 C for 3 hours,After completion of the reaction,The reaction was quenched by addition of 0.5 ml of acetic acid,50 ml of a 10% aqueous sodium bisulfite solution was added,The mixture was stirred at room temperature for 1 hour,The organic phase was separated,The organic phase was washed twice more with 100 ml of water,The obtained organic phase was distilled under reduced pressure to remove the solvent,The resulting residue was recrystallized from isopropanol (25 ml) and separated and dried to obtain the productYield: 76%

Reference： [1]Patent: CN105439929,2016,A .Location in patent: Paragraph 0037; 0038; 0039; 0040

33
[ 70627-52-0 ]
ethyl-(2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: CN105439929,2016,A

34
[ 3393-45-1 ]
[ 70627-52-0 ]
anti-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)-4-phenylazetidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%		To a solution of [RhCl(cod)]2(2 mol %) and <strong>[70627-52-0]N-(4-(benzyloxy)benzylidene)-4-fluoroaniline</strong>(1B, 0.5 mmol) in THF (1.25 mL) at room temperature was added BF3·Et2O (0.6 mmol), andthen it stirred for 30 min at the same temperature. Subsequently, 5,6-dihydro-2H-pyran-2-one (2h, 0.6 mmol) was added to the suspension mixture, and then 1.0 M Et2Zn in hexane (1.5 mmol, 1.5 mL) was gradually added to the mixture and stirred for 24 h. The mixture was quenched with sat. NH4Cl and extracted with AcOEt. The AcOEt layer was washed with sat. NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by column chromatography (AcOEt/hexane = 4:6) and anti diastereomer was obtained in 46% (93.3 mg) [2].

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 1608 - 1615

35
[ 3393-45-1 ]
[ 70627-52-0 ]
C₂₆H₂₆FNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With chloro(1,5-cyclooctadiene)rhodium(I) dimer; diethylzinc; aluminum isopropoxide; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere; Schlenk technique;Catalytic behavior;	General procedure: To a solution of [RhCl(cod)]2(2 mol %) in DMF at room temperature was added imine (1). Then, BF3·Et2O (1.2 equiv) wasadded to the mixture and stirred for 30 min at the same temperature. Subsequently, 5,6-dihydro-2H-pyran-2-one (2, 1.2 equiv)was added to the mixture and then 1.0 MEt2Zn in hexane(3 equiv) was gradually added to the mixture at room temperature, and the mixture was stirred for 24 h. The mixture wasquenched with sat. NH4Cl and extracted with AcOEt. TheAcOEt layer was washed with sat. NaCl and dried over MgSO4.The solvent was removed in vacuo, and the residue was purified by column chromatography to give the corresponding antiazetidin-2-one.

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 1608 - 1615

36
6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one [ No CAS ]
[ 70627-52-0 ]
4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one [ No CAS ]
[ 163380-15-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of [RhCl(cod)]2(2 mol %) and <strong>[70627-52-0]N-(4-(benzyloxy)benzylidene)-4-fluoroaniline</strong>(1B, 0.5 mmol) in THF (1.25 mL) at room temperature was added BF3·Et2O (0.6 mmol) was added to the mixture, and then it stirred for 30 min at the same temperature. Subsequently, 6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one (2j, 0.6 mmol) was added to the suspensionmixture, and then 1.0 M Et2Zn in hexane (1.5 mmol, 1.5 mL) was gradually added to the mixture and stirred for 24 h. The mixture was quenched with sat. NH4Cl and extracted with AcOEt. The AcOEt layer was washed with sat. NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by column chromatography (AcOEt/hexane = 5:5) to give 3Bj in 58% (144.9 mg).

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 1608 - 1615

37
C₂₇H₂₆FNO₄ [ No CAS ]
[ 70627-52-0 ]
3-[5-benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)methyl]-5-(4-fluoro-phenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8 g	With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -35 - -30℃;Inert atmosphere;	Example 10 Process for the Preparation of 3-[5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one 18 ml of Dichloromethane was added to 2.1 ml of TiCl4 at 20-25 C. under nitrogen atmosphere Cooled the reaction mass to 0 C., 2 ml of Ti(O-ipr)4 was added and stirred for about 15 minutes. To the reaction mass 50 ml Dichloromethane, 10 gms of 1-[5-Benzyloxy-5-(4-fluoro-phenyl)-pentanoyl]-5-phenyl-pyrrolidin-2-one and 13.7 gms of Imines were added at 20-25 C. under nitrogen atmosphere. The reaction mass was cooled -30to -35 C. and 5.8 gms of Diisopropyl ethyl amine was added. Stirred the reaction mass for about 15 minutes and TiCl4 solution was added. Stirred the reaction mass for about 2-3 hours at -30to -35 C. and 60 ml of isopropyl alcohol was added followed by 50 ml of Dichloromethane and stirred the reaction mass for about 60 minutes, 6% Tartaric acid solution was added to the reaction mass at 20-25 C. and stirred for about 2 hours. Separate the organic layer and extract the reaction mass with 100 ml of dichloromethane. Combined the organic layers and washed with H2O followed by brine solution. Separated the organic layer and dried over Sodium Sulfate. Distilled the solvent completely under reducing pressure at 50-55 C. and 500 ml of methanol was added. Stirred the reaction mass for about 1-2 hours at 20-25 C., filtered the compound, washed with methanol and dried at 60-65 C. to get 8 gms of 3-[5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one.

Reference： [1]Patent: US2016/280642,2016,A1 .Location in patent: Paragraph 0069

38
[ 1375257-24-1 ]
[ 70627-52-0 ]
(R)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		General procedure: To a solution of (S)-3-acetyl-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one (0.25 g, 0.9 mmol, 1.0 equiv.) in anhydrous THF (7 mL) at -78 C, LiHMDS (1.4 mL, 1.4 mmol, 1.5 equiv.) and TMEDA (0.2 mL, 1.4 mmol, 1.5 equiv.) were sequentially added under N2 atmosphere and stirred for 1h. Further, the imine (1.1 equiv. in 3 mL anhydrous THF) under N2 atmosphere was introduced into it and the reaction temperature was increased to 0 C. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aq. NH4Cl solution, extracted with EtOAc and further washed with brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude product which was further purified by column chromatography on silica gel (60-120 mesh) using a mixture of Hexane/EtOAc (9.5:0.5) as the eluent to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 346 - 348

39
[ 1185883-41-3 ]
[ 70627-52-0 ]
C₄₂H₄₀F₂N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.5%	With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -50℃; for 3.66667h;Inert atmosphere;	Under nitrogen, 4.4 g of titanium tetrachloride was added to methylene chloride and the temperature was lowered to 0 C. 2.4 g of tetraisopropyl titanate was added at this temperature and kept at 0 C for 30 min. 10 g of the starting material IV and 8.0 g of the compound (F) were dissolved in methylene chloride under a nitrogen atmosphere, and the mixture was cooled to -50 C. N, N-diisopropylethylamine (2.05 eq)The prepared titanium reagent was added dropwise to the reaction solution, and the solution was dropped for 40 minutes. Reaction was maintained at -50 C for 3 h, and the reaction was terminated by TLC. The reaction was quenched by the addition of isopropanol and methylene chloride keeping the temperature not exceeding -40 C. After stirring for 30 min, the reaction solution was poured into a pH = 7 tartaric acid buffer, and the solution was stirred. The organic phase was washed with water, saturated sodium chloride, dried, concentrated, beaten, filtered and dried to obtain 10 g of product IV-1 (yield: 62.5%).

Reference： [1]Patent: CN106279240,2017,A .Location in patent: Paragraph 0059; 0060; 0061

40
[ 75-77-4 ]
[ 70627-52-0 ]
[ 189028-95-3 ]
C₄₃H₄₄F₂N₂O₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		A 2 L three-necked flask was prepared, mechanically stirred, SM 2 (64.1 g, 1.5 eq), SM 1 (50 g, 1.0 eq) and dichloromethane (500 ml, 10 V) were added under nitrogen gas protection, Leave it in the tank, lower the temperature to -5 C with stirring, start the dropwise addition of diisopropylethylamine (DIPEA) (45.3 g, 2.5 eq), gradually make the solution into a clear solution.Chlorotrimethylsilane (TMSCl) (22.8 g, 1.5 eq) was slowly added dropwise, the internal temperature was maintained between -5 C. and 5 C., and the mixture was allowed to react for 2-3 hours with stirring, .Temperature lowering from -30 C. to -40 C. was continued and TiCl 4 (29.2 g, 1.1 eq) was added dropwise. After completion of the dropwise addition, reaction was carried out for 1 hour while maintaining the temperature as it was, and liquid chromatography . Dichloromethane (350 ml / 350 ml) was added dropwise under heat as it was, the temperature was controlled to -30 C. or lower by heat dissipation, stirred for 2 hours, further NaHSO 3 (250 ml) solution was added and stirred for 2 hours Reaction is carried out, liquid separation is carried out, the aqueous phase is extracted once with dichloromethane (250 ml), the organic phases are combined, dried with anhydrous sodium sulfate, filtered and concentrated.Dichloromethane (150 ml) was added to the concentrate and bistrimethylsilylacetamide (BSA) (36.94 g, 1.3 eq) was added and the mixture was heated to 50 C. and allowed to flow for 1 hour. Thin layer chromatography (TLC) was performed until completion of the reaction Monitor.The reaction solution was concentrated and dried, added with absolute ethanol (300 ml), stirred at room temperature for 1 hour, washed, extracted, filtered and dried to give an off-white solid of formula (III) (93 g) The yield is 93%, and the purity is 99%.

Reference： [1]Patent: JP2016/147843,2016,A .Location in patent: Paragraph 0017

41
[ 70627-52-0 ]
[ 189028-95-3 ]
[ 1185883-39-9 ]

Yield	Reaction Conditions	Operation in experiment
94%		A 1 L three-necked flask was prepared, mechanically stirred, SM 2 (45.8 g, 1.5 eq), SM 1 (35.7 g, 1.0 eq), dichloromethane (357 ml, 10 V) was added under nitrogen gas protection Leave in a low-temperature tank, lower the temperature to -5 C with stirring, start the dropwise addition of diisopropylethylamine (DIPEA) (32.5 g, 2.5 eq) and gradually make the solution into a clear solution.Reacted for 2 hours with stirring, monitored until the completion of the reaction, cooled continuously to -30 C., and TiCl 4 (20.9 g, 1.1 eq) was added dropwise. After completion of the dropwise addition, the temperature was maintained as it was React for 2 hours and monitor by liquid chromatography until completion of reaction.Dichloromethane (200 ml) was added dropwise at the same temperature, heat was released to control the temperature to -30 C. or lower, stirred for 2 hours, further added NaHSO 3 (150 ml) solution, reacted for 2 hours with stirring, The aqueous phase is extracted once with dichloromethane (150 ml), the organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated.

Reference： [1]Patent: JP2016/147843,2016,A .Location in patent: Paragraph 0020

42
[ 123-08-0 ]
[ 70627-52-0 ]

Reference： [1]Patent: JP2016/147843,2016,A

43
[ 100-44-7 ]
[ 70627-52-0 ]

Reference： [1]Patent: JP2016/147843,2016,A

44
[ 953805-20-4 ]
[ 70627-52-0 ]
[ 953805-22-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -5℃; for 3h;	In a 1000ml three-necked flask, 400 ml of a compound of III (44.1 g, 0.1 mol), IV (45.8 g, 0.15 mmol) in dichloromethane was added successively, The ice bath was cooled to -5 C, DIPEA (18.5 g, 0.15 mol) was added, A mixed solution of titanium tetraisopropoxide and titanium tetrachloride was slowly added dropwise at -5 C (the molar equivalents of the two solutions were 1: 1) After the dropwise addition, the reaction was carried out at -5 C for 3 hours, After the reaction, The reaction solution was poured into 500 ml of tartaric acid buffer solution of pH = 2, After stirring for 30 minutes, The organic dichloromethane layer was separated, The aqueous layer was extracted again with methylene chloride, The methylene chloride layers were then combined, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give 58.2 g of a white solid compound V, Yield 78%.

Reference： [1]Patent: CN106397292,2017,A .Location in patent: Paragraph 0053; 0095; 0096

45
[ 70627-52-0 ]
[ 953805-24-8 ]

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

46
[ 70627-52-0 ]
[ 189028-95-3 ]
C₄₀H₃₆F₂N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.9%	With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -30 - -20℃; for 5h;	The raw material (III) (10 g, 28.0 mmol)And the starting material (IV) (17 g, 55.7 mmol)Was added to a 500 mL three-necked flask,Installed thermometer,Addition funnel and drying tube,Dry methylene chloride (150 mL) was added,The mixture was cooled to -20 C.Diisopropylethylamine (5.8 mL, 33.3 mmol) was added,Temperature control to -30 .Isopropyl titanate (3.0 mL, 10 mmol) was added,Maintaining the temperature at -25 C to -30 C,Titanium tetrachloride (3.3 mL, 30 mmol) was added dropwise.Control temperature <-25 ,The reaction was stirred for 5 hours,The reaction end point was detected by TLC.A mixed solution of slow acetic acid / dichloromethane (10 ml / 10 ml) was added to the reaction mixture,Drop add 2N sulfuric acid 30ml,The temperature was raised to 30 C for 30 minutes,Add water 30ml,Take the organic layer,The aqueous layer was extracted with 50 ml of dichloromethane,Combined organic layer,Followed by water 50ml,Saline 50ml washing,Dried over anhydrous sodium sulfate.After the solvent was distilled off,Add methanol 50ml,Reflux evenly,Standing slowly inside temperature 35 ,filter,The filter cake was washed with methanol 10 ml x 2,The solid was added to 50 ml of methanol,Reflux for 4 hours,Standing slowly cooled to the internal temperature of 40 ~ 45 ,filter,Filter cake with a small amount of methanol washing,Dried to a white solid (11.3 g, 17.1 mmol)Yield 60.9%.

Reference： [1]Patent: CN102850390,2017,B .Location in patent: Paragraph 0019; 0020; 0021

47
[ 70627-52-0 ]
C₃₄H₃₅F₂NO₃Si [ No CAS ]

Reference： [1]Patent: CN102850390,2017,B

48
[ 793673-93-5 ]
[ 70627-52-0 ]
C₃₁H₂₇F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		Diisopropylethylamine (5.72 g, 56.6 mmol, 2 eq) was added to the reaction flask,14 ml of tetrahydrofuran,N-butyllithium solution (56.6 mmol, 2 eq),The reaction temperature was controlled at -50 ,Stir for 30 minutes,Compound C2 (5.5 g, 28.3 mmol, 1 eq) and 40 ml of tetrahydrofuran were added to the reaction flask,Continue to control the temperature at -50 for 25 minutes,DMPU (6 ml),4-benzyloxy-benzylidene-4-fluoroaniline (8.63g, 28.3mmol, 1eq),Tetrahydrofuran (70 ml) was added dropwise over 30 minutes,Dropping temperature of the process -50 ,The reaction was continued to maintain the reaction at -50 2 hours,Add 6ml acetic acid to quench the reaction,After the quenching reaction, the reaction solution was diluted with 200 ml of ethyl acetate,Then add 250ml of dilute hydrochloric acid at a concentration of 2%Separate the water phase,The organic phase was washed with 100 ml saturated brine again,Phase to get the organic phase,The solvent was removed by rotary evaporation,Column chromatography (petroleum ether: ethyl acetate = 5: 1)9.5g product was isolated,Yield 67%.

Reference： [1]Patent: CN107176920,2017,A .Location in patent: Paragraph 0051; 0052; 0053; 0054; 0055; 0056; 0057; 0058

49
[ 942485-56-5 ]
[ 70627-52-0 ]
[ 190595-65-4 ]

Yield	Reaction Conditions	Operation in experiment
88.94%	With N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride; In toluene; at 60℃;	Compound 3 (3.99 g, 10.0 mmol), compound 4 (3.55 g, 10.0 mmol) and N,O-bistrimethylsilylacetamide (BSA, 4.06 g, 20.0 mmol) were placed in 300 mL of toluene, and the temperature was raised to 60C. The mixture was stirred until the suspension was clear, tetrabutylammonium fluoride (TBAF, 0.1566 g, 0.6 mmol) was added, and the mixture was stirred at 60 DEG C. until most of the raw materials disappeared. After cooling, 10 mL of acetic acid was added and the toluene was concentrated under reduced pressure to remove toluene. The remaining oil was Drying under vacuum gave 4.418 g of Intermediate 5 with a yield of 88.94%.

Reference： [1]Patent: CN107793339,2018,A .Location in patent: Paragraph 0021; 0024; 0032; 0039

50
[ 70627-52-0 ]
[ 415960-63-3 ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 11886 - 11895

51
[ 70627-52-0 ]
C₃₉H₄₅F₂NO₄Si [ No CAS ]