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Chemical Structure| 76093-33-9
Chemical Structure| 76093-33-9
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Product Details of [ 76093-33-9 ]

CAS No. :76093-33-9 MDL No. :MFCD09952191
Formula : C16H16N2O6 Boiling Point : -
Linear Structure Formula :- InChI Key :JPXPPUOCSLMCHK-CQSZACIVSA-N
M.W : 332.31 Pubchem ID :748472
Synonyms :

Calculated chemistry of [ 76093-33-9 ]

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 5
Num. H-bond acceptors : 6.0
Num. H-bond donors : 2.0
Molar Refractivity : 90.2
TPSA : 121.45 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.98
Log Po/w (XLOGP3) : 2.19
Log Po/w (WLOGP) : 1.71
Log Po/w (MLOGP) : 0.59
Log Po/w (SILICOS-IT) : -0.02
Consensus Log Po/w : 1.29

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -3.14
Solubility : 0.244 mg/ml ; 0.000733 mol/l
Class : Soluble
Log S (Ali) : -4.37
Solubility : 0.014 mg/ml ; 0.0000422 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -3.12
Solubility : 0.25 mg/ml ; 0.000752 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.73

Safety of [ 76093-33-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 76093-33-9 ]

* 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 [ 76093-33-9 ]

[ 76093-33-9 ] Synthesis Path-Downstream   1~62

  • 1
  • [ 67-56-1 ]
  • (R)-2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid monocarbamoylmethyl ester [ No CAS ]
  • [ 76093-33-9 ]
  • 2
  • [ 108-24-7 ]
  • [ 76093-33-9 ]
  • C18H18N2O7 [ No CAS ]
  • 3
  • [ 76093-33-9 ]
  • [ 147779-45-1 ]
  • methyl 3-nitrooxypropyl (4S)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate [ No CAS ]
  • 4
  • [ 76093-33-9 ]
  • [ 119816-27-2 ]
  • [ 119746-72-4 ]
  • 5
  • [ 76093-33-9 ]
  • [ 119816-26-1 ]
  • [ 119746-78-0 ]
  • 6
  • [ 76093-33-9 ]
  • [ 88712-56-5 ]
YieldReaction ConditionsOperation in experiment
With phosphorus pentachloride; In dichloromethane; at -20℃; for 1h; Phosphorus pentachloride (1.66 g, 0.017 mol) was added to the solution of compound 12 (2.1 g,0.006 mol) in dichloromethane (28 mL) below -20 C, and stirred for 1 h. The reaction mixture was cooled to -30 C, and was added ethanol (10 mL, 0.17 mol), and stirred for 4 h. The reaction mixture was poured into saturated sodium carbonate solution (200 mL), and extracted with dichloromethane (200 mL). The organic phase was washed with water (300 mL), dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by flash column chromatography on silica gel,eluting with ethyl acetate/petroleum ether, 3:2, to yield 4 as a light yellow solid (1.2 g,55%).
  • 9
  • 3-allyl 5-methyl (4S)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate [ No CAS ]
  • [ 76093-33-9 ]
  • 10
  • [ 104757-53-1 ]
  • [ 76093-33-9 ]
  • (S)-2,6-Dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(S)-pyrrolidin-3-yl ester [ No CAS ]
  • 2,6-Dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid 3-((S)-1-benzyl-pyrrolidin-3-yl) ester 5-methyl ester [ No CAS ]
  • 11
  • [ 76093-33-9 ]
  • (4S)-dimethylaminoethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [ No CAS ]
  • 12
  • [ 76093-33-9 ]
  • (4S)-(ω-dimethylaminooctyl) methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate [ No CAS ]
  • 17
  • (R)-2-Acetyl-3-(3-nitro-phenyl)-4-[1-((R)-1-phenyl-ethylamino)-eth-(Z)-ylidene]-pentanedioic acid 5-allyl ester 1-methyl ester [ No CAS ]
  • [ 76093-33-9 ]
  • 18
  • [ 76093-33-9 ]
  • BAY 3628 [ No CAS ]
  • 19
  • [ 76093-33-9 ]
  • (S,R)-Benidipine [ No CAS ]
  • 20
  • [ 76093-33-9 ]
  • (S,S)-Benidipine [ No CAS ]
  • 22
  • [ 76093-33-9 ]
  • (4S)-(+)-methyl 2-(nicotinoylamino)ethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate [ No CAS ]
  • 23
  • [ 76093-33-9 ]
  • [ 104831-94-9 ]
  • 25
  • bis(carbamoylmethyl) 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine 3,5-dicarboxylate [ No CAS ]
  • [ 76093-33-9 ]
  • 26
  • [ 76093-33-9 ]
  • [ 126229-11-6 ]
  • 27
  • [ 76093-33-9 ]
  • [ 89226-75-5 ]
  • 28
  • [ 76093-33-9 ]
  • [ 126451-47-6 ]
  • 29
  • [ 76093-33-9 ]
  • [ 134028-04-9 ]
YieldReaction ConditionsOperation in experiment
50.9% e) Preparation of (-)(4R) 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)1,4-dihydropyridine-3-carboxylic acid A solution of 14.8 g (0.0379 mole) of the product obtained in (d) is stirred for one hour at room temperature in 450 ml of acetone in the presence of 90 ml of 1N hydrochloric acid. The reaction mixture is dried under reduced pressure, extracted with ethyl acetate and then washed with water. After drying and evaporation of the solvent, the residue is purified by washing in ethyl ether, giving 6.4 g of a yellow powder. Yield=50.9% [alpha]D =-17 (c=0.5, acetone)
Example 14 Preparation of (4R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3 -nitrophenyl)pyridine-3-carboxylic acid (3) STR27 (4R)-5-(2-acetamidoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-nitrophenyl)pyridine-3-carboxylic acid (10.0 mg) was dissolved in 1 ml of a methanol solution containing 1M sodium methoxide, and the mixture was stirred for 5 hours on an oil bath at 40 C. Under cooling the reaction mixture, 1N hydrochloric acid was added thereto to render pH 2, and 5 ml of deionized water and 5 ml of ethyl acetate were added to the mixture, followed by separation. The resulting organic layer was washed with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was thus obtained was purified by preparative TLC to obtain 8.0 mg of the objective compound. This had the same physical and chemical properties as the compound obtained in Example 12.
The authentic (R)-form of the title compound was prepared as follows. That is, 5 mg of (S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid prepared according to the method described by Shibanuma et al. (Chem. Pharm. Bull., 28(9), 2809-2812 (1980)) was dissolved in 0.5 ml of tetrahydrofuran. Then 2 mul of isobutyl chloroformate was added to the solution. After stirring for 10 minutes, 6 mul of triethylamine and 30 mul of N-acetyl-ethanolamine were added to the mixture followed by stirring for further 2 hours. After 5 ml of ethyl acetate was added to the reaction mixture, the mixture was washed with water and the resulting organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue thus obtained was purified on a preparative silica gel TLC (developing system, toluene-acetone; 1:1) to obtain 3 mg of the authentic (R)-form. The thus obtained authentic (R)-form compound showed the same residence time (14.0 minutes; moving phase 2.5% isopropanol/0.01M phosphate buffer (pH 7.1), flow rate: 0.8 ml/min) as that of the title compound obtained above on the column for optical resolution described above. With respect to the (S)-form, the residence time was 8.4 minutes under the same conditions. Furthermore, 10.0 mg of this compound was dissolved in 1 ml of methanol solution of 1N sodium methoxide. The solution was heated on an oil bath of 40 C. for 5 hours. Under cooling, 1N hydrochloric acid was added to the reaction mixture to adjust pH to 2. Then 5 ml of distilled water and 5 ml of ethyl acetate were added to the mixture followed by separation. The organic phase was washed with water and then dehydrated over Glauber's salt. The solvent was then distilled off in vacuum. The residue was purified by preparative TCL to give 8.0 mg of the methyl ester. The physicochemical properties of the methyl ester coincided with those of (R)-(-)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid obtained by the process of Shibanuma et al. described above. 1H-NMR (CD3 OD) delta: 8.09 (1H, t, J=2.2 Hz), 7.99 (1H, td, J=8.1, 2.2 & 1.1 Hz), 7.64 (1H, d, J=1.1 Hz), 7.44 (1H, t, J=8.1 Hz), 5.09 (1H, s), 8.62 (3H, s), 2.34 (3H, s), 2.88 (8H, s) [alpha]D27: -32.0--(c=0.30, methanol) [alpha]D27: -22.3--(c=0.30, acetone) MS:FAB (neg.) 331 (M--H)
Reference Example 24 Measurement of optical purity of (4R)-1,4-dihydro-2,6-dimethyl-3-?2-(2-carboxybenzoyl)[aminoethyl]oxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid STR44 To 50 mg of the (4R)-1,4-dihydro-2,6-dimethyl-3-?2(2-carboxybenzoyl)[aminoethyl]oxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid obtained in Example 8 was added 5 ml of sodium methoxide (28% methanol solution) and the mixture was stirred at 50 C. for 2 hours. After it was diluted with 10 ml of water, the reaction mixture was washed with 5 ml of ethyl acetate and the aqueous layer was adjusted to pH 3 before it was extracted 3 times with 10 ml each of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to dryness. The yellow substance thus obtained was purified on a column packed with 120 ml of Sephadex LH-20 (solvent: methanol) to obtain 22 mg of (4R)-1,4-dihydro-2,6-dimethyl-3-methyloxycarbonyl-4-(3-nitrophenyl) pyridine-5-carboxylic acid. The optical purity of this substance was analyzed by HPLC (mobile phase: hexane:ethanol:acetic acid=90:10:0.1, flow rate: 1.0 ml/minute, detection UV 254 nm) using an otical resolution column: CHIRALPAK AS (4.6 mm *250 mm) manufactured by Daicel Chemical Industries Ltd. As a result, it revealed that the optical purity of the substance was 100% and the retention time was 12.5 minutes. 1 H-NMR(CD3 OD): delta 8.09(1 H,s), 7.99(1 H,d,J=9.5 Hz), 7.65(1 H,d,J=7.7 Hz), 7.44(1 H,t,j=8.1 Hz), 5.09(1 H,s), 3.62(3 H,S), 2.34(3 H, s), 2.33(3 H,s)
With hydrogenchloride; Cinchonidin; In methanol; water; at 90℃; for 3.5h;Reflux; General procedure: (1) Preparation of (S)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid To a solution of 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (700g, 2.1mol) in methanol (14 L) was added cinchonidine (617g, 2.1mol). The mixture was stirred at 90C under reflux until cinchonidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for half an hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (S)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6 %.
With quinidine; In methanol; at 90℃; for 3h; General procedure: (1) Preparation of (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (700g, 2.1mol) in methanol (14 L) was added Quinidine (617g, 1.90mol). The mixture was stirred at 90C under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for half an hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl -4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6 %.

  • 31
  • [ 4377-33-7 ]
  • [ 76093-33-9 ]
  • 3-(2-pyridyl)methyl (4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In tetrahydrofuran; ethyl acetate; EXAMPLE 11 Production of 3-(1-methyl-2-pyridinium)methyl (4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylate iodide STR21 To a solution of 1 g (3.01 mmol) of (4R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid in 4 ml of THF were added 1.23 g (7.50 mmol) of 2-(chloromethyl)pyridine and 460 mg (3.35 mmol) of potassium carbonate and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with 50 ml of ethyl acetate, washed with water, and hydrated and dried over salt cake. Thereafter, the solvent was distilled off under reduced pressure to obtain 1.13 g of the residue. The residue was passed through a silica gel column for purification to obtain 673 mg of 3-(2-pyridyl)methyl (4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylate.
  • 32
  • [ 114208-23-0 ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium chloride; sodium methylate; In methanol; water; EXAMPLE 89 Synthesis of (-)-(R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid: The above compound was synthesised in accordance with the following reaction scheme: STR131 More specifically, under an ice-cooled condition, 10.89 g (28.3 mmol) of (+)-2-cyanoethyl methyl (S)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate was suspended in 30 ml of anhydrous methanol. To the above mixture, 5.73 g (29.7 mmol) of a 28% sodium methoxide was added. The reaction mixture was stirred at room temperature for one hour and water was added thereto. The reaction mixture was then washed with methylene chloride. With addition of 2N hydrochloric acid, the PH of the reaction mixture was adjusted to 3 to 4, and the reaction mixture was extracted with ethyl acetate. An organic layer was separated and washed with water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, whereby 9.34 g (100%) of the captioned compound was obtained. Melting point (C.) 171-172 C. (dec.) IR (cm-1, KBr) 3360, 1678, 1534, 1352 Mass spectrometry C16 H16 N2 O6 Calcd. 332.10081 Found 332.10107 NMR (delta, Acetone-d6) 2.37 (6H, s), 3.61 (3H, s), 5.18 (1H, s), 7.52 (1H, t, J=8 Hz), 7.74 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.09 (1H, s), 8.15 (1H, s), 10.4 (1H, s). Optical rotation [alpha]D25 =-19.3 [c=1,021, acetone]
  • 33
  • (4R)-1,4-dihydro-3-(2-cyanoethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid [ No CAS ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium methylate; In methanol; water; ethyl acetate; Example 13 Preparation of (4R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3 -nitrophenyl)pyridine - 3-carboxylic acid (2) STR26 (4R)-1,4-dihydro-3 -(2-cyanoethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid (10.0 mg) was dissolved in 1 ml of a methanol solution containing 1M sodium methoxide, and the mixture was stirred for 4 hours on an oil bath at 50 C. Under cooling the reaction mixture, 1N hydrochloric acid was added thereto to render pH 2, and 5 ml of deionized water and 5 ml of ethyl acetate were added to the mixture, followed by separation. The resulting organic layer was washed with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was thus obtained was purified by preparative TLC to obtain 4.0 mg of the objective compound. This had the same physical and chemical properties as the compound obtained in Example 12.
  • 34
  • [ 160748-90-3 ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid; In ethanol; water; ethyl acetate; Example 12 Preparation of (4R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid (1) STR25 To a solution of 13.8 mg of 2-tetrahydropyranyl (4S)1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylate in 0.5 ml of ethanol and 0.1 ml of water was added 6 mg of p-toluenesulfonic acid. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by preparative TLC to obtain 6.0 mg of the objective compound. 1 H-NMR (CD3 OD)delta: 8.09(1H,t,J=2.2 Hz), 7.99(1H,ddd,J=8.1 Hz, J=2.2 Hz, J=1.1 Hz),7.64(1H,d,J=1.1 Hz), 7.44(1H,t,J=8.1 Hz), 5.09(1H,s), 3.62(3H,s), 2.34(3H,s), 2.33(3H,s); [alpha]D27: -32.0 (c0.30, methanol); [alpha]D27: -22.3 (c0.30, acetone); MS:FAB(neg.)331(M-1).
YieldReaction ConditionsOperation in experiment
The resulting (R)-free base is then dissolved in acetone (100 mL), treated with HCl (1N, 120 mL) at 0 C., and allowed to stand for one hour at room temperature. Then, water (100 mL) is added, and the resulting precipitate is filtered to yield (R)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (mp=200 C., alphaD20 =-20.4 (c=0.51 acetone)).
  • 36
  • (R)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine [ No CAS ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In dichloromethane; water; The resolved mono-ester of formula 18 is then deprotected by acid hydrolysis using a dilute (about 1N to about 2N) mineral acid in a suitable water-miscible solvent (preferably acetone or THF) at a temperature between about 0 and about 15 C. for about 30 to about 120 minutes. For example, (R)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is dissolved in CH2 Cl2, treated with 1N HCl at 0 C., and allowed to stand for one hour at room temperature. Then, water (100 mL) is added, and the resulting precipitate is filtered to yield (R)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (19).
  • 37
  • C16H16N2O6*C19H22N2O [ No CAS ]
  • [ 76093-33-9 ]
  • 39
  • [ 21881-77-6 ]
  • [ 76093-33-9 ]
  • 40
  • [ 1404063-64-4 ]
  • [ 76093-33-9 ]
  • [ 1404062-92-5 ]
YieldReaction ConditionsOperation in experiment
56% (2) Preparation of (S)-3-[(S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (33.75 g, 0.1 mol) in dichloromethane was added 1 mL DMF. To the resulting mixture was slowly added oxalyl chloride (25.5 g, 0.2 mol) dropwisely under cooling in an ice bath. The reaction was conducted at 25 C. After the completion of reaction, the reaction solution was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (200 mL), (S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (14.75 g, 0.05 mol) and DIPEA (12.9 g, 0.1 mol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=80:1(volumetric ratio)) to produce the title product (S)-3-[(S)-1-(3,3-diphenylpropyl)-3-methyl-3-pyrrolidinyl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (17 g) in a yield of 56%. Four batches of product samples were measured for the optical activities, which were in a range of from +98 to -118 (temperature: 20 C., concentration: 2 mg/mL, the solvent was MeOH), wherein one batch of samples had an optical activity of +108.34. Molecular formula: C36H39N30 6 Mw: 609.2 MS(M+H): 610.3 1H-NMR (DMSO, 400 MHz) ll: 9.13-9.11 (lH, d),8.05-7.94 (2H, m), 7.61-7.49 (2H, m), 7.33-7.27 (8H, m),7.20-7.17 (2H, m), 4.93-4.88 (lH, d), 4.00-3.95 (lH, m),3.95-3.53 (lH, m), 3.53-3.52 (3H, d), 3.13 (2H, m), 2.84-2.83(4H, m), 2.42-2.36 (3H, m), 2.27-2.21 (6H, m), 2.23-2.21(lH, m), 1.49-1.41 (3H, d).
56% With oxalyl dichloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 25℃;Cooling with ice; (2) Preparation of (S)-3-[(S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (33.75g, 0.1mol) in dichloromethane was added 1mL DMF. To the resulting mixture was slowly added oxalyl chloride (25.5g, 0.2mol) dropwisely under cooling in an ice bath. The reaction was conducted at 25C. After the completion of reaction, the reaction solution was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (200mL), (S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin -3-ol (14.75g, 0.05mol) and DIPEA (12.9g, 0.1mol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 80:1(volumetric ratio)) to produce the title product (S)-3-[(S)-1-(3,3-diphenylpropyl) -3-methyl-3-pyrrolidinyl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (17 g) in a yield of 56 %. Four batches of product samples were measured for the optical activities, which were in a range of from +98 to +118 (temperature: 20C, concentration: 2 mg/mL, the solvent was MeOH), wherein one batch of samples had an optical activity of +108.34.
(R)-5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid(304g, 1.02mol)Dissolved in dichloromethane solution (3.4L), added DMF (34mL), cooled to -10 C,Oxalyl chloride (155.8 g, 1.23 mol) was slowly added dropwise, and the temperature was controlled to be below 0 C for 4 hours, and the reaction was monitored by TLC.(S)-1-((3,3-Diphenylpropyl)-3-methylpyrrolidin-3-ol (302 g, 1.02 mol)The dichloromethane solution (600 mL) was slowly added, and the temperature was controlled to be below 0 C for 1 hour.The reaction was monitored by TLC, and washed with water, 1% diluted hydrochloric acid, 5% aqueous sodium carbonate, and 5% brine.The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated3-((S)-1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl) 5-methyl (S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.The crude product (624 g) was used directly in the next step.
  • 41
  • [ 1404063-66-6 ]
  • [ 76093-33-9 ]
  • [ 1404062-94-7 ]
YieldReaction ConditionsOperation in experiment
51% (5) Preparation of (4S)-3-[1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (17.67 g, 53 mmol) in dichloromethane was added 1 mL DMF. To the resulting mixture was slowly added oxalyl chloride (8.1 g, 64 mmol) dropwisely under cooling in an ice bath. The reaction was conducted at 25 C. After the completion of reaction, the resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (120 mL), 1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-ol (13.6 g, 48 mmol) and DIPEA (12.38 g, 96 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=70:1 (volumetric ratio)) to produce (4S)-3-[1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (14.58 g) in a yield of 51%. Molecular formula: C35H37N3O6 Mw: 595.2 MS (M+H): 596.3 1H-NMR (DMSO, 400 MHz) delta: 9.16 (1H, s), 7.99-7.91 (2H, m), 7.57-7.51 (2H, m), 7.49-7.34 (8H, m), 7.32-7.23 (2H, m), 4.89-4.83 (1H, d), 4.52 (1H, s), 3.96-3.53 (2H, m), 3.52-3.33 (5H, m), 3.26-3.23 (2H, m), 2.26-2.23 (7H, m), 1.98-1.91 (1H, m), 1.42-1.26 (3H, m).
51% (5) Preparation of (4S)-3-[1-(2,2-diphenylethyl)-3-methylpyrrolidin -3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine -3,5-dicarboxylate According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (17.67g, 53mmol) in dichloromethane was added 1mL DMF. To the resulting mixture was slowly added oxalyl chloride (8.1g, 64mmol) dropwisely under cooling in an ice bath. The reaction was conducted at 25C. After the completion of reaction, the resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (120mL), 1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-ol (13.6g, 48mmol) and DIPEA (12.38g, 96mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 70:1 (volumetric ratio)) to produce (4S)-3-[1-(2,2-diphenylethyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (14.58 g) in a yield of 51 %. Molecular formula: C35H37N3O6 Mw: 595.2 MS (M+H): 596.3 1H-NMR(DMSO, 400 MHz) delta: 9.16 (1 H, s), 7.99-7.91 (2 H, m), 7.57-7.51 (2 H, m), 7.49-7.34 (8 H, m), 7.32-7.23 (2 H, m), 4.89-4.83 (1 H, d), 4.52 (1 H, s), 3.96-3.53 (2 H, m), 3.52-3.33 (5H, m), 3.26-3.23 (2 H, m), 2.26-2.23 (7 H, m), 1.98-1.91 (1H, m), 1.42-1.26 (3 H, m).
  • 42
  • [ 1404063-66-6 ]
  • [ 76093-33-9 ]
  • [ 1404062-95-8 ]
  • [ 1404062-96-9 ]
  • 43
  • [ 1404063-67-7 ]
  • [ 76093-33-9 ]
  • [ 1404062-97-0 ]
YieldReaction ConditionsOperation in experiment
47.3% To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (2.72 g, 8.18 mmol) in dichloromethane was added 0.1 mL DMF. To the resulting mixture was slowly added oxalyl chloride (2.08 g, 16.39 mmol) dropwisely under cooling in an ice bath. The reaction was conducted at 25 C. After the completion of reaction, the resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20 mL), 3-methyl-1-(3-phenylpropyl)pyrrolidin-3-ol (1 g, 4.56 mmol) and DIPEA (1.46 g, 11.30 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=87:1 (volumetric ratio)) to produce (4S)-3-[3-methyl-1-(3-phenylpropyl)pyrrolidinyl-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.15 g) in a yield of 47.3%. Molecular formula: C30H35N3O6 Mw: 533.2 MS (M+H): 534.3 1H-NMR (DMSO, 400 MHz) delta: 9.20-9.17 (1H, d), 9.16-7.97 (2H, m), 7.63-7.53 (2H, m), 7.30-7.19 (5H, m), 4.95-4.91 (1H, m), 3.56-3.55 (1H, m), 3.54-3.41 (4H, m), 3.40-3.15 (1H, m), 3.12-3.07 (4H, m), 2.61-2.49 (2H, m), 2.29 (6H, s), 1.96-1.90 (2H, m), 1.52-1.36 (3H, dd), 1.10-1.03 (2H, m).
47.3% To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (2.72g, 8.18mmol) in dichloromethane was added 0. 1 mL DMF. To the resulting mixture was slowly added oxalyl chloride (2.08g, 16.39mmol) dropwisely under cooling in an ice bath. The reaction was conducted at 25C. After the completion of reaction, the resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20mL), 3-methyl-1-(3-phenylpropyl)pyrrolidin-3-ol (1g, 4.56mmol) and DIPEA (1.46g, 11.30mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 87:1 (volumetric ratio)) to produce (4S)-3-[3-methyl-1-(3-phenylpropyl)pyrrolidinyl-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate (1.15 g) in a yield of 47.3 %. Molecular formula: C30H35N3O6 Mw: 533.2 MS (M+H): 534.3 1H-NMR(DMSO, 400 MHz) delta: 9.20-9.17 (1 H, d), 9.16-7.97 (2 H, m), 7.63-7.53 (2 H, m), 7.30-7.19 (5 H, m), 4.95-4.91 (1 H, m), 3.56-3.55 (1 H, m), 3.54-3.41 (4 H, m), 3.40-3.15 (1H, m), 3.12-3.07 (4 H, m), 2.61-2.49 (2 H, m), 2.29 (6 H, s), 1.96-1.90 (2H, m), 1.52-1.36 (3 H, dd), 1.10-1.03 (2 H, m).
  • 44
  • [ 1404063-68-8 ]
  • [ 76093-33-9 ]
  • [ 1404062-98-1 ]
YieldReaction ConditionsOperation in experiment
48% (2) Preparation of (4S)-3-(3-methyl-1-phenylethylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (2.9 g, 8.73 mmol) in dichloromethane was added 0.1 mL DMF. To the mixture was slowly added oxalyl chloride (2.2 g, 17.33 mmol) dropwisely in an ice bath. The reaction was conducted at 25 C. until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20 mL), 3-methyl-1-phenylethylpyrrolidin-3-ol (1 g, 4.87 mmol) and DIPEA (1.56 g, 12.1 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=78:1 (volumetric ratio)) to produce (4S)-3-(3-methyl-1-phenylethylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.21 g) in a yield of 48%. Molecular formula: C29H33N3O6 Mw: 519.2 MS (M+H): 520.3 1H-NMR (DMSO, 400 MHz) delta: 9.20-9.18 (1H, d), 8.03-7.97 (2H, m), 7.64-7.53 (2H, m), 7.34-7.21 (5H, m), 4.96-4.93 (1H, d), 3.56-3.54 (2H, m), 3.52-3.41 (3H, m), 3.34-3.17 (1H, m), 3.07-2.93 (2H, m), 2.50-2.49 (2H, m), 2.31-2.29 (6H, d), 2.26 (1H, m), 1.54-1.39 (3H, dd), 1.1 (1H, s), 1.05 (1H, t).
  • 45
  • [ 1404063-69-9 ]
  • [ 76093-33-9 ]
  • [ 1404062-99-2 ]
YieldReaction ConditionsOperation in experiment
45.6% To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (4.86g, 14.6mmol) in dichloromethane was added 0.1mL DMF. To the mixture was slowly added oxalyl chloride (3.68g, 29.0mmol) dropwisely in an ice bath. The reaction was conducted at 25C until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20mL), the crude product of 1-(3,5-difluorobenzyl)-3-methylpyrrolidin-3-ol (1.8g) and DIPEA (1.86g, 14.4mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 85:1 (volumetric ratio)) to produce (4S)-3-[1-(3,5-difluorobenzyl)-3-methyl-3-pyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.78 g) in a yield of 45.6% (two steps together). Molecular formula: C28H29F2N3O6 Mw: 541.2 MS (M+H): 543.3 1H-NMR(DMSO, 400 MHz) delta: 9.14 (1 H, t), 8.02-7.97 (2 H, m), 7.60-7.55 (2 H, m), 7.39-7.33 (2 H, m), 4.93-4.90 (1 H, d), 4.41-4.40 (2 H, m), 3.56-3.53 (6 H, m), 3.35 (1 H, s), 3.07 (1 H, s), 2.30-2.26 (6 H, m), 1.50-1.24 (3 H, dd), 1.10 (3 H, s).
1.78 g To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (4.86 g, 14.6 mmol) in dichloromethane was added 0.1 mL DMF. To the mixture was slowly added oxalyl chloride (3.68 g, 29.0 mmol) dropwisely in an ice bath. The reaction was conducted at 25 C. until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20 mL), the crude product of 1-(3,5-difluorobenzyl)-3-methylpyrrolidin-3-ol (1.8 g) and DIPEA (1.86 g, 14.4 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=85:1 (volumetric ratio)) to produce (4S)-3-[1-(3,5-difluorobenzyl)-3-methyl-3-pyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.78 g) in a yield of 45.6% (two steps together). Molecular formula: C28H29F2N3O6 Mw: 541.2 MS (M+H): 543.3 1H-NMR (DMSO, 400 MHz) delta: 9.14 (1H, t), 8.02-7.97 (2H, m), 7.60-7.55 (2H, m), 7.39-7.33 (2H, m), 4.93-4.90 (1H, d), 4.41-4.40 (2H, m), 3.56-3.53 (6H, m), 3.35 (1H, s), 3.07 (1H, s), 2.30-2.26 (6H, m), 1.50-1.24 (3H, dd), 1.10 (3H, s).
  • 46
  • [ 1404063-70-2 ]
  • [ 76093-33-9 ]
  • [ 1404063-03-1 ]
YieldReaction ConditionsOperation in experiment
56% (5) Preparation of (4S)-3-[1-diphenylmethyl-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (3.58 g, 10.8 mmol) in dichloromethane was added 1 mL DMF. To the mixture was slowly added oxalyl chloride (2.74 g, 21.6 mmol) dropwisely in an ice bath. The reaction was conducted at 25 C. until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (1 g, 3.7 mmol) and DIPEA (1.4 g, 10.8 mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=15:1 (volumetric ratio)) to produce (4S)-3-[1-diphenylmethyl-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.2 g) in a yield of 56%. Molecular formula: C34H35N3O6 Mw: 581.2 1H-NMR (DMSO, 400 MHz) delta: 9.19-9.13 (1H, m), 8.01-7.89 (2H, m), 7.73-7.68 (4H, m), 7.58-7.53 (2H, m), 7.41-7.34 (6H, m), 4.93-4.89 (1H, s), 3.77-3.69 (2H, m), 3.62-3.42 (3H, m), 3.37-3.22 (3H, m), 2.49-2.48 (1H, s), 2.28-1.99 (6H, d), 1.50-1.35 (3H, dd).
  • 47
  • [ 1404063-63-3 ]
  • [ 76093-33-9 ]
  • [ 1404062-91-4 ]
YieldReaction ConditionsOperation in experiment
56% (7) Preparation of (4S)-3-[1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (67.5 g, 0.2 mol) in dichloromethane was added 1.5 mL DMF. To the mixture was slowly added oxalyl chloride (51 g, 0.4 mol) dropwisely in an ice bath. The reaction was conducted at 25 C. After the completion of reaction, the resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (300 mL), 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (29.5 g, 0.1 mol) and DIPEA (25.8 g, 0.2 mol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25 C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=80:1 (volumetric ratio)) to produce S)-3-[1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl]5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (34 g) in a yield of 56%.
56% (7) Preparation of (4S)-3-[1-(3,3-diphenylpropyl)-3-methylpyrrolidin -3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (67.5g, 0.2mol) in dichloromethane was added 1.5mL DMF. To the mixture was slowly added oxalyl chloride (51g, 0.4mol) dropwisely in an ice bath. The reaction was conducted at 25C. After the completion of reaction, the resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (300mL), 1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-ol (29.5g, 0.1mol) and DIPEA (25.8g, 0.2mol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 80:1 (volumetric ratio)) to produce (4S)-3-[1-(3,3-diphenylpropyl)-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (34 g) in a yield of 56 %.
  • 48
  • [ 74936-72-4 ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
18.6% (1) Preparation of (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (700 g, 2.1 mol) in methanol (14 L) was added Quinidine (617 g, 1.90 mol). The mixture was stirred at 90 C. under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for half an hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6%.
18.6% With quinidine; In methanol; at 90℃; for 3h; (1) Preparation of (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (700g, 2.1mol) in methanol (14 L) was added Quinidine (617g, 1.90mol). The mixture was stirred at 90C under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for half an hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl -4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6 %.
18.6% With quinidine; In methanol; water; at 90℃; for 3.5h; (1) Preparation of (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (700g, 2.1mol) in methanol (14 L) was added Quinidine (617g, 1.90mol). The mixture was placed at 90C under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for half an hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6 %.
  • 49
  • 3-methyl-1-phenylethylpyrrolidin-3-ol [ No CAS ]
  • [ 76093-33-9 ]
  • [ 1404062-98-1 ]
YieldReaction ConditionsOperation in experiment
48% (2) Preparation of (4S)-3-(3-methyl-1-phenylethylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate According to Example 15, (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was synthesized. To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (2.9g, 8.73mmol) in dichloromethane was added 0.1 mL DMF. To the mixture was slowly added oxalyl chloride (2.2g, 17.33mmol) dropwisely in an ice bath. The reaction was conducted at 25C until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (20mL), 3-methyl-1-phenylethylpyrrolidin-3-ol (1g, 4.87mmol) and DIPEA (1.56g, 12.1mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 78:1 (volumetric ratio)) to produce (4S)-3-(3-methyl-1-phenylethylpyrrolidin-3-yl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.21 g) in a yield of 48 %. Molecular formula: C29H33N3O6 Mw: 519.2 MS (M+H): 520.3 1H-NMR(DMSO, 400 MHz) delta: 9.20-9.18 (1 H, d), 8.03-7.97 (2 H, m), 7.64-7.53 (2 H, m), 7.34-7.21 (5 H, m), 4.96-4.93 (1 H, d), 3.56-3.54 (2 H, m), 3.52-3.41 (3 H, m), 3.34-3.17 (1H, m), 3.07-2.93 (2 H, m), 2.50-2.49 (2 H, m), 2.31-2.29 (6 H, d), 2.26 (1H, m), 1.54-1.39 (3 H, dd), 1.1(1H, s), 1.05(1 H, t).
  • 50
  • [ 1404063-63-3 ]
  • [ 76093-33-9 ]
  • [ 1404063-03-1 ]
YieldReaction ConditionsOperation in experiment
56% (5) Preparation of (4S)-3-[1-diphenylmethyl-3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate To a solution of (R)-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (3.58g, 10.8mmol) in dichloromethane was added 1mL DMF. To the mixture was slowly added oxalyl chloride (2.74g, 21.6mmol) dropwisely in an ice bath. The reaction was conducted at 25C until the completion of reaction. The resulting mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added 1-(3,3-diphenylpropyl) -3-methylpyrrolidin-3-ol (1g, 3.7mmol) and DIPEA (1.4g, 10.8mmol) dropwisely under cooling in an ice bath respectively and successively. The reaction was conducted at 25C. After the completion of reaction monitored by HPLC, the reaction solution was washed with water thrice. The organic phase was dried over anhydrous sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness, and purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate = 15:1 (volumetric ratio)) to produce (4S)-3-[1-diphenylmethyl -3-methylpyrrolidin-3-yl] 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.2 g) in a yield of 56 %. Molecular formula: C34H35N3O6 Mw: 581.2 1H-NMR(DMSO, 400 MHz) delta: 9.19-9.13 (1 H, m), 8.01-7.89 (2 H, m), 7.73-7.68 (4 H, m), 7.58-7.53 (2 H, m), 7.41-7.34 (6 H, m), 4.93-4.89 (1 H, s), 3.77-3.69 (2 H, m), 3.62-3.42 (3 H, m), 3.37-3.22 (3H, m), 2.49-2.48 (1 H, s), 2.28-1.99 (6 H, d), 1.50-1.35 (3 H, dd).
  • 51
  • [ 102993-38-4 ]
  • [ 76093-33-9 ]
  • 52
  • [ 75130-24-4 ]
  • [ 76093-33-9 ]
  • 53
  • [ 76093-33-9 ]
  • [ 104713-75-9 ]
  • 54
  • [ 76093-33-9 ]
  • 3-(R)-1-benzylpyrrolidin-3-yl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate [ No CAS ]
  • 55
  • [ 76093-33-9 ]
  • [ 88712-56-5 ]
  • 56
  • [ 76093-33-9 ]
  • [ 101385-90-4 ]
  • [ 104713-75-9 ]
YieldReaction ConditionsOperation in experiment
at 50℃; (6) the compound of the above-mentioned compound (X) with benzyl quick (V) in the proton or non-protonic solvent reaction, the reaction temperature is 50 C, preferably 50 C, the reaction time is 7h, preferably 10h, compound (XI) can be obtained;
  • 57
  • [ 102993-38-4 ]
  • [ 76093-33-9 ]
  • [ 76093-34-0 ]
  • 58
  • [ 75130-24-4 ]
  • [ 76093-33-9 ]
  • [ 76093-34-0 ]
  • 59
  • [ 74936-72-4 ]
  • [ 76093-33-9 ]
  • [ 76093-34-0 ]
YieldReaction ConditionsOperation in experiment
(5) the compound of the above-mentioned compound (IX) in the proton or non-protonic solvent, using chiral organic alkali as resolving agent to split, the reaction temperature is 5 C, preferably 150 C, the reaction time is 2h, preferably 4h, the compounds can be obtained (X);
  • 60
  • methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-5-([(2S)-1-oxo-1-(propan-2-yloxy)propan-2-yl]oxy}carbonyl)-1,4-dihydropyridine-3-carboxylate [ No CAS ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
93.5% With sodium hydroxide; In water; acetone; at 20℃; for 3h; (S) -1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-3-pyridinecarboxylic acid- (S) -1'- 7.3 g of isopropoxy-1'-oxo-2'-propanol ester and 1.9 g of sodium hydroxide were dissolved in 50 ml of water, 40 ml of acetone was added, and the reaction was carried out at room temperature for 3 hours.Add 40ml of water to dilute, adjust the pH to 2-3 with 6mol / L hydrochloric acid, stir for 10min, suction filter, wash the filter cake with water,Drying gave 5.3 g of pale yellow product with a yield of 93.5%.
  • 61
  • methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-5-([(2S)-1-oxo-3-phenyl-1-(propan-2-yloxy)propan-2-yl]oxy}carbonyl)-1,4-dihydropyridine-3-carboxylate [ No CAS ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide; In water; acetone; at 20℃; for 3h; (S) -1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-3-pyridinecarboxylic acid- (S) -1'- 7.4 g of isopropoxy-1'-oxo-2'-phenylpropanol ester and 1.7 g of sodium hydroxide were dissolved in 50 ml of water, 40 ml of acetone was added, and the reaction was carried out at room temperature for 3 hours.Add 40ml of water to dilute, adjust the pH to 2-3 with 6mol / L hydrochloric acid, stir for 10min, suction filter, wash the filter cake with water,Drying gave 4.21 g of pale yellow product with a yield of 90.0%.
  • 62
  • methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-5-[(1S)-2-oxo-1-phenyl-2-(propan-2-yloxy)ethoxy]carbonyl}-1,4-dihydropyridine-3-carboxylate [ No CAS ]
  • [ 76093-33-9 ]
YieldReaction ConditionsOperation in experiment
94.4% With sodium hydroxide; In water; acetone; at 20℃; for 3h; (S) -1,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-3-pyridinecarboxylic acid (S) -2'-iso 8.7 g of propoxy-2'-oxo-1'-phenylethanol ester and 2 g of sodium hydroxide were dissolved in 50 ml of water, 40 ml of acetone was added, and the reaction was carried out at room temperature for 3 hours.Add 40ml of water to dilute, adjust the pH to 2-3 with 6mol / L hydrochloric acid, stir for 10min, suction filter, wash the filter cake with water,Drying gave 5.36 g of pale yellow product with a yield of 94.4%.
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