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Chemical Structure| 132335-47-8

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Product Details of [ 132335-47-8 ]

CAS No. :132335-47-8
Formula : C21H23NO5S
M.W : 401.48
SMILES Code : CN(C)CC[C@H](OC1=C2C=CC=CC2=CC=C1)C3=CC=CS3.O=C(O)C(O)=O
MDL No. :MFCD08458302
InChI Key :GYUDMXKAVMKVPS-FERBBOLQSA-N
Pubchem ID :11847533

Safety of [ 132335-47-8 ]

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

Computational Chemistry of [ 132335-47-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 28
Num. arom. heavy atoms 15
Fraction Csp3 0.24
Num. rotatable bonds 7
Num. H-bond acceptors 6.0
Num. H-bond donors 2.0
Molar Refractivity 110.2
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

115.31 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

3.4
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.25
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.8
Log Po/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.

1.9
Log Po/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

5.16
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.3

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.68
Solubility 0.0837 mg/ml ; 0.000208 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.

-4.31
Solubility 0.0198 mg/ml ; 0.0000493 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

-6.55
Solubility 0.000113 mg/ml ; 0.000000281 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Poorly 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

No
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

Yes
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

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.15 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.

0.56

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

1.0 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)

3.56

Application In Synthesis of [ 132335-47-8 ]

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

  • Upstream synthesis route of [ 132335-47-8 ]
  • Downstream synthetic route of [ 132335-47-8 ]

[ 132335-47-8 ] Synthesis Path-Upstream   1~10

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YieldReaction ConditionsOperation in experiment
75.6%
Stage #1: With sodium hydride In N,N-dimethyl acetamide at 70℃; for 0.333333 h;
Stage #2: at 110℃; for 1 h;
DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60percent sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 ° C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 ° C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6percent).
References: [1] Patent: JP2016/172704, 2016, A, . Location in patent: Paragraph 0027; 0053.
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  • [ 132335-44-5 ]
  • [ 132335-47-8 ]
References: [1] Organic Process Research and Development, 2009, vol. 13, # 5, p. 854 - 856.
[2] Patent: WO2009/87463, 2009, A2, . Location in patent: Page/Page column 7-8.
  • 3
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YieldReaction ConditionsOperation in experiment
84.2% at 20℃; for 21 h; Example 10; Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 moles, 0.8 eq) in water (30 mL) was then added. The resulting mixture was stirred for 21 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 40° C. to yield 10.87 g of the product as a white solid (Yield: 84.2percent; HPLC (peak area at 220 nm) oxalic acid 1.78percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.10percent, 1-naphthol 0.35percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 97.65percent; Titration: 99.5percent; Karl Fischer: 0.06percent; XRD as shown in FIG. 1 (Form A); IR essentially as shown in FIG. 3 (Form A); TGA DSC as shown in FIG. 2, mp onset 152.6° C.).
78.6% at 20℃; for 2 h; Example 12Preparation of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in isopropanol (30 mL) was then added dropwise. The resulting mixture was stirred for 2 hours and filtered. The filter cake was dried under vacuum at 50° C. to yield 10.14 g of the product as a white solid (Yield: 78.6percent; HPLC (peak area at 220 nm) oxalic acid 1.56percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.36percent; Titration: 99.4percent; Karl Fischer: 0.06percent; IR essentially as shown in FIG. 3, Form A).
78.9% at 20℃; for 16 h; Example 11Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in methanol (4 mL) was then added. An additional volume of isopropyl acetate (50 mL) was added for improved stirring. The resulting mixture was stirred for 16 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 55° C. to yield 10.21 g of the product as a white solid (Yield: 78.9percent; HPLC (peak area at 220 nm) oxalic acid 1.66percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.24percent; Titration: 100.1percent; Karl Fischer: 0.22percent; XRD as shown in FIG. 1 (Form A); IR as shown in FIG. 3 (Form A).
77% at 20℃; for 1 h; Preparation of DNT Oxalate
Example 6
To a solution of 2.1 g of DNT-base (12percent enantiomer R) dissolved in 12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate.
The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate.
After drying, in a vacuum oven for overnight, 2 g (77percent yield) of DNT-oxalate were obtained containing 12percent of enantiomer R.
88 % ee
Stage #1: With pyridine-SO3 complex In dimethyl sulfoxide; toluene for 0.5 h;
Stage #2: for 16 h;
Example 1Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl) Propylamine Oxalic Acid Salt(S-3-Dimethylamino-1-(2-thienyl)-1-propanol (50 g, 0.270 moles) and sodium hydroxide (21.6 g, 0.540 moles, 2 eq.) were heated in DMSO (500 mL) at 60-80° C. for 1 hour. The temperature was controlled at 60° C.+/-4° C. before 1-fluoronaphthalene (43.6 g, 38.5 mL, 0.299 moles) was added. The mixture heated at this temperature for 64 hours. Water (500 mL) was added, and the mixture extracted with toluene (2.x.500 mL). The organic layers were then combined and washed with water (500 mL). HPLC analysis of an evaporated aliquot showed the molar ratio of Compound IV to Compound S-II to be 90:10 and Compound IV to be 88percent ee. Pyridine sulfur trioxide (6.4 g, 0.040 moles) was added to the mixture, the mixture was stirred for 30 minutes, and was then washed with water (500 mL). The organic layers were then concentrated by distillation until 600 mL of solvent was removed, and ethyl acetate (500 mL) was added. Oxalic acid dihydrate (27.2 g, 0.216 moles) was then added. The resulting suspension was stirred for 16 hours and filtered to yield the product as a white solid. The resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59percent). The resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88percent ee.
92 % ee
Stage #1: With pyridine-SO3 complex In Isopropyl acetate; dimethyl sulfoxide at 20℃; for 1 h;
Stage #2: at 15 - 20℃; for 16 h;
Example 6Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium hydroxide (0.324 kg, 8.1 moles, 2 eq), potassium carbonate (126 kg, 9.1 moles, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (750 g, 4.05 moles), were heated in DMSO (7.5 L) at 80° C. for 3 hours and cooled to 40° C. 1-fluoronaphthalene (770'gi.5.3 mol, 1.3 eq) was then added over 5 minutes. Next, the mixture was heated at 40° C. for 17 hour and then at 50-60° C. for 40 hours. The molar ratio of product (Compound IV) to staring alcohol (Compound S-II) was 85.3:14.7, and Compound IV was 92percent ee as determined by HPLC of an aliquot. The mixture was then cooled to 20° C. and quenched with water (5 L). The mixture was divided in two and each portion was extracted twice with isopropyl acetate (2.x.2 L). The four organic phases were combined, washed with water (5 L), and pyridine sulphur trioxide complex (110 g, 0.69 moles, 0.17 eq.) was added. The mixture was then stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75percent; equivalent to 1.21 kg, (dry product)). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC. Compound IV oxalate salt was 92percent ee as determined by chiral HPLC.Example 7Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (8.635 g, 216 mmol, 2 eq), potassium carbonate (33.565 g, 243 mmol, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol), were heated in DMSO (200 mL) at 80° C. (temperature inside flask) under vacuum such that approximately 100 mL of DMSO were distilled in 1 hour. An additional 100 mL of DMSO were then added, and the mixture heated at 80° C. for a further 2 hours. Thereafter, the mixture was cooled to 40° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (17.35 g, 119 mmol, 1.1 eq) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analysed by NMR. Once an approximately 92percent conversion had been achieved (24 hours), as determined by the ratio of Compounds IV and S-II in the 1H-NMR spectrum, the mixture was cooled to 25° C., quenched with water (150 mL) and extracted twice with isopropyl acetate (2.x.100 mL). The two organic phases were combined, washed with water (75 mL), and pyridine sulphur trioxide complex (1.72 g, 10.8 mmol, 0.1 eq.) was added. The mixture was then stirred at 20° C. for 60 minutes and washed with water (150 mL). The aqueous layer was analysed to be pH 6.8. Oxalic acid dihydrate (10.9 g, 86 mmol, 0.8 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and homogenized to yield 41.83 g of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt as an off-white solid (Loss on drying: 6.94percent, Titration: 98.1percent, Karl Fischer: 0.06percent).

References: [1] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 6.
[2] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7.
[3] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 6-7.
[4] Patent: US2007/173541, 2007, A1, . Location in patent: Page/Page column 6.
[5] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 4.
[6] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7.
[7] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7.
[8] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 7-8.
[9] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 5.
[10] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 5-6.
[11] Patent: US2009/93645, 2009, A1, . Location in patent: Page/Page column 6.
[12] Patent: WO2010/79404, 2010, A2, . Location in patent: Page/Page column 7-8.
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References: [1] Patent: WO2011/33366, 2011, A2, . Location in patent: Page/Page column 23.
  • 5
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YieldReaction ConditionsOperation in experiment
80 % With oxalic acid In ISOPROPYLAMIDE; water; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol; ethyl acetate; mineral oil Example 4
Synthesis of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate
In 50 ml of dimethylacetamide 0.5 g of sodium hydride (suspension in mineral oil) is suspended.
Suspension is stirred and in few portions 2 g of (s)-3-(dimethylamino)-1-(thienyl)-propan-1-ol is added.
After the addition is completed the suspension is warmed up to 70°C. 1.27 ml of 1-fluoronaphthalene is added and the reaction mixture is heated to 110°C.
At this temperature the solution is stirred for another three hours.
Then the reaction solution is dissolved with 300 ml of water and extracted twice with 100 ml ether.
Combined ether phases are rinsed with water, dried with sodium sulphate end evaporated to dryness.
Obtained oil is dissolved in 50 ml ethyl acetate and 0.9 g of oxalic acid is added.
The suspension is further stirred for one hour, filtered off the product and washed with ethyl acetate.
The product is dried to obtain 3.5 g (80 percent) of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate.
References: [1] Patent: EP2133072, 2009, A1, .
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References: [1] Patent: WO2007/38253, 2007, A2, . Location in patent: Page/Page column 19.
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References: [1] Patent: WO2007/86948, 2007, A1, . Location in patent: Page/Page column 15.
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References: [1] Tetrahedron Letters, 1990, vol. 31, # 45, p. 7101 - 7104.
[2] Patent: WO2011/33366, 2011, A2, .
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References: [1] Tetrahedron Letters, 1990, vol. 31, # 45, p. 7101 - 7104.
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References: [1] Tetrahedron Letters, 1990, vol. 31, # 45, p. 7101 - 7104.
 

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