CN104892532A - Synthetic process of chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone - Google Patents
Synthetic process of chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone Download PDFInfo
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
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Abstract
Chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone compound can be used as a medicine and an organic intermediate. The invention discloses a synthetic process of the chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone compound. The synthetic process comprises reacting chiral aminoacid amide with o-halogen benzylhalogen in the presence of a copper catalyst and alkali to obtain the chiral 3-substituted 1,3,4,5-tetrahydro-1,4-benzodiazepine-2-ketone compound in high yield and enantiopurity.
Description
Technical field
This patent relates to the field of organic synthesis, pharmaceutical synthesis, organic chemical industry, concretely, is exactly replace 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine from amino acid amide and adjacent halogen benzyl halogen one-step synthesis chirality 3-
-2-ketone compounds.
Background technology
Benzene phenodiazine
class medicine mostly is Isosorbide-5-Nitrae-benzene phenodiazine
the derivative of-2-ketone, clinical conventional have kind more than 30.Although precursor structure is identical, different derivative emphasizes particularly on different fields in anxiety, anticonvulsion, tranquilizing soporific, of flaccid muscles and stable effect.Isosorbide-5-Nitrae-benzene phenodiazine
-2-ketone medicine was found at the end of the fifties, and first type is for stable peaceful with profit clothes.This compounds has good biological activity, is widely used, and is the core texture of a lot of medicine, as opiate receptor antagonist, vasopressin receptor antagonist, antiepileptic drug, anxiolytic, microbiotic, anti-AIDS medicine, antiphlogistic drug, soporific etc.
Except Isosorbide-5-Nitrae-benzene phenodiazine
diazepam, the Bromazepam of-2-ketone skeleton, camazepam, the benzene such as clonazepam, leoponex phenodiazine
outside class medicine, 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the compound of-2-ketone skeleton also show multiple pharmacologically active, such as, and endothelin-receptor antagonists (J.Med.Chem.2004,47,2776-2795), anti-AIDS (Bioorg.Med.Chem.1999,7,2427 – 2436), anti-ischemia (Bioorg.Med.Chem.Lett.2007,17,1326-1331), the orphan receptor gamma modulators (WO2013/64231A1,2013) etc. that RAR is relevant.
Mainly contain four kinds of synthesis 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazines
the method of-2-ketone compounds: (1) is by 1,3-dihydrobenzo [e] [Isosorbide-5-Nitrae] phenodiazine
[2+2] cycloaddition reaction (2) of-2-ketone compounds, (2) are by the condensation of 2-nitrobenzaldehyde and amino acid ester, reductive alkylation, catalytic hydrogenation, molecule inner ring condensation (Bioorg.Chem.2009,37,90-95; WO2013/64231A1,2013), the nucleophilic substitution reaction of (3) adjacent nitrobenzyl bromine or methanesulfonates and amino acid ester, reductive ring closure reaction (Bioorg.Med.Chem.Lett.2007,17,1326-1331; Synthesis 2005,2005,1881 – 1887), (4) o-Nitraniline and alpha bromoisobutyric acid ester as starting raw material through nucleophilic substitution reaction, hydrogenation, condensation (Bioorg.Med.Chem.1999,7,2427 – 2436).In a word, these synthetic methods at least need the synthetic operation process of more than two steps.
This patent discloses a kind of new synthesis technique, adopts the nucleophilic substitution reaction of the series connection of copper catalytic amino acid acid amides and adjacent halogen benzyl halogen and C-N coupling to obtain 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone.
Summary of the invention
The invention provides a kind of chirality 3-and replace 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the synthesis technique of-2-ketone compounds.
3-disclosed by the invention replaces 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the synthesis technique of-2-ketone compounds is completed by a step, namely in the presence of a base, and copper catalysis chiral aryl lactic amide and halogenated aryl hydrocarbon generation selectivity C-N linked reaction one-step synthesis chiral aryl lactoyl arylamine.
Set forth the present invention in more detail in conjunction with the following examples, do not think that they limit the scope of the present invention.
Embodiment
Embodiment one
L configuration phenylalanyl amine (0.75 mmole), adjacent iodine benzyl bromine (0.5 mmole), cuprous iodide (0.05 mmole), salt of wormwood (1 mmole) and N, N '-dimethyl methane amide (5 milliliters) be loaded on magnetic stirring bar, dry rub oral examination tube in, seal this test tube with flanging rubber plug, replace three times with high-purity argon gas.Then, 110 degrees Celsius of lower heated and stirred 24 hours.Question response mixed solution is cooled to room temperature, add water cancellation, then use 15 milliliters of extraction into ethyl acetate 3 times, merge organic phase, with anhydrous magnesium sulfate drying, filtration, decompression spin concentration, crude product purified by silica gel column chromatography, 3-benzyl 1,3 is obtained, 4 with mixed solvent (PE:EA=5:1 to the 1:1) wash-out of sherwood oil and ethyl acetate, 5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 92%.This phenyl lactoyl aniline carries out enantiomeric excess analysis with Chiralcel OJ-H chromatographic column (4.6 millimeters long × 5, mm dia × 250 micron grain size) (moving phase: normal hexane/Virahol volume ratio 70:30) that Daicel company of Chiral liquid chromatography post Japan produces on liquid chromatograph, the appearance time at room temperature detected is 16.3 minutes (R configurations) and 26.6 minutes (S configuration), and the enantiomeric excess value that analytical results shows this product is 96.8%ee (S configuration).(S)-3-benzyl-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, light yellow solid, fusing point 169-171 DEG C, [α]
d 13-28 (c0.4, acetone).
1h NMR (400MHz, CDCl
3) δ 7.83 (s, 1H), 7.31 (dd, J=7.7,1.4Hz, 1H), 7.27 (d, J=2.4Hz, 1H), 7.26 – 7.19 (m, 5H), 7.15 (td, J=7.4,1.1Hz, 1H), 6.96 (d, J=7.8Hz, 1H), 4.11 (d, J=13.7Hz, 1H), 3.87 (d, J=13.7Hz, 1H), 3.74 (dd, J=7.8,5.6Hz, 1H), 3.26 (dd, J=13.8,5.6Hz, 1H), 2.94 (dd, J=13.8,7.8Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 176.91 (s), 138.05 (s), 137.23 (s), 133.12 (s), 130.60 (s), 129.08 (d, J=17.8Hz), 127.39 (d, J=46.8Hz), 124.29 (s), 62.96 (s), 52.95 (s), 39.47 (s).
Embodiment two
Replace the L configuration atrolactamide in embodiment one with DL configuration phenylalanyl amine, obtain 3-benzyl-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine of racemization
-2-ketone, productive rate is 90%.
Embodiment three
Replace the L-phenylalanyl amine in embodiment one with D-alanimamides, obtain (R)-3-benzyl-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate is 90%, 96%ee (R configuration).
Embodiment four
Replace the L-phenylalanyl amine in embodiment one with L-alanimamides, obtain S configuration 3-methyl isophthalic acid, 3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 78%, white solid, fusing point 170-172 DEG C, [α]
d 13-289 (c 0.1, acetone).
1h NMR (400MHz, CDCl
3) δ 7.50 (s, 1H), 7.34 (s, 1H), 7.31 (d, J=7.4Hz, 2H), 7.22 – 7.16 (m, 1H), 6.98 (d, J=7.9Hz, 1H), 4.16 (d, J=12.9Hz, 1H), 3.92 (d, J=12.9Hz, 1H), 3.59 (q, J=6.6Hz, 1H), 1.33 (d, J=6.6Hz, 2H), 1.27 (s, 1H).
13c NMR (101MHz, CDCl
3) δ 174.98 (s), 137.61 (s), 131.09 (s), 129.77 (s), 128.70 (s), 125.43 (s), 120.81 (s), 53.45 (s), 48.97 (s), 16.92 (s).
Embodiment five
Replace the L-phenylalanyl amine in embodiment one with L-n-butyl amine acid amides, obtain S configuration 3-ethyl-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 56%, white solid, fusing point 109-112 DEG C, [α]
d 13+ 317 (c 0.1, acetone).
1h NMR (400MHz, CDCl
3) δ 7.66 (s, 1H), 7.27 (d, J=4.8Hz, 3H), 7.20 – 7.13 (m, 1H), 6.97 (d, J=7.8Hz, 1H), 4.11 (d, J=13.1Hz, 1H), 3.90 (d, J=13.1Hz, 1H), 3.34 (t, J=6.6Hz, 1H), 1.91 (tt, J=14.5,7.4Hz, 1H), 1.58 (dt, J=21.1,6.9Hz, 1H), 0.94 (td, J=7.5,3.1Hz, 3H).
13c NMR (101MHz, CDCl
3) δ 174.93 (s), 137.74 (s), 131.54 (s), 129.82 (s), 128.81 (s), 125.52 (s), 120.98 (s), 59.92 (s), 49.11 (s), 24.73 (s), 10.95 (s) .IR (KBr), ν (cm
-1) 3436,2964,2878,2817,1671,1583,1488,1390,1290,757,621.HRMS (ESI-TOF) m/z calcd for C11H15N2O [M+H
+] 191.1179; Found 191.1168.
Embodiment six
Replace the L-phenylalanyl amine in embodiment one with L-valine amide, obtain S configuration 3-sec.-propyl-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 85%, light yellow solid, fusing point 116-118 DEG C, [α]
d 13+ 58 (c 0.5, acetone).
1h NMR (400MHz, CDCl
3) δ 7.88 – 7.80 (m, 1H), 7.51 (d, J=2.7Hz, 1H), 7.34 – 7.28 (m, 3H), 7.18 – 7.12 (m, 2H), 7.01 – 6.93 (m, 1H), 3.97 – 3.82 (m, 2H), 3.69 (d, J=4.2Hz, 1H), 2.21 (dd, J=13.7,6.8Hz, 1H), 2.10 (ddd, J=9.2,6.9,3.5Hz, 1H), 0.96 – 0.93 (m, 6H).
13c NMR (101MHz, CDCl
3) δ 175.37 (s), 139.81 (s), 129.65 – 129.24 (m), 128.65 (d, J=8.4Hz), 125.20 (s), 120.88 (s), 67.53 (s), 65.17 (s), 57.58 (s), 53.49 (s), 31.38 (d, J=6.8Hz), 18.80 – 17.22 (m) .IR (KBr), ν (cm
-1) 3392,3254,2954,2924,2855,1631,1458,1384,1259,1093,1011,755,718,603.HRMS (ESI-TOF) m/z calcd for C12H17N2O [M+H
+] 205.1335; Found 205.1319.
Embodiment seven
Replace the L-phenylalanyl amine in embodiment one with L-leucyl amine, obtain S configuration 3-isobutyl--1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 91%, light yellow solid, fusing point 117-120 DEG C, [α]
d 13+ 269 (c 0.2, acetone).
1h NMR (400MHz, CDCl
3) δ 8.02 (s, 1H), 7.59 (d, J=8.5Hz, 1H), 7.19 – 7.11 (m, 1H), 6.96 (d, J=7.9Hz, 1H), 4.11 (d, J=13.1Hz, 1H), 3.91 (dd, J=13.2,7.1Hz, 1H), 3.47 (dd, J=7.3,6.1Hz, 1H), 2.96 (s, 3H), 2.88 (s, 3H), 1.43 (dd, J=6.0,3.6Hz, 1H), 0.92 (dd, J=8.5,5.2Hz, 1H), 0.85 (dd, J=6.4,1.6Hz, 5H), 0.74 (d, J=6.4Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 175.63 (s), 137.87 (s), 131.44 (s), 129.72 (s), 128.76 (s), 125.36 (s), 120.99 (s), 56.42 (s), 49.03 (s), 40.31 (s), 24.84 (s), 22.73 (d, J=83.0Hz).
Embodiment eight
Replace the L-phenylalanyl amine in embodiment one with L-benzene G-NH2, obtain S configuration 3-phenyl-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 58%, yellow solid, fusing point 145-147 DEG C, [α]
d 13+ 6 (c 0.1, acetone).
1h NMR (400MHz, CD
3cOCD
3) δ 9.02 (s, 1H), 7.41 – 7.36 (m, 2H), 7.32 – 7.18 (m, 5H), 7.16 – 7.09 (m, 2H), 4.69 (d, J=2.3Hz, 1H), 4.05 (q, J=14.1Hz, 2H), 2.10 (s, 1H).
13c NMR (101MHz, CDCl
3) δ 174.21 (s), 138.56 (s), 137.35 (s), 131.81 (s), 129.31 (s), 128.68 (s), 128.50 (d, J=1.3Hz), 128.09 (s), 125.15 (s), 120.84 (d, J=8.4Hz), 64.98 (d, J=12.0Hz), 49.35 (s) .IR (KBr) ν (cm
-1) 3428,2921,2856,1670,1588,1490,1379,756,704,665.HRMS (ESI-TOF) m/z calcd for C15H15N2O [M+H
+] 239.1179; Found 239.1147.
Embodiment nine
Replace the L-phenylalanyl amine in embodiment one with L-prolineamide, obtain S configuration 2,3,10,11a-tetrahydrochysene-1H-benzo [e] pyrrolo-[1,2-a] [Isosorbide-5-Nitrae] phenodiazine
-11 (5H)-one, productive rate 68%, white solid, fusing point 131-133 DEG C, [α]
d 13+ 341 (c 0.1, acetone).
1h NMR (400MHz, CD
3cOCD
3) δ 9.02 (s, 1H), 7.41 – 7.28 (m, 2H), 7.14 (ddd, J=12.8,9.6,4.4Hz, 2H), 3.93 (d, J=11.5Hz, 1H), 3.53 (dd, J=8.2,3.0Hz, 2H), 3.00 – 2.95 (m, 1H), 2.55 – 2.48 (m, 1H), 2.43 – 2.37 (m, 1H), 1.93 – 1.85 (m, 1H), 1.83 – 1.68 (m, 2H).
13c NMR (101MHz, CD
3cOCD
3) δ 172.03 (s), 139.85 (s), 131.84 (s), 130.58 (s), 129.26 (s), 125.46 (s), 121.90 (d, J=5.8Hz), 62.24 (s), 55.46 (d, J=3.2Hz), 54.57 (s), 24.98 (s), 24.53 (s).
Embodiment ten
Replace the L-phenylalanyl amine in embodiment one with L-tryptophyl amine, obtain S configuration 3-((3-indyl) methyl)-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 75%, white solid, fusing point 135-137 DEG C, [α]
d 13+ 312 (c 0.2, acetone).
1h NMR (400MHz, CD
3cOCD
3) δ 8.95 (s, 1H), 7.51 (d, J=7.9Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.18 (ddd, J=12.5,10.0,4.4Hz, 4H), 7.08 – 7.00 (m, 3H), 6.93 (dd, J=11.0,3.9Hz, 1H), 4.09 – 3.94 (m, 2H), 3.83 (dd, J=12.7,7.4Hz, 1H), 3.29 (dd, J=14.3,5.9Hz, 1H), 2.97 – 2.91 (m, 1H), 1.19 (t, J=7.1Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 174.59 (s), 137.43 (s), 136.29 (s), 131.25 (s), 129.51 (s), 128.67 (s), 125.31 (s), 123.64 (s), 122.04 (s), 120.89 (s), 119.45 (s), 118.97 (s), 111.70 (s), 111.31 (s), 59.22 (s), 49.38 (s), 27.45 (s).
Embodiment 11
Replace the L-phenylalanyl amine in embodiment one with L-tyramine amide, obtain S configuration 3-(4-hydroxybenzyl)-1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 90%, yellow solid, fusing point 166-168 DEG C, [α]
d 13+ 107 (c 0.3, acetone).
1h NMR (400MHz, DMSO-d
6) δ 9.74 (s, 1H), 9.05 (s, 1H), 7.20 – 7.08 (m, 2H), 6.99 (t, J=7.0Hz, 1H), 6.94 – 6.83 (m, 3H), 6.52 (d, J=8.4Hz, 2H), 3.77 – 3.58 (m, 2H), 3.23 (t, J=6.6Hz, 1H), 2.87 – 2.79 (m, 2H), 2.66 (s, 1H).
13c NMR (101MHz, DMSO-d
6) δ 172.71 (s), 155.50 (s), 138.62 (s), 131.31 (s), 130.19 (s), 129.27 (d, J=11.5Hz), 127.88 (d, J=27.6Hz), 124.31 (s), 120.51 (s), 114.81 (s), 59.75 (s), 48.26 (s), 36.23 (s) .IR (KBr) ν (cm
-1) 3255,3172,2900,2841,1662,1612,1513,1266,1232,1100,758,621.HRMS (ESI-TOF) m/z calcd for C16H17N2O2 [M+H
+] 269.1285; Found 269.1258.
Embodiment 12
Replace the adjacent iodine benzyl bromine in embodiment one with 1-bromo-2-brooethyl-4-anisole, obtain (S)-3-benzyl-7-methoxyl group-4,5-dihydro-1H-benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 82%, white solid, fusing point 188-190 DEG C, [α]
d 13+ 205 (c 0.1, acetone).
1h NMR (400MHz, CDCl
3) δ 7.51 (s, 1H), 7.27 – 7.23 (m, 5H), 7.22 – 7.18 (m, 2H), 6.89 (d, J=8.6Hz, 1H), 6.81 (dd, J=8.6,2.8Hz, 1H), 6.76 (d, J=2.8Hz, 1H), 4.07 (d, J=13.4Hz, 1H), 3.79 (s, 3H), 3.66 (dd, J=7.7,5.9Hz, 1H), 3.20 (dd, J=13.8,5.8Hz, 1H), 2.89 (dd, J=13.8,7.7Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 173.28 (s), 157.56 (s), 138.37 (s), 132.88 (s), 129.63 (s), 128.60 (s), 126.64 (s), 122.43 (s), 114.79 (s), 114.02 (s), 58.97 (s), 55.71 (s), 49.22 (s), 37.67 (s) .IR (KBr) ν (cm
-1) 3432,3240,3030,2925,2844,1672,1502,1251,1031,755,699,514.HRMS (ESI-TOF) m/z calcd for C17H19N2O2 [M+H
+] 283.1441; Found 283.1415.
Embodiment 13
With the bromo-6-of 5-(brooethyl) benzo [d] [1,3] between, dioxol replaces the adjacent iodine benzyl bromine in embodiment one, obtain (S)-7-benzyl-8,9-dihydro-5H-[1,3] dioxol also [4', 5':4,5] benzo [1,2-e] [Isosorbide-5-Nitrae] phenodiazine
-6 (7H)-one, productive rate 47%, white solid, fusing point 158-160 DEG C, [α]
d 13+ 111 (c 0.1, acetone).
1h NMR (400MHz, CD
3cOD
3) δ 8.78 (s, 1H), 7.27 (d, J=2.9Hz, 2H), 7.23 – 7.20 (m, 4H), 6.85 (s, 1H), 6.00 (dd, J=4.5,0.9Hz, 2H), 3.89 (d, J=13.1Hz, 1H), 3.74 (d, J=13.4Hz, 2H), 3.58 – 3.52 (m, 1H), 3.16 – 3.08 (m, 1H), 2.10 (s, 1H).
13c NMR (101MHz, CD
3cOD
3) δ 172.78 – 172.53 (m), 140.36 (s), 130.38 (s), 128.95 (s), 127.31 (s), 126.85 (s), 113.04 (s), 110.77 (s), 109.74 (s), 103.28 (s), 102.38 (s), 63.84 (s), 52.45 (s), 38.26 (s) .IR (KBr) ν (cm
-1) 3379,3249,3033,2908,2772,1666,1478,1232,1034,927,733,695.HRMS (ESI-TOF) m/z calcd for C17H17N2O3 [M+H
+] 297.1234; Found 297.1214.
Embodiment 14
Replace the adjacent iodine benzyl bromine in embodiment one with 1-bromo-2-chloromethyl-5-fluorobenzene, obtain (S)-3-benzyl-8-fluoro-4,5-dihydro-1H-benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 89%, light yellow solid, fusing point 111-113 DEG C, [α]
d 13-29 (c 0.4, acetone).
1h NMR (400MHz, CDCl
3) δ 7.28 – 7.23 (m, 5H), 7.14 – 7.09 (m, 2H), 7.02 (ddd, J=11.0,8.5,4.3Hz, 2H), 6.87 (td, J=8.2,2.6Hz, 1H), 3.81 (d, J=13.7Hz, 1H), 3.56 (d, J=13.7Hz, 1H), 3.31 (dd, J=10.1,4.0Hz, 1H), 3.23 (dd, J=13.8,3.9Hz, 1H), 2.69 (dd, J=13.8,10.2Hz, 1H).
13c NMR (101MHz, CDCl
3) δ 176.81 (s), 163.14 (s), 137.21 (s), 131.39 (d, J=8.7Hz), 129.04 (d, J=10.3Hz), 127.18 (s), 117.24 (d, J=24.7Hz), 114.01 (d, J=20.9Hz), 62.94 (s), 49.95 (s), 39.48 (s) .IR (KBr) ν (cm
-1) 3362,3269,3144,2933,1669,1605,1487,1394,1228,900,732,648.HRMS (ESI-TOF) m/z calcd for C16H16ClFN2NaO [M+NaHCl
+] 329.0827; Found 329.0780.
Embodiment 15
Replace the adjacent iodine benzyl bromine in embodiment one with 1-bromo-2-brooethyl-3-chlorobenzene, obtain (S)-3-benzyl-7-chloro-4,5-dihydro-1H-benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 42%, yellow solid, fusing point 100-102 DEG C, [α]
d 13+ 59 (c 0.5, acetone).
1h NMR (400MHz, CDCl
3) δ 7.31 (d, J=2.0Hz, 1H), 7.29 (d, J=1.6Hz, 1H), 7.18 – 7.13 (m, 4H), 7.09 (d, J=2.2Hz, 1H), 3.78 (d, J=14.1Hz, 1H), 3.64 – 3.55 (m, 1H), 3.34 (dt, J=11.0,5.5Hz, 1H), 3.26 – 3.20 (m, 1H), 2.72 (dd, J=13.9,10.1Hz, 1H), 1.88 (s, 1H), 1.25 (s, 1H), 0.89 – 0.82 (m, 1H).
13c NMR (101MHz, CDCl
3) δ 176.71 (s), 138.23 (s), 137.09 (s), 132.80 (s), 132.14 (s), 130.81 (s), 129.95 (s), 129.06 (d, J=3.2Hz), 128.77 (s), 127.25 (s), 63.05 (s), 50.11 (s), 39.45 (s) .IR (KBr), ν (cm
-1) 3356,3181,2924,2860,1651,1467,1401,1098,822,734,698,564.HRMS (ESI-TOF) m/z calcd for C16H16Cl2N2NaO [M+NaHCl
+] 345.0532; Found 345.0487.
Embodiment 16
Replace the adjacent iodine benzyl bromine in embodiment one with 1-bromo-2-brooethyl-3-chlorobenzene, obtain (S)-3-benzyl-6-chloro-4,5-dihydro-1H-benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 80%, yellow solid, fusing point 98-100 DEG C, [α]
d 13-38 (c 0.3, acetone).
1h NMR (400MHz, CD
3cOCD
3) δ 7.34 (s, 1H), 7.31 – 7.16 (m, 7H), 3.99 (d, J=12.7Hz, 1H), 3.90 (d, J=12.7Hz, 1H), 3.31 (dd, J=9.8,4.3Hz, 1H), 3.15 – 3.08 (m, 1H), 2.90 (s, 2H), 2.68 (dd, J=13.8,9.8Hz, 1H).
13c NMR (101MHz, CD
3cOCD
3) δ 175.98 (s), 138.95 (s), 136.55 (s), 135.94 (s), 130.52 (s), 129.87 (s), 129.34 (d, J=3.2Hz), 127.41 (s), 64.00 (s), 48.13 (s), 40.13 (s) .IR (KBr) ν (cm
-1) 3379,3196,3063,2926,2857,1720,1657,1433,1389,1322,1085,773,697.HRMS (ESI-TOF) m/z calcd for C16H16Cl2N2NaO [M+NaHCl
+] 345.0532; Found 345.0486.
Embodiment 17
Replace the adjacent iodine benzyl bromine in embodiment one with 1-bromo-2-brooethyl-4-trifluoromethylbenzene, obtain (S)-3-benzyl-7-trifluoromethyl-4,5-dihydro-1H-benzo [e] [Isosorbide-5-Nitrae] phenodiazine
-2-ketone, productive rate 82%, yellow solid, fusing point 74-76 DEG C, [α]
d 13-18 (c 0.6, acetone).
1h NMR (400MHz, CDCl
3) δ 7.45 (d, J=1.9Hz, 1H), 7.42 (d, J=5.1Hz, 2H), 7.37 (d, J=8.2Hz, 1H), 7.27 (d, J=3.1Hz, 1H), 7.17 – 7.12 (m, 3H), 6.24 (d, J=3.0Hz, 1H), 4.15 – 4.08 (m, 1H), 3.87 (d, J=14.1Hz, 1H), 3.68 (d, J=14.1Hz, 1H), 3.36 (dd, J=10.0,4.1Hz, 1H), 3.26 (dd, J=13.9,4.1Hz, 1H), 1.94 (s, 1H).
13c NMR (101MHz, CDCl
3) δ 176.39 (s), 137.36 (d, J=5.2Hz), 136.76 (s), 129.94 (s), 128.95 (s), 128.72 (d, J=2.4Hz), 126.91 (s), 126.47 (d, J=3.7Hz), h25.25 (t, J=3.7Hz), 124.76 (s), 122.06 (s), 62.94 (s), 49.82 (s), 39.13 (s) .IR (KBr), ν (cm
-1) 3376,3193,2925,2859,1656,1405,1330,1172,1126,1082,831,698,519.HRMS (ESI-TOF) m/z calcd for C17H16ClF3N2NaO [M+NaHCl
+] 379.0795; Found 379.0756.
Embodiment 18
Cuprous bromide replaces the cuprous iodide in embodiment one, (S)-3-benzyl 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the productive rate of-2-ketone is 54%.
Embodiment 19
Cuprous bromide replaces the cuprous iodide in embodiment one, (S)-3-benzyl 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the productive rate of-2-ketone is 46%.
Embodiment 20
Cesium carbonate replaces the salt of wormwood in embodiment one, (S)-3-benzyl 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the productive rate of-2-ketone is 90%.
Embodiment 21
N, N '-dimethyl ethanamide replaces the N in embodiment one, N '-dimethyl methane amide, (S)-3-benzyl 1,3,4,5-tetrahydro benzo [e] [Isosorbide-5-Nitrae] phenodiazine
the productive rate of-2-ketone is 87%.
Embodiment 22
When replacing the temperature of reaction of in embodiment one 110 DEG C by the temperature of reaction of 90 DEG C, the productive rate of S configuration phenyl lactoyl aniline is 82%.
Embodiment 23
During reaction times with 24 hours that to replace for 12 hours in embodiment one, the productive rate of S configuration phenyl lactoyl aniline is 47%.
Embodiment 23
When replacing L configuration phenylalanyl amine (0.75 mmole) in embodiment one and adjacent iodine benzyl bromine (0.5 mmole) raw material dosage with L configuration phenylalanyl amine (0.5 mmole) and adjacent iodine benzyl bromine (0.75 mmole), the productive rate of S configuration phenyl lactoyl aniline is 84%.
Claims (5)
1. a chirality 3-replaces 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine
the synthesis technique of-2-ketone, is characterized in that: under the existence of copper catalyst and alkali, and chiral amino acid amide and adjacent halogen benzyl halogen react and generates chirality chirality 3-and replace 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine
-2-ketone.
2. a kind of chirality 3-described in claims 1 replaces 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine
the synthesis technique of-2-ketone, is characterized in that said chiral amino acid amide refers to L configuration, D configuration and DL amino acids acid amides; Amino acid amide refers to alanimamides, n-butyl amine acid amides, valine amide, leucyl amine, prolineamide, benzene G-NH2, phenylalanyl amine, tryptamines acid amides, tyramine amide; Adjacent halogen benzyl halogen refers to these compounds adjacent iodine benzyl bromine, adjacent bromobenzyl bromine, adjacent bromine chloride, adjacent bromobenzyl chlorine and phenyl ring having chlorine, fluorine, methoxy substitution base; The ratio of chiral amino acid amide and adjacent halogen benzyl halogen is 1.5:1 to 1:1.5 (mol ratio).
3. a kind of chirality 3-described in claims 1 replaces 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine
the synthesis technique of-2-ketone, is characterized in that said copper catalyst refers to cuprous iodide, cuprous bromide and cuprous chloride; Mantoquita consumption is 10% (mole) of adjacent halogen benzyl halogen consumption.
4. a kind of chirality 3-described in claims 1 replaces 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine
the synthesis technique of-2-ketone, is characterized in that said alkali refers to salt of wormwood and cesium carbonate; The consumption of alkali is 2 times of molar weights of adjacent halogen benzyl halogen consumption.
5. a kind of chirality 3-described in claims 1 replaces 1,3,4,5-tetrahydrochysene-Isosorbide-5-Nitrae-benzene phenodiazine
the synthesis technique of-2-ketone, is characterized in that said temperature of reaction is 90 to 110 degrees Celsius; Reaction times is 12 to 24 hours.
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| WO2012129353A1 (en) * | 2011-03-22 | 2012-09-27 | Bristol-Myers Squibb Company | Bis(fluoroalkyl)-1,4-benzodiazepinone compounds |
| CN102911126A (en) * | 2012-11-20 | 2013-02-06 | 成都理工大学 | Synthesis of 2-aryl quinazolone from benzyl halide and 2-amobenzamide |
| CN103130806A (en) * | 2011-11-24 | 2013-06-05 | 南开大学 | Phenanthroindo(quio)lizidine alkaloid derivative, and preparation, anti-TMV activity, anti-HIV activity and anti-tumor activity thereof |
| CN103980212A (en) * | 2014-05-15 | 2014-08-13 | 南京工业大学 | Method for synthesizing benzodiazepine heterocyclic derivative by one-pot method |
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| CN103130806A (en) * | 2011-11-24 | 2013-06-05 | 南开大学 | Phenanthroindo(quio)lizidine alkaloid derivative, and preparation, anti-TMV activity, anti-HIV activity and anti-tumor activity thereof |
| CN102911126A (en) * | 2012-11-20 | 2013-02-06 | 成都理工大学 | Synthesis of 2-aryl quinazolone from benzyl halide and 2-amobenzamide |
| CN103980212A (en) * | 2014-05-15 | 2014-08-13 | 南京工业大学 | Method for synthesizing benzodiazepine heterocyclic derivative by one-pot method |
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