452339-73-0|(R)-5-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one| Ambeed

Structure of 452339-73-0

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Quality Control of [ 452339-73-0 ] Purity: 97% SDS Specification

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Product Details of [ 452339-73-0 ]

CAS No. :	452339-73-0
Formula :	C₁₃H₁₅NO₄
M.W :	249.26
SMILES Code :	O=C1O[C@H](C2=CC=C(OC(C)(C)OC3)C3=C2)CN1
MDL No. :	MFCD21362968
InChI Key :	JUEBDVANOFZMMX-NSHDSACASA-N
Pubchem ID :	10933894

Safety of [ 452339-73-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 452339-73-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	6
Fraction Csp3	0.46
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	67.38
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	56.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.2
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.36
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.26
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.26
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.19
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.65

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.42
Solubility	0.941 mg/ml ; 0.00378 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.16
Solubility	1.74 mg/ml ; 0.007 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.48
Solubility	0.0829 mg/ml ; 0.000333 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.85 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.17

Application In Synthesis of [ 452339-73-0 ]

* 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.

Downstream synthetic route of [ 452339-73-0 ]

[ 452339-73-0 ] Synthesis Path-Downstream 1~35

1
[ 94749-73-2 ]
[ 452339-73-0 ]
[ 590410-68-7 ]

References: [1]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.

2
[ 452339-72-9 ]
[ 452339-73-0 ]

Yield	Reaction Conditions	Operation in experiment
90.2%	With heteropoly acid; In ethyl acetate; at 10 - 15℃;	Take (1) 5g of raw materials was added to 40ml of ethyl acetate was stirred, then add 0.05 heteropoly acid crystals 10-15 C reaction3-5h, HPLC detection of the reaction solution, when (1) the type of raw material no longer down to stop the reaction, cooled to room temperature; using a pore size of 0.2 micronsMicroporous membrane filter to remove heteropoly acid crystals, washed, concentrated to give the product.
70%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 10 - 20℃; for 1h;	Example 7 Preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (IX) Compound VIII (1.0eqt) in DMF (10V) was cooled to 10-15 C., added potassium tert-butoxide (1.1 eqt) slowly in portions. The reaction mass was allowed to stir over a period of one hour at room temperature. The mixture was cooled to 10 C. and chilled water was added. This was allowed to stir over a stipulated time period and filtered, suck dried. The crude product thus obtained was dissolved in DMF (?0.2V) and was cooled to 10-15 C. and slowly added drop wise ice cold water. The precipitated mass was allowed to stir for 1 h at 10-15 C. The reaction mass was filtered, suck dried and the product was dried under vacuum at 54-55 C. over a period of time 5-6 h, to obtain highly chiral pure titled compound. Yield: 70%; purity by HPLC: 99.99%; Chiral purity: R-isomer: 99.97%; S-isomer: 0.03%
		tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37g) in DMF [(600MOI)] was added dropwise to a stirred suspension of sodium hydride [(60%] oil dispersion, [11.] 9g) in DMF [(160MOL)] with cooling such that the internal temperature remained at [0] under nitrogen. The mixture was stirred at [21] for 2 h. The mixture was [RECOOLED] to [0] and 2M HCI (134ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried [(MGS04)] and evaporated to give the title compound (63.55g) LCMS RT = 2.66min.

	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 21℃; for 2h;	tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37g) in DMF (600ML) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11. 9g) in DMF (160MI) with cooling such that the internal temperature remained at 0 under nitrogen. The mixture was stirred at 21 for 2 h. The mixture was recooled to 0 and 2M HCI (134ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MGS04) and evaporated to give the title compound (63.55g) LCMS RT = 2.66min.
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 21℃; for 2h;	tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37g) in DMF (600ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11.9g) in DMF (160mol) with cooling such that the internal temperature remained at 0 under nitrogen. The mixture was stirred at 21 for 2 h. The mixture was recooled to 0 and 2M HCl (134mol) was added. The mixture was diluted with water and the product was extracted with EtOAc twice. The solution was washed with brine twice, dried (MgSO4) and evaporated to give the title compound (63.55g). LCMS RT=2.66min.
		tert-Butyl (2R)-2-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37g) in DMF (600ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11. 9g) in DMF (160ml) with cooling such that the internal temperature remained at 0 under nitrogen. The mixture was stirred at 21 for 2 h. The mixture was recooled to 0 and 2M HCI (134ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MgS04) and evaporated to give the title compound (63.55g) LCMS RT = 2.66min.
700 mg	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Inert atmosphere;	100mL three bottles, Nitrogen protection, 0 C, Compound 1 _15 (1 g, 3. Lmmo 1) was dissolved in N, N-dimethylformamide (10 mL) Potassium tert-butoxide (38111 ^, 3.41) 11] 101) was added. The reaction was carried out at room temperature for 3 hours. Ethyl acetate (50 mL) Washed sequentially with water (50 mL) and saturated brine (50 mL) Organic phase dry, filter, concentrate, Recrystallization from a mixed solution (20 mL) of ethyl acetate and petroleum ether (1/20 of the ratio) gave 700 mg of a white solid.

References: [1]Patent: CN106957313,2017,A .Location in patent: Paragraph 0014-0015.
[2]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.
[3]Patent: US2015/239862,2015,A1 .Location in patent: Paragraph 0133; 0134.
[4]Patent: WO2004/22547,2004,A1 .Location in patent: Page 43-44.
[5]Patent: WO2004/37773,2004,A1 .Location in patent: Page 46.
[6]Patent: WO2003/72539,2003,A1 .Location in patent: Page/Page column 46-47.
[7]Patent: WO2003/91204,2003,A1 .Location in patent: Page/Page column 38-39.
[8]Patent: CN107188813,2017,A .Location in patent: Paragraph 0054; 0079-0080.

3
[ 102293-80-1 ]
[ 452339-73-0 ]

References: [1]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.
[2]Patent: US2015/239862,2015,A1 .
[3]Patent: CN107188813,2017,A .

4
[ 452339-73-0 ]
(R)-(-)-salmeterol [ No CAS ]

References: [1]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.

5
[ 452339-73-0 ]
[ 590410-69-8 ]

References: [1]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.

6
[ 452339-71-8 ]
[ 452339-73-0 ]

References: [1]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.
[2]Patent: US2015/239862,2015,A1 .
[3]Patent: CN107188813,2017,A .

7
[ 452339-70-7 ]
[ 452339-73-0 ]

References: [1]Organic and biomolecular chemistry,2003,vol. 1,p. 1106 - 1111.
[2]Patent: US2015/239862,2015,A1 .
[3]Patent: CN107188813,2017,A .

8
[ 208925-08-0 ]
[ 530-62-1 ]
[ 452339-73-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine; In chloroform; at 20℃;	Intermediate 34. (/?)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one; To a solution of (f?)-2-amino-1-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanol (2.53 g, 11.3 mmol) in chloroform (12 ml.) was added carbonyldiimidazol (2.75 g, 17 mmol) and triethylamine (2.37 ml_, 17 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate (25 ml_). The organic layer was washed with water (2 x 10 ml_), brine (10 ml_), dried (Na2SO4), and the solvent reduced under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (1 :2) as eluent yielded the title compound (1.63 g, 51%).1H NMR (300 MHz, CDCI3): 1.55 (s, 6 H); 3.54 (t, J=8.1 Hz, 1H); 3.94 (t, J=8.7 Hz, 1H); 4.86 (s, 2H); 5.10 (bs, 1H); 5.56 (t, J=8.1 Hz, 1H); 6.85 (d, J=8.5 Hz, 1H); 7.04-7.07 (m, 1H); 7.15-7.18 (m, 1H).

References: [1]Patent: WO2006/122788,2006,A1 .Location in patent: Page/Page column 54.

9
[6-BROMOHEXYL] [4-(3-IODOPHENVL) BUTYL] ether [ No CAS ]
[ 452339-73-0 ]
[ 671777-40-5 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium hydride (60% dispersion in oil 1.26 g) was added to a stirred, cooled (ice-bath) solution of (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxazolidinone (5.47 g) in dry DMF (50 [ML)] under nitrogen and the mixture was stirred for 15 min at 5 [C.] A solution of 6-bromohexyl [4- (3-IODOPHENYL) BUTYL] ether (10.7 g) in DMF (30 ml) was then added dropwise over 10 min. The mixture was stirred for 2 h at ambient temperature, then poured into aqueous solution of ammonium chloride and extracted into ethyl acetate. The combined extracts were washed with water, dried [(NA2SO4)] and evaporated. The residue was purified on biotage (90 g cartridge) eluting with ether-hexane (3: 2) to give the title compound (9.8 g). LCMS RT= 4.20 min.
		Sodium hydride (60% dispersion in oil 1.26 g) was added to a stirred, cooled (ice-bath) solution of (5R)-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-2-oxazolidinone (5.47 g) in dry DMF (50 ml) under nitrogen and the mixture was stirred for 15 min at 5 C. A solution of 6-bromohexyl 4- (3-IODOPHENYL) BUTYL ether (10.7 g) in DMF (30 ML) was then added dropwise over 10 min. The mixture was stirred for 2 h at ambient temperature, then poured into aqueous solution of ammonium chloride and extracted into ethyl acetate. The combined extracts were washed with water, dried (NA2SO4) and evaporated. The residue was purified on biotage (90 g cartridge) eluting with ether-hexane (3: 2) to give the title compound (9.8 g). LCMS RT= 4.20 min.
		Sodium hydride (60% oil dispersion, 1.26 g) was added to a stirred, cooled (ice-bath) solution of (5R)-5- (4H-1, 3-benzodioxin-6-yl)-2-oxazolidinone (5.47 g) in dry DMF (50 ML) under nitrogen and the mixture was stirred for 15 min at 5 C. A solution of 6-bromohexyl 4- (3-IODOPHENYL) BUTYL ether (10.7 g) in DMF (30 ml) was then added dropwise over 10 min. The mixture was stirred for 2 h at ambient temperature, then poured into aqueous solution of ammonium chloride and extracted into ethyl acetate. The combined extracts were washed with water, dried (NA2SO4) and evaporated. The residue was purified on a biotage cartridge (90 g) eluting with ether-hexane (3: 2) to give the title compound (9.8 g). LCMS RT= 4.20 min.

References: [1]Patent: WO2004/22547,2004,A1 .Location in patent: Page 44.
[2]Patent: WO2004/37773,2004,A1 .Location in patent: Page 47.
[3]Patent: WO2004/39762,2004,A1 .Location in patent: Page 36.

10
[ 629-03-8 ]
[ 452339-73-0 ]
[ 503068-33-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5R)-5-(2, 2-DIMETHYL4H-1, 3-BENZODIOXIN-6-YL)-1, 3-OXAZOLIDIN-2-ONE (2. 00g) (WO 02/066422) in DMF (60ML) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 385mg) and the mixture stirred at 20 for 30min. A solution of 1,6-dibromohexane (4. 94MOI) was added and the mixture was stirred at 20 for 3h. Phosphate buffer solution (pH 6.5, 30MI) and water (150ML) were added and the mixture was extracted with ET20. The extract was washed with water and dried (Na2SO4). The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica gel. Elution with DCM then MEOH-DCM (1: 50) gave the title compound (2. 565G). LCMS RT = 3. 71 min.

References: [1]Patent: WO2004/37768,2004,A2 .Location in patent: Page 31-32.

11
{4-[(6-bromohexyl)oxy]-1,1-dimethylbutyl}benzene [ No CAS ]
[ 452339-73-0 ]
[ 686734-43-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5R)-5-(2, 2-DIMETHYL4H-1, 3-BENZODIOXIN-6-YL)-1, 3-OXAZOLIDIN-2-ONE (2.73g) (WO 02/066422) in DMF (25ML) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 526mg) and the mixture stirred at 20 for 15MIN. A solution of {4- [(6-BROMOHEXYL) oxy] -1, 1-dimethylbutyl} benzene (4.117g) in DMF (5ml) was added and the mixture was stirred at 20 for 3h. Phosphate buffer solution (pH 6.5, 25ml) and water (50ML) were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (NA2SO4). The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica gel. Elution with EtOAc-cyclohexane (2: 3) gave the title compound (5. 234G). LCMS RT = 4. 10MIN.

References: [1]Patent: WO2004/37768,2004,A2 .Location in patent: Page 30-31.

12
[ 594862-63-2 ]
[ 452339-73-0 ]
[ 686351-12-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (5R)-5- (2, 2-DIMETHYL-4H-1, 3-BENZODIOXIN-6-YL)-1, 3-OXAZOLIDIN-2-ONE (WO 0266422) (2. 00g) in DMF (25ML) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0. 38g) and the mixture was stirred at room temperature for 15 min. A solution of 4-[(6-BROMOHEXYL) OXY]-1-BUTENE (2. 07G) in DMF (5ml) was added dropwise and the mixture stirred for 3h. The reaction was quenched with water and partitioned between water and EtOAc. The organic phase was washed with brine, dried (MGS04), and evaporated to dryness. The residual oil was purified on a silica SPE bond elut cartridge (50G) using a gradient of 10%-30% EtOAc in cyclohexane (GRADMASTETM). The appropriate fractions were evaporated to give the title compound (2.66g) LCMS RT = 3.47 min.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 159 - 170.
[2]Patent: WO2004/37773,2004,A1 .Location in patent: Page 53-54.

13
[ 452340-52-2 ]
[ 452339-73-0 ]
[ 452340-53-3 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5R)-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin-2-one (EXAMPLE 1VI) (500mg) in DMF (15ML) under nitrogen at 0 was treated with sodium hydride (60% dispersion in mineral oil, 96mg) and the mixture stirred at 20 for 10 min. A SOLUTION OF 6-BROMOHEXYL 4-PENTYN-1-YL ether (WO 02/066422) (545mg) in DMF (1 ML) was added and the mixture stirred at 20 for 18 h. Phosphate buffer solution (pH 6. 5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (NA2SO4). Solvent EVAPORATION IN VACUO gave a residue, which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (2: 3) gave the title compound (700mg). LCMS RT = 3.48min.

References: [1]Patent: WO2004/37773,2004,A1 .Location in patent: Page 56.

14
[ 102294-98-4 ]
[ 452339-73-0 ]
[ 452339-74-1 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin-2-one (4 G) in DMF (25 ml) was added to a suspension of sodium hydride (60% oil dispersion, 1.32 g) in DMF (10 ml) at 0 C and the mixture was stirred for 10 min. A solution of 6-bromohexyl but-3-ynyl ether (5 g) in DMF (15 ml) was added and the cooling bath was removed. The mixture was stirred for 18 h and then concentrated under reduced pressure. The residue was purified by column chromatography on flash silica gel eluting with heptane-ether (2: 1) and then with neat ether to give the title compound (5.8 g). LCMS RT = 3.26 min.
		(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10g) in DMF (100ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 2.33g) in DMF (50ml) with stirring under nitrogen and maintaining the internal temperature at 0. Stirring was continued at 0-5 for 1 h. The mixture was recooled to 0 and a solution of 6-bromohexyl but-3-ynyl ether (14.7g) in DMF (50moi) was added over 1 min. The mixture was then stirred at 20-30 for 2 h. 2M HCl (9ml) was added and the mixture was partitioned between water and diethyl ether. The aqueous layer was extracted with more diethyl ether and the combined organic layers were washed twice with brine. After drying (MgSO4) the solution was concentrated and loaded onto a column of silica gel (600g) set up in diethyl ether: petroleum ether (bp 40-60) (1 : 2). The column was eluted successively with this mixture, then (1 : 1) and the diethyl ether to give the title compound (13.88g). LCMS RT=3.45min.

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 2280 - 2288.
[2]Patent: WO2004/39762,2004,A1 .Location in patent: Page 41-42.
[3]Patent: WO2003/72539,2003,A1 .Location in patent: Page/Page column 47.
[4]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 6026 - 6032.

15
[ 688798-45-0 ]
[ 452339-73-0 ]
[ 688798-46-1 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium hydride (60% oil dispersion, 1.4g) was added to a stirred solution of (5R)- (2, 2- DIMETHYL-4H-1, 3-BENZODIOXIN-6YL)-1, 3OXAZOLIDIN-2-ONE (6. 0G) in dry dimethylformamide (80ML) at 0 under nitrogen. After 20 min a solution of 1- {4- [ (6-BROMOHEXYL) oxy] butyl}-4- iodobenzene (12.6g) in dry dimethylformamide (30ML) was added dropwise. The mixture was stirred for 15h at ambient temperature. The mixture was poured into an aqueous ammonium chloride solution (700MI) and extracted into ethyl acetate. The organic extracts were washed with water, dried (NA2SO4) and evaporated. Purification by chromatography on a biotage cartridge (90g) using ether-petroleum ether (40-60) (4: 1) gave the title compound as a clear oil (10G). LCMS RT = 4.19 min.

References: [1]Patent: WO2004/39762,2004,A1 .Location in patent: Page 44.

16
[ 620600-84-2 ]
[ 452339-73-0 ]
[ 620600-85-3 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin-2-one (82mg) in DMF under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 16mg) and the mixture stirred at 200 for 10min. A solution of 1- (2-bromoethyl)-4- (4- phenylbutoxy) benzene (110mg) in DMF (1ml) was added and the mixture was stirred at 20C for 2h. Phosphate buffer solution (pH 6.5, 10ml) and water (20ml) were added and the mixture was extracted with EtOAc. The combined extracts were washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was partially purified by SPE (5g). Elution with DCM then EtOAC-cyclohexane (1: 1) gave material which was further purified by flash chromatography on silica gel. Elution with EtOAc- petroleum ether (3: 2) gave the title compound (75g). LCMS RT = 3.92min.

References: [1]Patent: WO2003/91204,2003,A1 .Location in patent: Page/Page column 69-70.

17
[ 620599-97-5 ]
[ 452339-73-0 ]
[ 620600-21-7 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin-2-one (Example 1 viii) (503mg) in DMF (10mL) was treated with sodium hydride (60% dispersion in mineral oil) (97mg) under nitrogen for 20 min. A solution of 1-[2-(benzyloxy) ethoxy] -4- (2-bromoethyl) benzene (676mg) in DMF (5 mL) was added and the reaction stirred for a further 2 h. The reaction mixture was concentrated in vacuo then the residue was prified by chromatography (Biotage, 40g) eluting with EtOAc-petroleum ether (2: 3) to give the title compound (585mg). LCMS RT = 3.66 min

References: [1]Patent: WO2003/91204,2003,A1 .Location in patent: Page/Page column 47.

18
[ 620599-99-7 ]
[ 452339-73-0 ]
[ 620600-00-2 ]

Yield	Reaction Conditions	Operation in experiment
		(5R)-5-(2, 2-Dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3-oxazolidin-2-one (651 mg) in DMF (15mL) was treated with sodium hydride (84mg) under nitrogen and stirred for 1 h. A solution of 2- [4- (2-bromoethyl) phenoxy] ethyl acetate (500mg) in DMF (5mL) was added and the reaction mixture was stirred for a further 2 h. This was then concentrated in vacuo and the residue was taken up in EtOAc, washed with water, brine and dried (MgS04). The solution was concentrated in vacuo and the residue was purified by chromatography (Biotage, 90g) eluting with cyclohexane-EtOAc (2: 1) to give the title compound (355mg). LCMS RT=3. 26min.

References: [1]Patent: WO2003/91204,2003,A1 .Location in patent: Page/Page column 39.

19
[ 452340-26-0 ]
[ 452339-73-0 ]
[ 452340-27-1 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 2280 - 2288.

20
[ 452340-40-8 ]
[ 452339-73-0 ]
[ 452340-41-9 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 2280 - 2288.

21
[ 452340-33-9 ]
[ 452339-73-0 ]
[ 452340-34-0 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 2280 - 2288.

22
[ 503068-24-4 ]
[ 452339-73-0 ]
[ 503068-25-5 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 4522 - 4530.

23
[ 503068-31-3 ]
[ 452339-73-0 ]
[ 1228049-08-8 ]

References: [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 4522 - 4530.

24
[ 503068-78-8 ]
[ 452339-73-0 ]
[ 503068-27-7 ]