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[ CAS No. 41789-95-1 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 41789-95-1
Chemical Structure| 41789-95-1
Chemical Structure| 41789-95-1
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Product Details of [ 41789-95-1 ]

CAS No. :41789-95-1 MDL No. :MFCD04618244
Formula : C9H13NO Boiling Point : -
Linear Structure Formula :- InChI Key :FIFKRPFWLHBMHL-UHFFFAOYSA-N
M.W : 151.21 Pubchem ID :5152225
Synonyms :

Calculated chemistry of [ 41789-95-1 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.33
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 45.51
TPSA : 21.26 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -9.6 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.22
Log Po/w (XLOGP3) : -3.35
Log Po/w (WLOGP) : 1.26
Log Po/w (MLOGP) : 1.53
Log Po/w (SILICOS-IT) : 1.83
Consensus Log Po/w : 0.7

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.13
Solubility : 2030.0 mg/ml ; 13.4 mol/l
Class : Highly soluble
Log S (Ali) : 3.48
Solubility : 455000.0 mg/ml ; 3010.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -3.35
Solubility : 0.0675 mg/ml ; 0.000447 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 41789-95-1 ]

Signal Word:Danger Class:N/A
Precautionary Statements:P261-P264-P270-P280-P304+P341-P305+P351+P338-P330-P403-P501 UN#:N/A
Hazard Statements:H302-H318-H334 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 41789-95-1 ]

* 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 [ 41789-95-1 ]
  • Downstream synthetic route of [ 41789-95-1 ]

[ 41789-95-1 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 16928-30-6 ]
  • [ 41789-95-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 575 - 585
[2] Helvetica Chimica Acta, 2009, vol. 92, # 12, p. 2754 - 2761
[3] Organic Letters, 2011, vol. 13, # 4, p. 600 - 603
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7219 - 7222
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3568 - 3581
  • 2
  • [ 591-31-1 ]
  • [ 74-89-5 ]
  • [ 41789-95-1 ]
YieldReaction ConditionsOperation in experiment
100% With sodium tetrahydroborate In methanol; water at 0℃; for 2 h; To a solution of 3-methoxybenzaldehyde (180 g, 1.32 mol) in methanol (1 L) was added a 40percent aqueous solution of methylamine (113 ml, 1.31 mol) followed by 1 hour stirring at 00C. Sodium borohydride (75 g, 1.98 mol) was added portionwise at 00C and the reaction mixture was stirred for 1 hour. The solution was concentrated to a smaller volume then, was diluted with water (200 mL) and the resulting solution was extracted with methylene chloride (3 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude N-methylbenzylamine (220 g, quantitative) as clear oil, which was used in the next step without further purification: 1H ΝMR (CDCl3, 500 MHz) δ.7.23 (t, J = 8.0 Hz, IH), 6.926.88 (m, 2H), 6.816.78 (m, IH), 3.80 (s, 3H), 3.73 (s, 2H), 2.45 (s, 3H), 2.07 (broad s, IH).
99% With sodium tetrahydroborate In methanol; water at 0 - 20℃; To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 niL) at room temperature was added methylamine (130 mL of 40percent in water, 1.5 mol). The resulting solution was cooled to 00C and sodium borohydride (83 g, 2.3 mol) was added in batches. The reaction solution was stirred at 00C for 2 h, then warmed to room temperature, concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1 : 1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158,5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3x). The combined methylene chloride extracts were washed with 1 : 1 water/brine, dried over sodium sulfate and concentrated in vacuo to give additional benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) 7.24 (t, /= 8.4 Hz, IH), 6.91^6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).
29%
Stage #1: at 0 - 20℃; for 15.3333 h;
Stage #2: With sodium tetrahydroborate In methanol; 20C at 0 - 20℃; for 2 - 3 h;
Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Example 19 Preparation of (+)-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)(morpholino)methanone, L-tartrate salt Step A: To a stirred solution of methylamine (40percent in water) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 h, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 20 Preparation of (+)-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)methanamine, maleate salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 h, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 21 Preparation of (+)-1-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)cyclopropanamine, maleate salt Step A: To a stirred solution of methylamine (40percent in water) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 hours, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 22 Preparation of (+)-4-((2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)methyl)morpholine, L-tartrate salt Step A: To a stirred solution of methylamine (40percent in water) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 hours, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1 N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6 N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 23 Preparation of (+)-5-(4-chlorophenyl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-8-carbonitrile, maleate salt and (-)-5-(4-chlorophenyl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-8-carbonitrile, maleate salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 h, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in H2O, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.) and the combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 33 Preparation of (+)-5-methyl-3-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-1,2,4-oxadiazole, L-tartrate salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 hours, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 34 Preparation of (+)-4-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)morpholine, maleate salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 hours, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 36 Preparation of (+)-1-(2-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyrrolidin-2-one, maleate salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 hours, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in water, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).Example 39 Preparation of (+)-5-(4-chlorophenyl)-2-methyl-8-(6-methyl-pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, hydrochloride salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction mixture was allowed to stir at room temperature under N2 overnight. The reaction was then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was allowed to stir for 3 hours. The mixture was then concentrated under reduced pressure, dissolved in H2O, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were then extracted with 1 N HCl (3.x.) and the pH of the combined HCl extracts was adjusted to 10 by addition of 6 N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Example 47 Preparation of (-)-4-(5-(4-chlorophenyl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)morpholine, maleate salt Step A: To a stirred solution of methylamine (40percent in H2O) (28.2 mL, 327.6 mmol) in methanol (100 mL) at room temperature was added m-anisaldehyde (20.6 mL, 163.8 mmol) as a solution in methanol (50 mL) dropwise over 20 minutes. The reaction was stirred at room temperature under N2 for 15 hours, then cooled to 0° C. and sodium borohydride (6.19 g, 163.8 mmol) was added in portions. After warming to room temperature, the reaction was stirred for 3 hours, then the mixture was concentrated under reduced pressure, dissolved in H2O, and extracted with methylene chloride (3.x.). The combined methylene chloride extracts were extracted with 1N HCl (3.x.) and the combined HCl extracts adjusted to pH 10 by addition of 6N NaOH. The aqueous mixture was then extracted with methylene chloride (3.x.). The combined methylene chloride extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amine (25.0 g, quantitative yield) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 1H), 6.91-6.89 (m, 1H), 6.89 (s, 1H), 6.82-6.79 (m, 1H), 3.81 (s, 3H), 3.74 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added a solution of methylamine in water (130 mL, 1.5 mol, 40 wt. percent solution). The resultant solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added to it in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined dichloromethane extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Example 94 Preparation of (+/-)-5-(5-chlorothiophen-2-yl)-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine, citrate salt Step A: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added 40percent methylamine in water (130 mL, 1.5 mol). The resultant solution was cooled to 0° C. and then sodium borohydride (83 g, 2.3 mol) was added in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined methylene chloride extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Example 102 Preparation of (+/-)-8-methoxy-2-methyl-5-(thiophen-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, citrate salt Step A: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added 40percent methylamine in water (130 mL, 1.5 mol). The resultant solution was cooled to 0° C. and then sodium borohydride (83 g, 2.3 mol) was added in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined organic extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).; Step B: To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added 40percent methylamine in water (130 mL, 1.5 mol). The resultant solution was cooled to 0° C. and then sodium borohydride (83 g, 2.3 mol) was added in portions. The reaction solution was stirred at 0° C. for 2 hours and then warmed to room temperature. The resultant reaction mixture was concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3.x.). The combined methylene chloride extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H).
29% With sodium tetrahydroborate In methanol; water; methylamine at 0 - 20℃; for 2 h; Enzymatic reaction To a solution of m-anisaldehyde (205 g, 1.5 mol) in methanol (800 mL) at room temperature was added methylamine (130 mL of 40percent in water, 1.5 mol). The resulting solution was cooled to 0° C. and sodium borohydride (83 g, 2.3 mol) was added in batches. The reaction solution was stirred at 0° C. for 2 h, then warmed to room temperature, concentrated in vacuo and diluted with water. The organic phase was separated, diluted with ethyl acetate, washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give the desired benzylamine (158.5 g, 70percent) as a clear oil. The combined aqueous extracts were extracted with dichloromethane (3×). The combined methylene chloride extracts were washed with 1:1 water/brine, dried over sodium sulfate and concentrated in vacuo to give additional benzylamine (66.7 g, 29percent) as a clear oil: 1H NMR (300 MHz, CDCl3) 7.24 (t, J=8.4 Hz, 1H), 6.91-6.78 (m, 3H), 3.81 (s, 3H), 3.73 (s, 2H), 2.46 (s, 3H)

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