70918-54-6|(S)-1,4-Benzodioxane-2-carboxylic acid| Ambeed

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Quality Control of [ 70918-54-6 ] Purity: 97% SDS Specification

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Product Details of [ 70918-54-6 ]

CAS No. :	70918-54-6
Formula :	C₉H₈O₄
M.W :	180.16
SMILES Code :	O=C([C@H]1OC2=CC=CC=C2OC1)O
MDL No. :	MFCD00239408
InChI Key :	HMBHAQMOBKLWRX-QMMMGPOBSA-N
Pubchem ID :	687061

Safety of [ 70918-54-6 ]

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

Computational Chemistry of [ 70918-54-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	43.89
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.76 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.34
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	1.4
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.91
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.	0.4
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	1.08
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.02

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.11
Solubility	1.38 mg/ml ; 0.00768 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.	-2.17
Solubility	1.2 mg/ml ; 0.00668 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	-1.57
Solubility	4.84 mg/ml ; 0.0269 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	No
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.	-6.4 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

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)	2.75

Application In Synthesis of [ 70918-54-6 ]

* 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 [ 70918-54-6 ]

[ 70918-54-6 ] Synthesis Path-Downstream 1~35

1
1,4-benzodioxane-2-carboxylic acid [ No CAS ]
[ 70918-54-6 ]

References: [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 49 - 57.
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

2
[ 541-41-3 ]
[ 70918-54-6 ]
C₁₂H₁₂O₆ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

3
[ 251104-21-9 ]
[ 70918-54-6 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

4
[ 4739-94-0 ]
[ 70918-54-6 ]
(R)-ethyl 2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylate [ No CAS ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.

5
[ 70918-54-6 ]
[ 401947-96-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; In toluene; at 0℃; under 760.051 Torr; for 4h;Reflux;	General procedure: Thionyl chloride (4 eq) was added dropwise at 0 C to a solutionof (R)- or <strong>[70918-54-6](S)-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid</strong> (1eq) in toluene (5 mL). The mixture was stirred at reflux for 4 h. Thesolvent was then evaporated to dryness affording 13 and 14,respectively, as a yellow oil in quantitative yield.

References: [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 259 - 269.
[2]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.
[3]Chirality,2018,vol. 30,p. 943 - 950.

6
[ 67-56-1 ]
[ 70918-54-6 ]
(S)‐methyl 1,4‐benzodioxane‐2‐carboxylate [ No CAS ]

References: [1]Tetrahedron Asymmetry,2003,vol. 14,p. 3779 - 3785.

7
1,4-benzodioxane-2-carboxylic acid [ No CAS ]
[ 70918-54-6 ]
[ 70918-53-5 ]

References: [1]Tetrahedron Asymmetry,2003,vol. 14,p. 3779 - 3785.
[2]Tetrahedron Asymmetry,2005,vol. 16,p. 1639 - 1643.

8
[ 120-80-9 ]
[AlO₄Al₁₂(OH)24(H₂O)12]⁷⁺ [ No CAS ]
[ 70918-54-6 ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.

9
[ 70918-54-6 ]
UK-35494-27(S) [ No CAS ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.
[2]Tetrahedron Letters,2013,vol. 54,p. 6420 - 6422.

10
[ 70918-54-6 ]
[ 401941-54-6 ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.
[2]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.
[3]Tetrahedron Letters,2013,vol. 54,p. 6420 - 6422.

11
[ 70918-54-6 ]
(+)-Doxazosin hydrochloride [ No CAS ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.

12
[ 70918-54-6 ]
(+)-(S)-doxazosin mesylate [ No CAS ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 2169 - 2174.

13
[ 70918-54-6 ]
(1S,2S,5S)-2-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-amino}-5-phenoxy-cyclopentanol [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

14
[ 70918-54-6 ]
(1R,2R,5R)-2-[(R)-1-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)methyl]-amino}-5-phenoxy-cyclopentanol [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

15
[ 70918-54-6 ]
[ 251104-28-6 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

16
[ 70918-54-6 ]
[ 251104-27-5 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4214 - 4224.

17
1-adamantan-1-yl-2-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-ylamino)-ethanol [ No CAS ]
[ 70918-54-6 ]
[4-(2-adamantan-1-yl-2-hydroxy-ethylamino)-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl]-(S)-2,3-dihydro-benzo[1,4]dioxin-2-yl-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 15h;	1 -Adamantan-1 -yl-2-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-ylamino)-ethanol(Intermediate 5, 45 mg, 0.00014 mol), (S)-2,3-dihydro-benzo[l,4]dioxine-2 -carboxylic acid (26 mg,0.00015 mol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (28 mg, 0.00015 mol), 1- hydroxybenzotriazole hydrate (22 mg, 0.00015 mol) and N,N-diisopropylethylamine (60 mg, 0.0005 mol) were stirred in methylene chloride (3 mL) at room temperature for 15 hours. The mixture was purified by flash chromatography (12 g of silica gel, 0-10% methanol in dichloromethane gradient) to give the desired product as a white solid (65 mg, 96% yield).LCMS (0.1% formic acid modifier) calculated. (M+l)+ 490.59, observed 491.3.1H NMR (CDCl3) δ 8.45 (s, IH), 6.91-6.86 (m, 4H), 5.09-4.11 (m, 6 H), 3.88-3.75 (m, 2H), 3.36-3.29 (m,2H), 3.04-3.01 (m, 2H), 2.00 (s, 3H), 1.76-1.58 (m, 12H).

References: [1]Patent: WO2007/28022,2007,A2 .Location in patent: Page/Page column 55.

18
[ 6638-79-5 ]
[ 70918-54-6 ]
[ 1020746-80-8 ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 5115 - 5123.

19
[ 70918-54-6 ]
[ 13992-25-1 ]
[ 1192721-80-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6738 - 6741.

20
[ 70918-54-6 ]
UK-36528-27(R) [ No CAS ]

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

21
[ 70918-54-6 ]
[ 687974-13-6 ]

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

22
[ 70918-54-6 ]
C₁₀H₉F₃O₅S [ No CAS ]

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

23
[ 70918-54-6 ]
[ 62501-72-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃;Inert atmosphere;	General procedure: A solution of (R)-methyl 1,4-benzodioxan-2-carboxylate (R)-17a (1 mmol) in anhydrous THF (10 mL) was slowly added under a nitrogen atmosphere, to a suspension of LiAlH4 (2 mmol) in anhydrous THF (50 mL). The mixture was stirred at room temperature until the completion of the reaction as indicated by TLC. After hydrolysis with small amounts of water, the suspension obtained was filtered and the THF removed. The residue was diluted with water and extracted with ether. The organic layers were dried, filtered, and concentrated to obtain pure alcohol ( S)- 2 after recrystallization from diethyl ether, in 85% yield as a white solid

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

24
[ 70918-54-6 ]
[ 61045-70-3 ]

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

25
[ 70918-54-6 ]
[ 60998-61-0 ]

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

26
[ 70918-54-6 ]
[ 57260-71-6 ]
[ 1415584-44-9 ]

Yield	Reaction Conditions	Operation in experiment
95%		General procedure: Triethylamine (2 mmol) and HOBT (1 mmol) were added to acid (S)-1 (1 mmol) dissolved in THF/ DCM (9:1 ratio) at 0 C. After 10 min of mixing, Boc-piperazine was slowly added. The reaction was then left to stir overnight. After completion of the reaction, the mixture was dissolved in ethyl acetate and extracted with 10% HCl to remove the basic reagents. The organic layer was washed with water, dried in vacuo, and purified by column chromatography to give the desired compound in 95% yield as a white solid, mp. 134 C; [α]D20=+51.5 (c 1, CHCl3); 1H NMR: δ 1.46 (m, 9H), 3.31-3.45 (m, 5H), 3.52-3.60 (m, 2H), 4.32-4.45 (dd, J = 4, 8 Hz, 1H), 4.47-4.51 (dd, J = 2.6, 12 Hz, 1H), 4.81-4.83 (q, J = 2.4, 8 Hz, 1H), 6.82-6.91 (m, 4H); 13C NMR: δ 28.09, 41.84, 45.45, 64.78, 70.45, 80.62, 110.57, 117.15, 121.44, 122.16, 142.11, 143.01, 154.56, 165.31; HRMS (ESI) Calcd for C18H24N2NaO5 (M+Na): 371.1583. Found: 371.1589.
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dichloromethane; at 0℃;	Triethylamine (2 mmol) and hydroxybenzotriazole (HOBt) (1 mmol) were added to the acid (S)-1 (1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.5 mmol) dissolved in THF:DCM (9:1 ratio) at 0 C, after 10 minutes of mixing, mono-Boc-piperazine was added slowly. The reaction was kept for stirring overnight. After completion of the reaction, mixture was dissolved in ethyl acetate (3x20 mL) and extracted with 10% HCl to remove the basic reagents. The organic layer was washed with water (1x20 mL), dried and evaporated under vacuum and purified by column chromatography (silica gel 0-20% EtOAc/Hexane) to get the desired compound in 95% yield as a white solid.

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.
[2]Tetrahedron Letters,2013,vol. 54,p. 6420 - 6422.

27
[ 3663-79-4 ]
[ 70918-54-6 ]

Yield	Reaction Conditions	Operation in experiment
42%		General procedure: Racemic methyl 1,4-benzodioxan-2-carboxylate 17a (50 mg), aqueous phosphate buffer (2.5 mL, 0.1 M, pH. 7.1), n-butanol (500 μl), and wet whole cells of Arthrobacter sp. lipase (100 mg) were shaken (320 rpm) continuously at 25 ± 1 C. After a certain degree of conversion (∼42%) as indicated by chiral high performance liquid chromatography (HPLC), the reaction was terminated by adding ethyl acetate and centrifuging the mixture at 10,000-15,000 g to remove the enzyme and the suspended particles. The clear solution was decanted and the centrifuged mass was extracted separately with ethyl acetate (3 × 25 mL). The organic layers were combined, washed with water, and treated with 2 M NaOH solution to give (S)-2,3-hydrobenzo[1,4]dioxane-2-carboxylic acid as its salt. The salt was neutralized with dilute HCl to give enantiomerically pure (S)-2,3-dihydrobenzo[1,4]dioxane-2-carboxylic acid (yield 42%). ee = 99%; mp = 102-103 C; [α]D25=-61.0 (c 1, CHCl3); Abs, config. (S); {lit.23b [α]25D=-63.8(c 1, CHCl3); ee = 99.0%; mp 97.5 C}; HPLC conditions {OJ-H chiral column, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate: 0.5 mL/min, t1 = 20.78 and t2 = 22.87 min}. The organic layer was dried and evaporated under reduced pressure to furnish the optically active unhydrolyzed ester. ee = 73%; mp = 58-61 C; [α]D25=+46.4(c 1, CHCl3) [lit.23b [α]D25=57.0 (c 1, CHCl3), mp 78.1]; Abs. config. (R); HPLC conditions {OJ-H chiral column, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate: 0.5 mL/min, t1 = 31.74 and t2 = 33.34 min}. The enantiomerically pure ester with ee = 99%; mp = 73-76 C; [α]25D=+55.4 (c 1, CHCl3); Abs. config. (R); {lit.23b [α]D25=+57.0 (c 1, CHCl3); ee = 99.4%; mp 78.5 C}, was obtained in the case of hydrolysis with diisopropylether as the co-solvent (Table 2, entry 13).

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.
[2]Tetrahedron Letters,2016,vol. 57,p. 2009 - 2011.

28
[ 3663-79-4 ]
[ 70918-54-6 ]
[ 70918-53-5 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Racemic methyl 1,4-benzodioxan-2-carboxylate 17a (50 mg), aqueous phosphate buffer (2.5 mL, 0.1 M, pH. 7.1), n-butanol (500 μl), and wet whole cells of Arthrobacter sp. lipase (100 mg) were shaken (320 rpm) continuously at 25 ± 1 C. After a certain degree of conversion (∼42%) as indicated by chiral high performance liquid chromatography (HPLC), the reaction was terminated by adding ethyl acetate and centrifuging the mixture at 10,000-15,000 g to remove the enzyme and the suspended particles. The clear solution was decanted and the centrifuged mass was extracted separately with ethyl acetate (3 × 25 mL). The organic layers were combined, washed with water, and treated with 2 M NaOH solution to give (S)-2,3-hydrobenzo[1,4]dioxane-2-carboxylic acid as its salt. The salt was neutralized with dilute HCl to give enantiomerically pure (S)-2,3-dihydrobenzo[1,4]dioxane-2-carboxylic acid (yield 42%). ee = 99%; mp = 102-103 C; [α]D25=-61.0 (c 1, CHCl3); Abs, config. (S); {lit.23b [α]25D=-63.8(c 1, CHCl3); ee = 99.0%; mp 97.5 C}; HPLC conditions {OJ-H chiral column, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate: 0.5 mL/min, t1 = 20.78 and t2 = 22.87 min}. The organic layer was dried and evaporated under reduced pressure to furnish the optically active unhydrolyzed ester. ee = 73%; mp = 58-61 C; [α]D25=+46.4(c 1, CHCl3) [lit.23b [α]D25=57.0 (c 1, CHCl3), mp 78.1]; Abs. config. (R); HPLC conditions {OJ-H chiral column, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate: 0.5 mL/min, t1 = 31.74 and t2 = 33.34 min}. The enantiomerically pure ester with ee = 99%; mp = 73-76 C; [α]25D=+55.4 (c 1, CHCl3); Abs. config. (R); {lit.23b [α]D25=+57.0 (c 1, CHCl3); ee = 99.4%; mp 78.5 C}, was obtained in the case of hydrolysis with diisopropylether as the co-solvent (Table 2, entry 13).

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

29
[ 4739-94-0 ]
[ 70918-54-6 ]

Yield	Reaction Conditions	Operation in experiment
42%		General procedure: Racemic methyl 1,4-benzodioxan-2-carboxylate 17a (50 mg), aqueous phosphate buffer (2.5 mL, 0.1 M, pH. 7.1), n-butanol (500 μl), and wet whole cells of Arthrobacter sp. lipase (100 mg) were shaken (320 rpm) continuously at 25 ± 1 C. After a certain degree of conversion (∼42%) as indicated by chiral high performance liquid chromatography (HPLC), the reaction was terminated by adding ethyl acetate and centrifuging the mixture at 10,000-15,000 g to remove the enzyme and the suspended particles. The clear solution was decanted and the centrifuged mass was extracted separately with ethyl acetate (3 × 25 mL). The organic layers were combined, washed with water, and treated with 2 M NaOH solution to give (S)-2,3-hydrobenzo[1,4]dioxane-2-carboxylic acid as its salt. The salt was neutralized with dilute HCl to give enantiomerically pure (S)-2,3-dihydrobenzo[1,4]dioxane-2-carboxylic acid (yield 42%). ee = 99%; mp = 102-103 C; [α]D25=-61.0 (c 1, CHCl3); Abs, config. (S); {lit.23b [α]25D=-63.8(c 1, CHCl3); ee = 99.0%; mp 97.5 C}; HPLC conditions {OJ-H chiral column, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate: 0.5 mL/min, t1 = 20.78 and t2 = 22.87 min}. The organic layer was dried and evaporated under reduced pressure to furnish the optically active unhydrolyzed ester. ee = 73%; mp = 58-61 C; [α]D25=+46.4(c 1, CHCl3) [lit.23b [α]D25=57.0 (c 1, CHCl3), mp 78.1]; Abs. config. (R); HPLC conditions {OJ-H chiral column, eluent 2-propanol-hexane-triflouroacetic acid (5:95:0.1), flow rate: 0.5 mL/min, t1 = 31.74 and t2 = 33.34 min}. The enantiomerically pure ester with ee = 99%; mp = 73-76 C; [α]25D=+55.4 (c 1, CHCl3); Abs. config. (R); {lit.23b [α]D25=+57.0 (c 1, CHCl3); ee = 99.4%; mp 78.5 C}, was obtained in the case of hydrolysis with diisopropylether as the co-solvent (Table 2, entry 13).

References: [1]Tetrahedron Asymmetry,2012,vol. 23,p. 1615 - 1623.

30
[ 16603-67-1 ]
[ 70918-54-6 ]
[ 1195978-75-6 ]

Yield	Reaction Conditions	Operation in experiment
66%		Carbonyldiimidazole (0.47 g) is added to a solution of <strong>[70918-54-6](S)-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid</strong> (0.63 g) in dichloromethane (6 mL). The resulting solution is stirred at room temperature for 1 h before (2R,6R,11R)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol is added. The solution is further stirred at room temperature overnight. Then, dichloromethane (30 mL) is added and the resulting solution is washed with water. After drying (Na2SO4), the solvent is evaporated to give the product as a white foam-like solid. [0798] Yield: 0.70 g (66% of theory) [0799] Mass spectrum (ESI+): m/z=380 [M+H]+ [0800] The product is additionally purified by HPLC on reversed phase (H2O/MeCN) in case the purity after the procedure described above is insufficient.

References: [1]Patent: US2011/269791,2011,A1 .Location in patent: Paragraph 0796; 0797; 0798; 0799.

31
[ 62501-71-7 ]
[ 70918-54-6 ]

References: [1]Tetrahedron Letters,2013,vol. 54,p. 6420 - 6422.
[2]Patent: CN108250177,2018,A .

32
[ 62501-72-8 ]
[ 70918-54-6 ]

Yield	Reaction Conditions	Operation in experiment
85%		(R)-1,4-benzenedioxane-2-methanol (100 g, 0.6 mol) was dissolved in dichloromethane (1 L).Add potassium bromide aqueous solution (14 g, 0.12 mol, water 500 mL),Tempo (1.8 g, 0.012 mol), aqueous potassium hydrogencarbonate (120 g, 1.2 mol),Stir for 10 minutes after the addition.The reaction system was cooled to 0-5 C in an ice bath.Slowly add sodium hypochlorite aqueous solution (10%, 860 mL).Keep the temperature of the system below 10 C, keep the temperature for 3 hours after the completion of the dropwise addition, naturally heat up, and react at room temperature for another 10 hours.After completion of the reaction, excess sodium hypochlorite was quenched with aqueous sodium thiosulfate (74 g, 0.3 mol, water 100 mL). The reaction system is adjusted to a pH greater than 12 with a 50% aqueous sodium hydroxide solution.Layered,The aqueous phase was extracted once more with dichloromethane. Divide twice the dichloromethane. The aqueous phase is adjusted to pH less than 2 with hydrochloric acid, then extracted three times with dichloromethane, and the organic phase is combined three times.Dry and concentrated,That is, 92 g of the target (S)-1,4-benzodioxane-2-carboxylic acid was obtained in a yield of 85%.
	With potassium permanganate; potassium hydroxide; In water; acetone; at 0℃; for 0.5h;	General procedure: The alcohol (S)-2 (0.4 g, 3.0 mmol) dissolved in acetone (3 mL) was added to an aqueous solution (containing KOH, 0.18 g in 40 mL H2O). A solution of aqueous KMnO4 (50%) was added dropwise at 0C with stirring until the color of permanganate was retained for 30 min. After the consumption of the starting material, the excess permanganate was decomposed by the dropwise addition of MeOH. Solvents were evaporated to dryness, the residue suspended in dichloromethane (3x30 mL) and acidified with 10% HCl. The organic solvent was removed under reduced pressure to obtain the desired acid in 70% yield as a white solid.

References: [1]Patent: CN108250177,2018,A .Location in patent: Paragraph 0060; 0070; 0071; 0072; 0101; 0114.
[2]Tetrahedron Letters,2013,vol. 54,p. 6420 - 6422.

33
(S)-N-((R)-1-phenylethyl)-2,3-dihydrobenzo [b][1,4]dioxine-2-carboxamide [ No CAS ]
[ 3886-69-9 ]
[ 70918-54-6 ]

References: [1]Tetrahedron Letters,2016,vol. 57,p. 2009 - 2011.

34
[ 70918-54-6 ]
(S)-N-((R)-1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 259 - 269.

35
(S)‐methyl 1,4‐benzodioxane‐2‐carboxylate [ No CAS ]
[ 70918-54-6 ]

References: [1]Chirality,2018,vol. 30,p. 943 - 950.

Historical Records

Technical Information

• Arndt-Eistert Homologation • Hunsdiecker-Borodin Reaction • Passerini Reaction • Preparation of Amines • Preparation of Carboxylic Acids • Reactions of Amines • Reactions of Carboxylic Acids • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Ugi Reaction

Related Functional Groups of
[ 70918-54-6 ]

Carboxylic Acids

A176169 [3663-80-7]

2,3-Dihydrobenzo[b][1,4]dioxine-2-carboxylic acid

Similarity: 1.00

A238561 [13794-15-5]

2-(4-Methoxyphenoxy)propanoic acid

Similarity: 0.89

A249332 [94050-90-5]

(R)-2-(4-Hydroxyphenoxy)propanoic acid

Similarity: 0.89

A145676 [33632-74-5]

3,4-Dihydro-2H-benzo[b][1,4]dioxepine-2-carboxylic acid

Similarity: 0.82

A292386 [943-45-3]

2-Methyl-2-phenoxypropanoic acid

Similarity: 0.82

Related Parent Nucleus of
[ 70918-54-6 ]

Benzodioxans

A176169 [3663-80-7]

2,3-Dihydrobenzo[b][1,4]dioxine-2-carboxylic acid

Similarity: 1.00

A447938 [4739-94-0]

Ethyl 2,3-dihydrobenzo[1,4]dioxine-2-carboxylate

Similarity: 0.94

A227188 [4442-54-0]

2,3-Dihydro-1,4-benzodioxine-6-carboxylic acid

Similarity: 0.61

A163137 [4442-53-9]

2,3-Dihydrobenzo[b][1,4]dioxine-5-carboxylic acid

Similarity: 0.59

A147738 [29668-44-8]

2,3-Dihydrobenzo[b][1,4]dioxine-6-carbaldehyde

Similarity: 0.59

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CAS No.: 70918-54-6

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