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Structure of 103-67-3 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Journal of Physical Chemistry, 1996, vol. 100, # 26, p. 10981 - 10988
5
[ 107-15-3 ]
[ 103-67-3 ]
[ 74-89-5 ]
[ 4152-09-4 ]
Reference：
[1] Journal of the American Chemical Society, 1983, vol. 105, # 15, p. 5002 - 5011
6
[ 107-15-3 ]
[ 103-67-3 ]
[ 4152-09-4 ]
Reference：
[1] Journal of the American Chemical Society, 1973, vol. 95, p. 3038 - 3039
7
[ 120-92-3 ]
[ 103-67-3 ]
[ 2439-56-7 ]
Reference：
[1] Tetrahedron Letters, 1979, p. 4183 - 4184
8
[ 127-17-3 ]
[ 103-67-3 ]
[ 600-21-5 ]
Reference：
[1] Tetrahedron Letters, 1979, p. 4183 - 4184
9
[ 773837-37-9 ]
[ 103-67-3 ]
[ 41470-36-4 ]
[ 3010-05-7 ]
[ 14321-25-6 ]
[ 61802-83-3 ]
[ 51643-97-1 ]
[ 73355-62-1 ]
Yield
Reaction Conditions
Operation in experiment
16 %Spectr.
With dipotassium peroxodisulfate; ruthenium(IV) oxide hydrate; water In chloroform at 20℃; for 3 h;
General procedure: To a solution of NaCN [196 mg (4 mmol) in 10 mL of water] was added RuO2.xH2O (10-15 mg), followed by amine (1 mmol in 10 mL of CHCl3) and the co-oxidant (4 mmol of NaIO4 or NaIO3, and 3 mmol of K2S2O8; each in 10 mL of water), in this order, and the reaction mixture was vigorously stirred at room temperature for 3 hours. The mixture was filtered from a black solid and the two layers of the filtrate separated (Note). The aqueous layer was extracted with CHCl3, the new organic layer combined with the older one, anhydrized (Na2SO4), and the solvent removed to give the residue I. The last aqueous layer was acidified with HCl, the CHCl3-extraction repeated in order to obtain the residue II. Known quantities (usually 0.2 mmol) of p-dimethoxybenzene (DMB; internal standard) were added in residues I and II, the new mixtures taken up in CDCl3 and the NMR and GC-MS spectra recorded. For most reaction products, the yields were calculated against DMB from the NMR data. In the case of compounds in small amounts or difficultly discernible by NMR (like 24 or 25), the yields obtained from the MS spectra against DMB were corrected using known mixtures of DMB and pure compounds. As usually,10 the yield of benzaldehyde (23) in Table 1 includes that of benzoic acid. Identification of the various reaction products was performed on preliminary experiments, by adding small amounts of pure compounds into the analyzed CDCl3 solutions and comparing the new NMR and GC spectra with the older ones. Meanwhile, the aforementioned residues were chromatographed on columns filled with silica gel or neutral alumina and eluted with hexane (or benzene)/ethyl acetate (or CH2Cl2) mixtures. The substrates 1a-b, practically the main constituents of the samples, remained at the start point and could be recovered with methanol as eluent. The NMR and GC analyses of the various fractions evidenced the existence of all major compounds listed in Scheme 1 and clarified the formation of some products (like 9a-b, 24, 25), hardly observable in more complex mixtures. At the same time, puresamples of 14a-b were obtained this way. As mentioned in the main text, column chromatography cannot be used to separate from the reaction mixtures sensitive compounds such as 2a-b. Note. Sometimes, acetic acid (1 mL) was added before adding the co-oxidant (T1-3,4,9). In this case, the reaction mixture was first basified (aq. Na2CO3), before the filtration step.
Reference：
[1] Revue Roumaine de Chimie, 2016, vol. 61, # 4-5, p. 319 - 325
10
[ 103-67-3 ]
[ 19499-60-6 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 2458
[2] Patent: CN105001096, 2017, B,
11
[ 7697-37-2 ]
[ 103-67-3 ]
[ 19499-60-6 ]
[ 19499-61-7 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 2458
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1810
12
[ 103-67-3 ]
[ 29194-04-5 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 22, p. 4350 - 4360
[2] Synthesis, 1990, # 3, p. 253 - 255
[3] Synthesis, 1990, # 3, p. 253 - 255
[4] Journal of Organic Chemistry, 1947, vol. 12, p. 617,680
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7219 - 7222
13
[ 93-56-1 ]
[ 103-67-3 ]
[ 29194-04-5 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 7, p. 2328 - 2331
14
[ 96-09-3 ]
[ 103-67-3 ]
[ 29194-04-5 ]
Reference：
[1] Journal of the Chemical Society, 1963, p. 1385 - 1400
[2] Journal of the American Chemical Society, 1958, vol. 80, p. 6060,6063[3] Journal of the American Chemical Society, 1959, vol. 81, p. 203,207
[4] Journal of Organic Chemistry, 1951, vol. 16, p. 1434,1437
15
[ 103-67-3 ]
[ 19499-61-7 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 2458
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1810
16
[ 7697-37-2 ]
[ 103-67-3 ]
[ 19499-60-6 ]
[ 19499-61-7 ]
Reference：
[1] Journal of the Chemical Society, 1926, p. 2458
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1810
17
[ 103-67-3 ]
[ 149692-49-9 ]
Reference：
[1] Archiv der Pharmazie, 1993, vol. 326, # 4, p. 209 - 215
[2] Archiv der Pharmazie, 1993, vol. 326, # 4, p. 209 - 215
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 1468
[4] Arkivoc, 2012, vol. 2012, # 3, p. 49 - 65
cis-N-benzyl-4-hydroxy-N-methylcyclohexane-carboxamide[ No CAS ]
trans-N-benzyl-4-hydroxy-N-methylcyclohexane-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;
EXAMPLE 9 N-benzyl-4-({(1R)-1-(4-chloro-benzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-yl-methyl)piperidin-1-yl]-2-oxoethyl}amino)-N-methylcyclo-hexanecarboxamide hydrochloride (compound No. 78) 9.1: N-benzyl-4-hydroxy-N-methylcyclohexane-carboxamide 2.0 g of <strong>[3685-22-1]4-hydroxycyclohexane carboxylic acid</strong> are dissolved in 69 ml of dichloromethane in the presence of 3.58 ml of N-methylbenzylamine, of 3.74 g of hydroxybenzotriazole, of 5.32 g of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride and of 4.94 ml of diisopropylethylamine. The mixture is stirred at ambient temperature for 16 h. After hydrolysis, 14 ml of a 1N aqueous hydrochloric acid solution are added. Extraction is carried out with dichloromethane until the aqueous phase is completely depleted. The organic phase is washed with H2O and then a saturated aqueous sodium chloride solution. After drying over MgSO4 and concentration to dryness, the crude obtained is chromatographed, elution being carried out with a gradient of methanol in dichloromethane ranging from 0percent to 10percent. 3.57 g of N-benzyl-4-hydroxy-N-methylcyclohexanecarboxamide are obtained (mixture of cis and trans stereoisomers). 9.2: N-benzyl-N-methyl-4-oxocyclohexane-carboxamide
Step 1: To a solution of N-benzyl-N-methylamine (3.7 cm3) in dry dichloromethane (40 cm3), cooled to 0 C. was added with stirring, <strong>[5349-17-7]4-bromoacetylpyridine hydrobromide</strong> (4.0 g). The reaction was allowed to warm to room temperature, then stirred for a further 18 hr. The solvent was stripped at reduced pressure, and the residue partitioned between ethyl acetate and dilute aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), evaporated, and the residue subjected to chromatography on silica gel, eluent 5% methanol in dichloromethane, to afford 4-(N-benzyl-N-methylaminoacetyl)pyridine, 1.49 g, 43%, as a yellow gum.
43%
In dichloromethane; at 0 - 20℃; for 18h;
Step 1: To a solution of N-benzyl-N-methylamine (3.7 cm3) in dry dichloromethane (40 cm3), cooled to 0 C. was added with stirring, <strong>[5349-17-7]4-bromoacetylpyridine hydrobromide</strong> (4.0 g). The reaction was allowed to warm to room temperature, then stirred for a further 18 hr. The solvent was stripped at reduced pressure, and the residue partitioned between ethyl acetate and dilute aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), evaporated, and the residue subjected to chromatography on silica gel, eluent 5% methanol in dichloromethane, to afford 4-(N-benzyl-N-methylaminoacetyl)pyridine, 1.49 g, 43%, as a yellow gum.
With aluminum (III) chloride; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 24h;
Example 3 (lS, 2R)-2-Hydroxymethyl-1-phenyl-cyclopropanecarboxylic acid benzyl-methyl-amide To a solution of (LYS, 5R)-1-phenyl-3-oxa-bicyclo [3.1. 0] hexan-2-one (10.5 g, 60.0 mmol) in CH2Cl2 (200 mL) was added AlCl3 (16.0 g, 120 mmol) and then the mixture was cooled to 0 C, and then benzyl methyl amine (240 mmol, as a 2. 0M solution of benzyl methyl amine in THF) was added slowly. The mixture was stirred at room temperature for 24 H, and then the reaction was quenched with saturated aqueous NH4C1. After addition of CH2C12 and H20, the resulting mixture was partitioned. The organic layer was washed with 1N HC1 and brine, dried (NA2S04), evaporated, and purified by column chromatography (silica gel; AcOEt/hexane, 1: 4) to give (LS, 2R)-2-HYDROXYMETHYL-L-PHENYL-CYCLOPROPANECARBOXYLIC acid benzyl-methyl-amide.
1-Benzyl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea[ No CAS ]
[ 103-67-3 ]
Yield
Reaction Conditions
Operation in experiment
94%
1-Benzyl-3-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1-methyl-urea Using <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine</strong> and N-benzylmethylamine the title compound was obtained as an off-white solid (94%), MS: m/e =413 (M+H+).
2-(N-benzylmethylamino)methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-one hydrochloride[ No CAS ]
[ 529-34-0 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; paraformaldehyde; In ethanol; water;
Step D 2-(N-Benzylmethylamino)methyl-6-fluoro-3,4-dihydro-2H-naphthalene-1-one hydrochloride To an ice-cooled solution of N-benzylmethylamine (5.67 cm3) in ethyl alcohol (60 cm3) was added hydrochloric acid (5 M, 10 cm3). <strong>[703-67-3]6-Fluoro-3,4-dihydro-2H-naphthalene-1-one</strong> (6.00 g) and paraformaldehyde (1.32 g) were then added and the resulting mixture was stirred and heated to reflux for 4 h. Upon cooling, the alcohol was removed under reduced pressure and water (100 cm3) was added. The remaining tetralone was extracted into diethyl ether (100 cm3) and the aqueous mixture was then extracted further with dichloromethane (2*100 cm3). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Trituration with diethyl ether and filtration provided the title compound (3.18 g) as a white solid.
a (R)-3-(N-Benzyl-N-methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (S)-3-methanesulphonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (Example 14) (2.43 g, 9.2 mmol) and N-benzyl-N-methylamine (3.5 g, 27 mmol) was stirred and heated at 100 C. for 3 hours, under nitrogen. The N-benzyl-N-methylamine was removed in vacuo, and the residue was partitioned between dichloromethane/water. The aqueous was further extracted with dichloromethane (*1). The combined extracts were washed with brine (*2), dried (Na2 SO4) filtered and evaporated. The residue was purified by chromatography on silica gel, eluding with 20% ethyl acetate/hexane to afford the title amine (1.64 g, 61%) as an oil; delta (250 MHz, CDCl3) 1.46 (9H, s, t Bu), 1.80-2.05 (2H, m), 2.10 (3H, s, NCH3), 2.95-3.80 (7H, m), 7.24-7.34 (5H, m, ArH).
9-Ethyl-4-[N-(phenylmethyl)methylamino]-2-(methylthio)imidazo[5,1-h]-pteridin-6(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 30 9-Ethyl-4-[N-(phenylmethyl)methylamino]-2-(methylthio)imidazo[5,1-h]-pteridin-6(5H)-one Prepared by treatment of 4,6-dichloro-5-nitro-2-(methylthio)pyrimidine with N-benzyl methylamine, followed by reaction with 2-ethylimidazole, reduction with tin (II) chloride, and cyclization with carbonyldiimidazole.
Example 30 9-Ethyl-4-[N-(phenylmethyl)methylamino]-2-(methylthio)imidazo[5,1-h]pteridin-6(5H)-one Prepared by treatment of 4,6dichloro-5-nitro-2-(methylthio)pyrimidine with N-benzyl methylamine, followed by reaction with 2-ethylimidazole, reduction with tin (II) chloride, and cyclization with carbonyldiimidazole.
trans-1-Benzyl-3-benzylmethylamino-4-hydroxypyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; water;
(a) trans-1-Benzyl-3-benzylmethylamino-4-hydroxypyrrolidine 19.4 g (0.1 mol) of 90% strength <strong>[75390-09-9]3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane</strong> are heated under reflux with 14.5 g (0.12 mol) of benzylmethylamine in 100 ml of dioxane and 200 ml of water overnight. The mixture is extracted with CHCl3, the extracts are dried with K2 CO3 and concentrated and the residue is subjected to incipient distillation up to 160 C. (oil bath temperature). Crude yield: 18.3 g Content: 100% (determined by gas chromatography)
triethylammonium 2,2-dimethyl-6β-(triphenylmethylamino)penicillanate[ No CAS ]
[ 541-41-3 ]
[ 76-83-5 ]
[ 551-16-6 ]
[ 103-67-3 ]
2,2-dimethyl-6β-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hexane; chloroform; ethyl acetate; triethylamine;
EXAMPLE 19 2-Dimethyl-6beta-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam To a suspension of <strong>[551-16-6]6-aminopenicillanic acid</strong> (30.6 g) in chloroform (150 mL) was added triethylamine (27.8 mL). The mixture was stirred at room temperature until almost completely in solution at which time trityl chloride (21.7 g) was added in one portion. The reaction was stirred at room temperature for 60 hrs to give a solution of triethylammonium 2,2-dimethyl-6beta-(triphenylmethylamino)penicillanate. A 40 mL portion of the above solution was cooled to 0° C. in an ice bath and additional triethylamine (2.8 mL) was added. Ethyl chloroformate (2.0 mL) was then added and after 1/2 hour N-methylbenzylamine (5 mL) was added via pipette below the surface of the reaction. After 1/2 hour further stirring at room temperature, was poured into water and extracted with methylene chloride (2*). The extracts were washed with dilute hydrochloric acid, sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. The residue was flash chromatographed using a solvent gradient of 20 to 30percent ethyl acetate/hexane to give 2.2 g of 2,2-dimethyl-6beta-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam NMR (CDCl3): delta 1.33(s,3H), 1.60(s,3H), 2.87(2 close s,3H), 3.33(br d,1H,10 Hz), 4.3-4.7(m,4H), 4.80(2 close s,1H), 7.0-7.8(m,20H).
With hydrogenchloride; In water; acetonitrile; at 10 - 65℃;
EXAMPLE 1 Mannich Reaction: Synthesis of 3-(benzyl-methyl-amino)-2-methyl-1-(3-methoxy-phenyl)-propan-1-one (V) In a four-neck 1 L flask equipped with reflux, thermometer and mechanical stirrer, the following are loaded: 95% w/w paraformaldehyde (19.2 g, 0.638 moles) and acetonitrile (300 mL/234 g, 5.70 moles). The mixture is cooled to a temperature less than 10 C., then the following are loaded: 97% w/w N-benzylmethylamine (77.3 g, 0.638 moles), 36% HCl (70.9 g/60.0 mL, 0.70 moles). Finally, 99.7% 1-(3-methoxy-phenyl)-propan-1-one (100 g, 0.608 moles) is added. The reaction mixture is heated at 65+-5 C. for 20-24 hours and the conversion is verified by means of HPLC. Upon completed reaction, the solution is concentrated under vacuum at 35-50 C. and 200-300 mL of solvent is collected. Added to the mixture are: toluene (100 ml) and purified water (200 ml), and stirring proceeds for 30 minutes at ambient temperature. The phases are separated and toluene (200 ml) is added to the aqueous phase. The pH is brought to 11-13 with 28% NaOH (about 105 g). The mixture is stirred for 30 minutes and the phases separated. The toluene phase is distilled under vacuum at 35-45 C. IPA (100 mL) is then added and the residue solvent is distilled. 201 g of pale yellow oil are obtained, 97% yield with a HPLC purity of 87%. The oil thus obtained is used as is for the subsequent step.
In a four-neck 1 L flask equipped with reflux, thermometer and mechanical stirrer, the following are loaded: 95% w/w paraformaldehyde (19.2 g, 0.638 moles) and acetonitrile (300 mL/234 g, 5.70 moles). The mixture is cooled to a temperature less than 10C, then the following are loaded: 97% w/w N-benzylmethylamine (77.3 g, 0.638 moles), 36% HC1 (70.9 g/60.0 mL, 0.70 moles). Finally, 99.7% l-(3-methoxy-phenyl)-propan- 1-one (100 g, 0.608 moles) is added. The reaction mixture is heated at 65 +/- 5C for 20- 24 hours and the conversion is verified by means of HPLC. Upon completed reaction, the solution is concentrated under vacuum at 35-50C and 200-300 mL of solvent is collected. Added to the mixture are: toluene (100 ml) and purified water (200 ml), and stirring proceeds for 30 minutes at ambient temperature. The phases are separated and toluene (200 ml) is added to the aqueous phase. The pH is brought to 11-13 with 28% NaOH (about 105 g). The mixture is stirred for 30 minutes and the phases separated. The toluene phase is distilled under vacuum at 35-45C. IPA (100 mL) is then added and the residue solvent is distilled.201 g of pale yellow oil are obtained, 97% yield with a HPLC purity of 87%. The oil thus obtained is used as is for the subsequent step
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
4-(2-Methoxy-2-oxoethyl)benzoic acid (A) (50 mg) was dissolved in DMF (1 mL) and diisopropylethylamine (50 ??), HATU (110 mg) and N-methyl benzylamine (35 mg) were added. The reaction was allowed to stand at room temperature overnight. Ethyl acetate (5 mL) was added and the reaction was washed with 1 M aqueous citric acid, water and saturated aqueous sodium bicarbonate. The organic layer was dried (MgS04) filtered and concentrated under reduced pressure to give methyl 2-(4- (benzyl(methyl)carbamoyl)phenyl)acetate (B). LCMS method A, (ES+) 298, RT = 1.07 min.
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 20h;Inert atmosphere; Sealed tube;
Step 1 To a degassed solution of <strong>[29681-42-3]4-bromo-pyridine-2-carboxylic acid methyl ester</strong> (650 mg, 3.0 mmol, 1 eq) in toluene (15 mL) were added cesium carbonate (1.9 g, 6.0 mmol, 2 eq), N-methylbenzylamine (0.5 mL, 3.9 mmol, 1.3 eq), BINAP (93 mg, 0.15 mmol, 0.05 eq) and palladium acetate (34 mg, 0.15 mmol, 0.05 eq). The mixture was heated in a sealed tube at 100 C. during 20 h. After cooling, the mixture was poured on water (10 mL) and extracted with ethyl acetate (3*10 mL). The organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography using dichloromethane and methanol (100/0 to 97/3) to afford 4-(benzyl-methyl-amino)-pyridine-2-carboxylic acid methyl ester as a yellow oil (230 mg, 30% yield).
30%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 20h;Sealed tube;
Step 1 To a degassed solution of <strong>[29681-42-3]4-bromo-pyridine-2-carboxylic acid methyl ester</strong> (650 mg, 3.0 mmol, 1 eq) in toluene (15 mL) were added cesium carbonate (1.9 g, 6.0 mmol, 2 eq), N-methylbenzylamine (0.5 mL, 3.9 mmol, 1.3 eq), BINAP (93 mg, 0.15 mmol, 0.05 eq) and palladium acetate (34 mg, 0.15 mmol, 0.05 eq). The mixture was heated in a sealed tube at 100 C. during 20 h. After cooling, the mixture was poured on water (10 mL) and extracted with ethyl acetate (3*10 mL). The organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography using dichloromethane and methanol (100/0 to 97/3) to afford 4-(benzyl-methyl-amino)-pyridine-2-carboxylic acid methyl ester as a yellow oil (230 mg, 30% yield).
3-(2-(benzyl(methyl)amino)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;
General procedure: A creamy white solid of 3-(2-chloroethyl)- 2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-4-one (5) (1.0eq) in N,N-dimethylformamide was taken, pottasium carbonate (3.0 eq) was added to the reaction mixture and then the appropriate aliphatic/ aromatic/heterocyclic amines (1.0 eq) were added and the reaction mixture was heated at 80 °C for 8h. The progress of the reaction was monitored by TLC. Upon completion, the solvent was removed by water wash and extracted with ethyl acetate. The organic layer was washed with 10percent ammonium chloride solution and finally water wash was given to organic layer and dried with anhydrous sodium sulphate. The solvent was evaporated to get crude product which was purified by column chromatography over silica gel (60-120mesh) using hexane: ethyl acetate(8:2) as an eluent.
2-(8-(benzyl(methyl)amino)octyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; for 16h;Reflux;
General procedure: 2-(omega-Bromoalkyl)-isoindoline-1,3-dione (1 equiv) with N-methylbenzylamine (1 equiv) or its substituted analog in the presence of K2CO3 (3 equiv) was stirred in acetonitrile under reflux for 16 h. Once the reaction was finished, the solvent was evaporated under vacuum, producing a residue that was further dissolved in 50 mL of 5 M NaOH and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane to dichloromethane/methanol 98:2), yielding a yellow oil. The final product was obtained in the form of hydrochloride salt. The following compounds were obtained.
7-(N-benzyl-N-methylamino)-1-ethyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.48%
With copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 150℃; for 12h;
In a 25 mL single neck flask, the intermediate 4 (0.5 g, 1.85 mmol) from Step 4, N-methyl(phenyl)methanamine (1.34 g, 1 1.1 1 mmol), Cul (0.04 g, 0.19 mmol) and 1- methylpyrrolidin-2-one (3 mL) were added and the resulting mixture was heated at 150 0 C for 12 h and worked up. The reaction mixture was partitioned in dichloromethane/water and the organic layer was separated. The organic phase was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain the pure 7-(N-benzyl-N-methylamino)- 1 -ethyl-6-fluoro- 1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid (23 mg); Yield: 5.48%; 1H NMR(400 MHz, CDCb): 515.24 (s, 1H), 8.59 (s, 1H), 8.05 (d, J=14, 1H), 7.26-7.38 (m, 5H), 6.61 (d, J=6.8, 1H), 4.64 (s, 2H), 4.16-4.18 (m, 2H), 3.15 (s, 3H), 1.38-1.41 (t, 3H); MS(ESI): 355.0(M+H); HPLC: 96.7%.
With dipotassium peroxodisulfate; ruthenium(IV) oxide hydrate; water; In chloroform; at 20℃; for 3h;pH Ca. 9;
General procedure: To a solution of NaCN [196 mg (4 mmol) in 10 mL of water] was added RuO2.xH2O (10-15 mg), followed by amine (1 mmol in 10 mL of CHCl3) and the co-oxidant (4 mmol of NaIO4 or NaIO3, and 3 mmol of K2S2O8; each in 10 mL of water), in this order, and the reaction mixture was vigorously stirred at room temperature for 3 hours. The mixture was filtered from a black solid and the two layers of the filtrate separated (Note). The aqueous layer was extracted with CHCl3, the new organic layer combined with the older one, anhydrized (Na2SO4), and the solvent removed to give the residue I. The last aqueous layer was acidified with HCl, the CHCl3-extraction repeated in order to obtain the residue II. Known quantities (usually 0.2 mmol) of p-dimethoxybenzene (DMB; internal standard) were added in residues I and II, the new mixtures taken up in CDCl3 and the NMR and GC-MS spectra recorded. For most reaction products, the yields were calculated against DMB from the NMR data. In the case of compounds in small amounts or difficultly discernible by NMR (like 24 or 25), the yields obtained from the MS spectra against DMB were corrected using known mixtures of DMB and pure compounds. As usually,10 the yield of benzaldehyde (23) in Table 1 includes that of benzoic acid. Identification of the various reaction products was performed on preliminary experiments, by adding small amounts of pure compounds into the analyzed CDCl3 solutions and comparing the new NMR and GC spectra with the older ones. Meanwhile, the aforementioned residues were chromatographed on columns filled with silica gel or neutral alumina and eluted with hexane (or benzene)/ethyl acetate (or CH2Cl2) mixtures. The substrates 1a-b, practically the main constituents of the samples, remained at the start point and could be recovered with methanol as eluent. The NMR and GC analyses of the various fractions evidenced the existence of all major compounds listed in Scheme 1 and clarified the formation of some products (like 9a-b, 24, 25), hardly observable in more complex mixtures. At the same time, puresamples of 14a-b were obtained this way. As mentioned in the main text, column chromatography cannot be used to separate from the reaction mixtures sensitive compounds such as 2a-b. Note. Sometimes, acetic acid (1 mL) was added before adding the co-oxidant (T1-3,4,9). In this case, the reaction mixture was first basified (aq. Na2CO3), before the filtration step.
A mixture of terf-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (INT 1 , 4.25 g, 16.02 mmol)) and N-Methyl-1-phenylmethanamine (6.20 mL, 48.07 mmol) was stirred and heated at 100 C for 3 h, under nitrogen. The residue was portioned between DCM/water. The aqueous phase was further extracted with dichloromethane. The combined extracts were washed with brine and dried (Na2S04) filtered and evaporated. The crude product thus obtained was purified by flash chromatography on silica gel, gradient CH:AcOEt from (100:0) to (70:30) to give the title compound as yellow oil (2.93 g, 63% yield). HPLC-MS (Method A): Ret, 2.20 min; ESI+-MS m/z, 291 (M+1 ).
(S)-tert-butyl 3-(benzyl(methyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.93 g
at 100℃; for 3h;Inert atmosphere;
A mixture of the compound obtained in step a (4.25 g, 16.02 mmol)) and N-methyl-iphenylmethanamine (6.20 mL, 48.07 mmol) was stirred and heated at 100 C for 3 h,under nitrogen. The residue was partitioned between DCM/water. The aqueous phase was further extracted with dichloromethane. The combined extracts were washed with brine, dried (Na2SO4) filtered and evaporated. The crude product thus obtained was purified by flash chromatography on silica gel, gradient CH:AcOEt from (100:0) to (70:30) to give the title compound as yellow oil (2.93 g, 63% yield).HPLC-MS (Method A): Ret, 2.20 mm; ESI+-MS m/z, 291 (M+1).
dimethyl-2-((benzylmethylamino)methyl)-2-fluoromalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
General procedure: In a 50 mL two-necked flask containing dichloromethane (10 mL) were added the amine (17 mmol) followed by the aldehyde (15 mmol) and the resulting reaction mixture was allowed to stir at rt for 2 h, before the fluorinated dicarbonyl system (10 mmol) was added. The reaction mixture was stirred at rt for 16 h, evaporated and the residue dissolved in dichloromethane (20 mL), washed with distilled water (2×20 mL), dried over magnesium sulfate and evaporated, to give the desired product. Further purification by distillation or column chromatography eluting from hexane/ethyl acetate was carried out when appropriate. Analytical and spectroscopic data for each individual compound are listed below. For NMR data only resonances of one diastereoisomer or conformer is given for clarity.
N-benzyl-4,6-dichloro-N-methylpicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 16h;
50% Propylphosphonic anhydride solution in ethyl acetate (20.0 mL, 31.5 mmol) was added to a suspension of <strong>[88912-25-8]4,6-dichloropicolinic acid</strong> (3.0 g, 15.7 mmol), N-methyl-1- phenylmethanamine (2.8 g, 23.6 mmol) and diisopropylethylamine (13.5 mL, 78.9 mmol) in dichloromethane (50 mL) at 0C. The reaction mixture was warmed to room temperature and stirred for 16h. The reaction mixture was quenched with saturated sodium bicarbonate solution, the organic product was extracted with dichloromethane (3x40 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate and solvent was evaporated under reduced pressure to get crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh, 30% ethyl acetate in petroleum ether as eluent) to afford 3.5 g of N-benzyl-4,6-dichloro-N-methylpicolinamide as pale yellow oil. Yield: 75%. (0666) ES-MS [M+H]+: 295.1 ; Rt = 1.99 min (Method B). (0667) 1H NMR (400 MHz, DMSO-d6) delta: 7.93-7.90 (m, 1H), 7.85-7.80 (m, 1H), 7.40-7.27 (m, 5H), 4.67 (s, 1H), 4.49 (s, 1H), 2.84 (d, = 14 Hz, 3H).
In dichloromethane; at 40℃; for 16h;Inert atmosphere;
General procedure: Benzyl amine (1 equiv) was dissolved in dichloromethane. The corresponding aryl boronic acid 24 (1 equiv) was added to the reaction solution followed by glyoxylic acid (1 equiv) under an atmosphere of nitrogen. The reaction mixture was warmed up to 40 C and temperature maintained for 16 hours. Reaction mixture was concentrated under reduced pressure. Crude reaction mixture purified via reverse phase preparative HPLC to afford compound of general structure 25.
(±)-1-(tert-butyl) 2-methyl (cis)-4-(benzyl(methyl)amino)piperidine-1,2-dicarboxylate[ No CAS ]
(±)-1-(tert-butyl) 2-methyl (trans)-4-(benzyl(methyl)amino)piperidine-1,2-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%; 18%
(±) 1-(tert-Butyl) 2-methyl (R)-4-oxopiperidine-1,2-dicarboxylate (10 g, 38.9 mmol) was dissolved in MeOH (50 mL). N-Methylbenzylamine (8 mL, 62 mmol) was added, followed by acetic acid (1 mL, 17.4 mmol). The reaction was stirred at room temperature for 1 h. After cooling the mixture to 0 oC, NaBH3CN (3.7 g, 59 mmol) was added in one portion. The reaction was warmed to room temperature and stirred for 15 h. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO4, filtered, and then concentrated under vacuum. Purification by silica chromatography (20-50% EtOAc in hexanes) yielded (±)1-(tert- butyl) 2-methyl (cis)-4-(benzyl(methyl)amino)piperidine-1,2-dicarboxylate (A) (3.96 g, 28%) as the second-highest major component on TLC (when visualized with iodine stain), and (±) 1-(tert- butyl) 2-methyl (trans)-4-(benzyl(methyl)amino)piperidine-1,2-dicarboxylate (B) (2.49 g, 18%) as the lowest major non-baseline TLC component. A: 1H NMR (methanol-d4) d: 7.20-7.40 (m, 5H), 4.49 (m, 1H), 3.70-3.85 (m, 2H), 3.67 (s, 3H), 3.35-3.50 (m, 1H), 3.30 (m, 1H), 2.45-2.60 (m, 2H), 2.10 (m, 1H), 2.07 (s, 3H), 1.93-2.00 (m, 1H), 1.70-1.78 (m, 1H), 1.47 (s, 9H). B: 1H NMR (methanol-d4) 1:1 mixture of rotamers d: 7.33 (d, J=4.3 Hz, 4H), 7.23-7.29 (m, 1H), 4.89-4.99 (m, 1H), 4.03-4.09 (m, 1H), 3.67-3.72 (m, 3H), 3.63 (s, 2H), 2.84-3.05 (m, 1H), 2.39- 2.50 (m, 2H), 2.23 (s, 3H), 1.70-1.92 (m, 2H), 1.51-1.57 (m, 1H), 1.46 (br d, 9H)
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