CN102382031A - 3 - substituted allylic ester oxindole and preparation method thereof - Google Patents
3 - substituted allylic ester oxindole and preparation method thereof Download PDFInfo
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Abstract
The invention discloses 3 - substituted allylic ester oxindole and a preparation method thereof. Under the action of organic bases of n-butyl lithium or potassium bis(trimethylsilyl)amide (KHMDS) and the like, 3 - substituted oxindole and 3 - (1 - imidazolyl) methyl acrylate are subjected to an addition-elimination reaction to obtain the 3 - substituted allylic ester oxindole. In the invention, a quaternary carbon atom is successfully built, and simultaneously, a class of novel oxindole is synthesized for the first time. The compound can be used for synthesis of an active ingredient physostigmine of medicinal plants and other natural products by structural modification, a new way for artificially synthesizing a large number of physostigmine is opened, and the 3 - substituted allylic ester oxindole has a practical application value.
Description
Technical field
The present invention relates to one type of new Oxoindole and preparation method, especially a kind of 3-substituted allyl ester Oxoindole and preparation method thereof.
Background technology
Suc as formula (
) shown in, the acylimidazole compounds can react rapidly with nucleophilic reagent and generate carboxylic acid, ester class and amides (Thomas C.; Schmir, G. L.
J Am Chem Soc79,1663,1957; Staab, H. A.; Rohr, W.; Mannschreck, A.
Angew Chem.73,143,1961; Long time of deer island, the loyal state in field, Synthetic Organic Chemistry 45,863,1987).Primitive reaction mechanism be nucleophilic reagent at first with acyl carbonyl generation nucleophilic addition(Adn), imidazoles is partly eliminated then.In this reaction process, imidazolyl makes the activation of acyl carbonyl as the sub-attractive group of forceful electric power, also is good leavings group simultaneously, and making is swift in response carries out.
Formula (
)
There is document to report; (β-aminoenone) type vinylogue (vinylogue) as amides also can pass through addition-elimination process and the reaction of all kinds of nucleophilic reagent to beta-aminoenones; Generate ketene compounds (Ficinni, J. through amino exchange with nucleophilic reagent; Normant, H.
Bull Chim Soc. France1294,1964; Weintraub, P. M.
Chem. & Ind.1497,1966; Duhamel, P.; Duhamel, L.; Truxillo, V.
Tetrahedron Lett.51,1974; Schiess, P.
Helv. Chim. Acta.55,238,1972; The west tail is built a man of virtue and ability, deer island, and Synthetic Organic Chemistry 34,526,1976 are kept in long time, table U.S.A; Kashima, C.; Yamamoto, Y.
Bull Chem Soc Jpn.52,1735,1979).Particularly can select to reaction, generate β-displacement ketenes (formula
) with Grignard reagent or organo-metallic lithium reagent.But the electronics attraction power of ketene carbonyl is compared obviously and is in a disadvantageous position with Nitroenamine (nitroenamine) nitro.
Formula (
)
The deer island long inferior people study the β-imidazoles ketene compounds that has both acylimidazole class and beta-aminoenones class two compounds character.Mainly be to serving as that (long time of deer island, the loyal state in field, Synthetic Organic Chemistry 45,863,1987 are studied in main reaction with amine, alcohols, phenols, thio-alcohol Ji Geshi reagent etc. with β-imidazoles ketene and analogue; Kashima, C.; Yamamoto, Y.
Heterocycles19,1211,
1982; Kashima, C.; Tajima, T.; Shimizu, M.; Omote, Y.
J. Heterocyclic Chem., 19,1325,
1982; Kashima, C.; Tajima, T.; Shimizu, M.; Omote, Y.
Heterocycles20,1811,
1983; Tajima, T.; Shimizu, M.; Omote, Y.
Heterocycles21,171,
1984).For example, Grignard reagent as nucleophilic reagent can attack 3-(1-imidazolyl) methyl acrylate the charcoal atom of β-position, generate the alpha, beta-unsaturated esters analog derivative.In addition; Triethylamine exists down, the reaction (formula
) of nucleophilic reagent generation same-types such as β-imidazoles ketene can same methyl alcohol, tetramethyleneimine.
Formula (
)
But, but do not report about the addition-elimination reaction of β under alkaline condition-imidazoles ketene and methylene radical and methyne compounds.The direction of research is to expand to the category that reacts with active methylene base class to the reaction of β-imidazoles ketene and Organoalkyl metallic compound at present, on the number of carbochain, increases by three carbon atoms (Stowell, J. C. when forming tertiary carbon atom
Chem. Rev.84,409,
1984).
Summary of the invention
The technical problem that the present invention will solve provides the comparatively complicated Oxoindole of a kind of simple method preparation, i.e. 3-substituted allyl ester Oxoindole and preparation method thereof is for synthetic drugs provides a kind of practical new way.
For solving the problems of the technologies described above, the technical scheme 1 that the present invention adopts is:
A kind of 3-substituted allyl ester Oxoindole, suc as formula the compound shown in (I) or the formula (II):
Wherein, R
1Be selected from C
1-10Alkyl, C
2-10Thiazolinyl, benzyl, substituted benzyl, alkoxyalkyl or protection aminoalkyl group;
R
2Be selected from hydrogen, C
1-10Alkyl, C
2-10Thiazolinyl, benzyl or substituted benzyl;
R
3Be selected from hydrogen, C
1-5Alkyl or C
1-5Alkoxyl group;
R
4Be selected from C
1-10Alkyl, C
2-10Thiazolinyl, benzyl and substituted benzyl, phenyl or substituted-phenyl.
Above-mentioned C
1-10Alkyl is like methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group etc.; Said C
2-10Thiazolinyl is like vinyl, propenyl, 1, crotyl etc.; Said substituted benzyl is like halogeno-benzyl, nitrobenzyl, methoxy-benzyl, methyl-benzyl etc.; Said alkoxyalkyl is like methoxyl group, oxyethyl group, tert.-butoxy, benzyloxy, phenoxy etc.; Said protection aminoalkyl group, like N, N '-dibenzyl amino ethyl or N-benzyl-N-benzyloxycarbonyl amino-ethyl.
Preferably, R
3Be hydrogen or methoxyl group; R
2Be hydrogen or benzyl; R
4Be methyl; R
1Be methyl, benzyl, 3-methyl-2-butene base, benzyloxy ethyl, N, N '-dibenzyl amino ethyl or N-benzyl-N-benzyloxycarbonyl amino-ethyl.
Preferred, said 3-substituted allyl ester Oxoindole is:
1,3-dimethyl--5-methoxyl group-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1,3-dimethyl--2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
3-methyl-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1,3-benzyl-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
3-(3-methyl-2-butene base)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(3-methyl-2-butene base)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(3-benzyloxy ethyl)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(N, N-dibenzyl amino ethyl)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(N-benzyl-N-benzyloxycarbonyl amino-ethyl)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters or
1-benzyl-3-(2-methoxycarbonyl ethylidene)-2,3-dihydro-2-oxo--1
H-indoles.
Technical scheme 2 of the present invention has provided a kind of preparation method of 3-substituted allyl ester Oxoindole, and it carries out according to following step:
(1) compound shown in the formula (III) forms the enolization compound in-50 ℃ ~ 20 ℃ Wasserstoffatomss of in aprotic solvent, removing the 3-position under the effect of organic bases, more above-mentioned enolization compound is cooled to-90 ℃～20 ℃;
(2) 3-(1-imidazolyl) methyl acrylate is joined in the cooled enolization compound, be warming up to-40 ℃～20 ℃ generation addition-elimination reactions then and obtain compound shown in formula (I) or the formula (II);
Preferably, said organic bases is n-Butyl Lithium or potassium hexamethyldisilazide, and said organic bases and formula (III) mol ratio is 1～2:1.
Said aprotic solvent is THF, toluene, ether or glycol dimethyl ether, and the best is a THF.
The reaction times is 30min ~ 12h in the step (1), preferred 1h; Preferred-20 ℃ ~ 0 ℃ of temperature of reaction, the best is 0 ℃.
The consumption of 3-(1-imidazolyl) methyl acrylate and the mol ratio of formula (III) are 1:1～2:1 in the step (2).
When step (2) reaction finishes, add diluted acid, like 0.5 M Hydrogen chloride cancellation reaction, the also dilute sulphuric acid of available different concns or dilute acetic acid etc. to reaction solution.Reaction solution is with ethyl acetate extraction twice, and organic phase is concentrating under reduced pressure behind saturated common salt water washing, anhydrous sodium sulfate drying.Residue through column chromatography refining the purpose product.
The beneficial effect that adopts technique scheme to produce is:
(1) the present invention is through test of long duration; Found under the effect of n-Butyl Lithium or potassium hexamethyldisilazide (KHMDS); 3-replace oxidized indole compounds can with 3-(1-imidazolyl) methyl acrylate one type of new Oxoindole of mechanism generation through addition-elimination; When the 3-position forms quaternary carbon atom, three carbon atoms have been increased on the carbon chain lengths.The new Oxoindole of this type through structural modification with the synthesizing of natural product, like a minute Physostigmine (Physostigmine) and Eserethole.For the synthetic in a large number Physostigmine of manual work opens up a new way, has the value of practical application.
(2) compound method of the present invention is simple, is convenient to large-scale industrial production.
Embodiment
Following examples are with Oxoindole
6-14Be substrate, the carburetting reaction of the thricarbon atom of addition-cancellation of the present invention is studied.
Oxoindole wherein
6-9(Fuji, K.; Kawabata, T.; Ohmori, T.; Shang, M.; Node, M.
Heterocycles47,951,
1998) and
14(Hirose, N.; Sohda, S; Toyoshima, S.
Yakugaku Zasshi91,1323,
1971) be known compound.Compound
10Can pass through known compound
14The carbanion that under the n-Butyl Lithium effect, produces and the reaction of 4-bromo-2-methyl-2-butene n-Butyl Lithium prepare.Synthetic compound
11The benzyl reaction of tryptophol (tryptophol) in acetic acid before this handled (Savige, W. E. with concentrated hydrochloric acid and methyl-sulphoxide then; Fontana, A.
J. Chem. Soc., Chem Commun. 599,
1976).With 3 normal benzyl chlorine the reaction of 50% aqueous sodium hydroxide solution and tryptamines (tryptamine) get final product compound
4With
5Use the methyl-sulphoxide oxygenated compound
4Can obtain the Oxoindole inductor
12Compound
5With the Cbz-Cl reaction, can obtain with the methyl-sulphoxide oxidation again
13
Embodiment 1: compound (
3) preparation:
Under the step 1) argon shield, with compound
2(41g 210mmol) is dissolved in THF (1000mL), in dry ice-propanone is bathed, be cooled to-78 ℃ after through dripping n-Butyl Lithium (1.56mol/L, hexane solution 210mmol) (137mL) in 30 minutes.After dropwising, 0 ℃ of stirring reaction 30 minutes, be cooled to again-78 ℃ subsequent use as solution A.
2 1
Step 2) with compound
1(64g 420mmol) is dissolved in the THF (1500mL), and slowly is added drop-wise in the solution A at-78 ℃.After dropwising, reaction is warming up to 0 ℃ stirs 1h.Reaction through flaggy monitor to feedstock conversion fully after, in reaction solution, add ice-cold 0.5mol/L hydrochloric acid (5000ml), fully stir the back with ethyl acetate extraction (7000ml * 3) three times.Organic layer extracting solution after the merging, extracting solution is cleaned through saturated aqueous common salt, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated into dried, and residuum obtains white crystal with ETHYLE ACETATE-sherwood oil recrystallization
3(53g, 90%).mp?86～87℃,IR(KBr)ν(cm
-1)：2961，1712，1498，1294，1041，822，775，628。
1HNMR?(200?MHz)?(CDCl
3)δ：1.55(s,?3H),?3.20(s,?3H),?3.71(s,?3H),?3.81(s,?3H),?5.91,?7.00(ABq,?J?=?15.9Hz,?2H),?6.76～6.87(m,?3H)。EI-MS?(
m/z)?:?275?(M
+)。Ultimate analysis (C
15H
17NO
4) measured value (theoretical value, %): C 65.54 (65.44), and H 6.19 (6.22), and N 5.08 (5.09).
Embodiment 2 ~ 6
The point different with embodiment 1 is referring to table 1.The yield of prepared compound 3 is seen table 1.
Table 1
| Embodiment | Compound 2 and 1 mol ratio | Reaction solvent | Reaction times | Temperature of reaction | Productive rate (%) |
| 2 | 1:1 | THF | 1.0h | 0℃ | 73 |
| 3 | 1:1 | Toluene | 1.5h | 0℃ | 26 |
| 4 | 1:1 | Ether | 1.5h | 0℃ | 14 |
| 1 | 1:2 | THF | 1.0h | 0℃ | 90 |
| 5 | 1:2 | THF | 1.0h | 20℃ | 43 |
| 6 | 1:2 | THF | 8.0h | -40℃ | 35 |
Can find out from table 1; With the THF is reaction solvent; The reaction mol ratio of active methylene group compounds and β-imidazolyl-alpha, beta-unsaturated esters class be 1:2 as preferred embodiment, temperature of reaction is a top condition at 0 ℃ then; Still have big content of starting materials residue even prolong reaction during low temperature, the side reaction increase reduces yield greatly but temperature is higher.
Embodiment 7: compound (
15) preparation
Use compound
6(33mg, 0.20mmol), n-Butyl Lithium (1.56 M hexane solution, 129 μ l, 0.20mmol) and compound
1(61mg 0.40mmol), prepares compound according to the step of embodiment 1
15Residue gets colorless oil (43mg, 87%) through preparation TLC refining (hexane:EtOAc=4:1).IR(KBr)?ν(cm
-1)：2929,?1715,?1612,?1494,?1471,?1375,?1348,?1314,?757。
1HNMR?(200?MHz)?(CDCl
3)?δ：1.56(s,?3H),?3.23(s,?3H),?3.71(s,?3H),?5.91,?7.01(ABq,?
J?=?15.8?Hz,?2H),?6.89(d,?
J?=?9.4?Hz,?1H),?7.11-7.37(m,?3H)。EI-MS?(
m/z)?:?245?(M
+)。
Embodiment 8: compound (
16) preparation
Use compound
7(77mg, 0.52mmol), n-Butyl Lithium (1.56 M hexane solution, 672 μ l, 1.05mmol) and
1(159mg 1.05mmol), prepares compound according to the step of embodiment 1
16Residue gets colorless oil through preparation TLC refining (hexane:EtOAc=4:1)
16(120mg, 99%).IR(KBr)?ν(cm
-1)：3181,?1709,?1619,?1473,?1309,?1174,?756,?683,?654。
1HNMR?(200?MHz)?(CDCl
3)?δ：1.60(s,?3H),?3.72(s,?3H),?5.94,?7.03(ABq,?
J?=?15.8?Hz,?2H),?6.96-7.31(m,?14H),?8.84(s,?1H)。EI-MS?(
m/z)?:?231?(M
+)。
Embodiment 9: compound (
17) preparation
Use compound
8(62mg, 0.20mmol), n-Butyl Lithium (1.56 M hexane solution, 128 μ l, 0.20mmol) and
1(60mg 0.40mmol), prepares compound according to the step of embodiment 1
17Residue gets white solid through preparation TLC refining (hexane:EtOAc=6:1)
17(63mg, 80%).mp?134～135℃,IR(KBr)?ν(cm
-1)：3029,?1715,?1641,?1610,?1492,?1315,?1194,?1004,?760,?697。
1HNMR?(200?MHz)?(CDCl
3)?δ：3.29,?3.44(ABq,?
J?=?13.1?Hz,?2H),?3.75(s,?3H),?4.49,?4.97(ABq,?
J?=?16.0?Hz,?2H),?5.99,?7.18(ABq,?
J?=?15.3?Hz,?2H),?6.44(d,?J?=?8.8?Hz,?1H),?6.65(d,?
J?=?7.9?Hz,?1H),?6.91(d,?
J?=?6.7?Hz,?1H),?7.04-7.30(m,?13H)。Ultimate analysis (C
26H
23NO
3) measured value (theoretical value, %): C 78.73 (78.57), and H 5.74 (5.83), and N 3.54 (3.52).
Embodiment 10: compound (
18) preparation
Use compound
9(43mg, 0.21mmol), n-Butyl Lithium (1.56 M hexane solution, 275 μ l, 0.43mmol) and
1(65mg 0.43mmol), prepares compound according to the step of embodiment 1
18Residue gets white solid through preparation TLC refining (hexane:EtOAc=4:1)
18(47mg, 76%).mp?100～101℃,IR(KBr)?ν(cm
-1)：3239,?1712,?1680,?1475,?1322,?1196,?753。
1HNMR?(200?MHz)?(CDCl
3)?δ：1.51(s,?3H),?1.59(s,?3H),?2.71(m,?2H),?3.72(s,?3H),?4.90(t,?
J?=?7.5?Hz,?1H),?5.91,?7.12(ABq,?
J?=?15.9?Hz,?2H),?6.96(d,?
J?=?7.8?Hz,?1H),?7.02-7.30(m,?3H),?9.07(s,?1H)。Ultimate analysis (C
17H
19NO
3) measured value (theoretical value, %): C 71.61 (71.56), and H 6.68 (6.71), and N 4.84 (4.91).
Embodiment 11: compound (
19) preparation
At first make compound 10:
Under the argon shield, at-78 ℃ to compound
14(4.65g, 20.8mmol) drip in THF (50ml) solution n-Butyl Lithium (1.65M hexane solution, 12.6ml, 20.8mmol).After moving to 0 ℃ of stirring 30min., be cooled to-78 ℃ once again.(3.6ml 31.2mmol), is transferred to-30 ℃ and stirs 2h in above-mentioned solution, to drip 4-bromo-2-methyl-2-butene.After reaction finishes, add saturated aqueous ammonium chloride cancellation reaction, ethyl acetate extraction.Organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue obtains compound through column chromatography refining (hexane:EtOAc=95:5)
10(3.67g, 60%).mp?52～53℃,IR(KBr)?ν(cm
-1)：2913,?1713,?1613,?1488,?1466,?750,?679。
1HNMR?(200?MHz)?(CDCl
3)?δ：1.60(s,?3H),?1.66(s,?3H),?2.74(t,?
J?=?6.6,?6.0?Hz,?2H),?3.57(t,?
J?=?6.0?Hz,?1H),?5.73,?5.10(ABq,?J?=?15.7?Hz,?2H),?5.06(t,?
J?=?6.6?Hz,?1H),?6.68(d,?
J?=?7.6?Hz,?1H),?7.00(t,?
J?=?7.6?Hz,?1H),?7.11-7.34(m,?7H)。EI-MS?(
m/z)?:?291?(M
+)。Ultimate analysis (C
20H
21NO) measured value (theoretical value, %): C 82.67 (82.44), H 7.21 (7.26), N 4.76 (4.81).
Use compound then
10(58mg, 0.20mmol), n-Butyl Lithium (1.56 M hexane solution, 128 μ l, 0.20mmol) and
1(61mg 0.40mmol), prepares compound according to the method for embodiment 1
19Residue gets white solid through preparation TLC refining (hexane:EtOAc=4:1)
19(57mg, 75%).mp?92～93℃,IR(KBr)?ν(cm
-1)：2915,?1711,?1641,?1491,?1467,?1367,?1307,?1176,?1003,?758。
1HNMR?(200?MHz)?(CDCl
3)?δ：1.54(s,?3H),?1.57(s,?3H),?2.61-2.93(m,?2H),?3.73(s,?3H),?4.68,?5.13(ABq,?
J?=?15.8?Hz,?2H),?4.80(t,?
J?=?8.3?Hz,?1H),?5.93,?7.15(ABq,?
J?=?15.9?Hz,?2H),?6.70(d,?
J?=?7.8?Hz,?1H),?7.02-7.32(m,?10H)。Ultimate analysis (C
14H
15NO
3) measured value (theoretical value, %): C 76.96 (76.77), and H 6.68 (6.71), and N 3.66 (3.73).
Embodiment 12: compound (
20) preparation
At first prepare compound 11:
Under the argon shield, (76.8mmol) the middle anhydrous n-hexane (10ml) that adds leaves standstill after the stirring NaH, takes out supernatant with syringe for 60% in oil, 3.07g.Repetitive operation twice is in residue suspension and DMF (30ml).Drip tryptophol (tryptophol) (5.16g, DMF 32.0mmol) (45ml) solution, stirring at room 30min. then in 0 ℃.Be cooled to 0 ℃ once again, (7.6ml, DMF 64.0mmol) (20ml) solution is at stirring at room 3h to drip benzyl chloride.In reaction solution, add frozen water, use extracted with diethyl ether then.Organic phase is used the saturated common salt water washing, anhydrous sodium sulfate drying, and solution decompression concentrates.Residue obtains colorless oil 1-benzyl-3-(2-benzyloxyethyl)-1H-indole (9.68g, 86%) through column chromatography refining (hexane:EtOAc=95:5).Under the argon shield, acetate (100ml) solution of this oily matter is at room temperature added DMSO, and (11.8ml, 165.9mmol) (9.7ml 118.5mmol), stirs 9h then with 37% concentrated hydrochloric acid.In reaction solution, add entry, use extracted with diethyl ether.Organic layer is with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate drying, solvent concentrating under reduced pressure.Residue obtains white solid through column chromatography refining (hexane:EtOAc=9:1)
11(7.03g, 85%).mp?64～66℃,IR(KBr)?ν(cm
-1)：1695,?1613,?1488,?1466,?1361,?1344,?748,?695。
1HNMR?(200?MHz)?(CDCl
3)?δ：2.31(q,?
J?=?6.6?Hz,?2H),?3.63-3.70(m,?3H),?4.45(s,?2H),?4.84(s,?2H),?6.70(d,?
J?=?7.7?Hz,?1H),?6.98(t,?
J?=?7.7,?7.4?Hz,?1H),?7.12-7.31(m,?12H)。EI-MS?(
m/z)?:?357(M
+)。
Use compound then
11(71mg, 0.20mmol), n-Butyl Lithium (1.56 M hexane solution, 128 μ l, 0.20mmol) and
1(60mg 0.40mmol), prepares compound according to the method for embodiment 1
20Residue gets colorless oil through preparation TLC refining (hexane:EtOAc=6:1)
20(73mg, 83%).IR(KBr)?ν(cm
-1)：2922,?1714,?1610,?1488,?1362,?1276,?1105,?751,?698。
1HNMR?(200?MHz)?(CDCl
3)?δ：2.18-2.67(m,?2H),?3.31-3.39(m,?2H),?3.71(s,?3H),?4.15,?4.28(ABq,?
J?=?11.9?Hz,?2H),?4.65,?4.84(ABq,?
J?=?15.8?Hz,?2H),?5.87,?7.11(ABq,?
J?=?15.8?Hz,?2H),?6.72(d,?
J?=?7.3?Hz,?1H),?7.01-7.29(m,?15H)。EI-MS?(
m/z)?:?441?(M
+)。Ultimate analysis (C
28H
27NO
4) measured value (theoretical value, %): C 76.11 (76.17), and H 6.31 (6.16), and N 2.92 (3.17).
Embodiment 13: compound (
4) and (
5) preparation
Under the argon shield, with tryptamine (9.61g, 60mmol) and BnNEt
3(6.83g, 30mmol) with the dissolving of 50% aqueous sodium hydroxide solution, (21.4ml 186mmol), stirs 2h to Cl then to add benzyl chloride under the room temperature.In reaction solution, add entry, extracted with diethyl ether.Organic phase is washed with the protection salt solution, behind the anhydrous sodium sulfate drying, and concentrating under reduced pressure.Refining (hexane:EtOAc=9:1～1:1) obtains colorless oil to residue through column chromatography
4(17.56g, 68%) and yellow oil
5(5.51g, 27%).
4：IR(KBr)?ν(cm
-1)：3027,?2796,?1494,?1453,?1359,?1129,?1028,?739,?699。
1HNMR?(200?MHz)?(CDCl
3)?δ：2.76-3.02(m,?4H),?3.67(s,?4H),?5.21(s,?4H),?6.83(s,?1H),?6.97-7.40(m,?19H)。EI-MS?(
m/z)?:?430?(M
+)。Ultimate analysis (C
31H
30N2) measured value (theoretical value, %): C 86.51 (86.47), H 7.22 (7.02), N 6.27 (6.51).
5：IR(KBr)?ν(cm
-1)：3027,?2916,?1467,?1357,?1172,?1113,?739,?698。
1HNMR?(200?MHz)?(CDCl
3)?δ：2.99(s,?4H),?3.80(s,?2H),?5.25(s,?2H),?6.94(s,?1H),?7.06-7.29(m,?13H),?7.63(dd,?
J?=?6.9,?1.5?Hz,?1H)。EI-MS?(
m/z)?:?340?(M
+)。
Embodiment 14: compound (
12) preparation
Under the argon shield, to compound
4(17.56g, (20.3ml, 286.3mmol) (16.8ml 204.5mmol), stirs 9h with 37% concentrated hydrochloric acid to add DMSO in acetate 40.9mmol) (150ml) solution under the room temperature.Use extracted with diethyl ether after in reaction solution, adding entry.Organic phase is with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate drying.Residue gets white crystal through normal hexane-re-crystallizing in ethyl acetate
12(15.0g, 82%).mp?110～111℃,IR(KBr)?ν(cm
-1)：2794,?1711,?1613,?1489,?1452,?1357,?747,?698。
1HNMR?(200?MHz)?(CDCl
3)?δ：1.87-2.40(m,?2H),?2.64-2.78(m,?2H),?3.47,?3.77(ABq,?
J?=?13.6?Hz,?2H),?3.66(q,?
J?=?5.0?Hz,?1H),?4.82,?4.93(ABq,?
J?=?12.8?Hz,?2H),?6.60(d,?
J?=?7.2?Hz,?1H),?6.80(t,?
J?=?7.5,?7.2?Hz,?1H),?7.09(t,
?J?=?7.8,?7.5?Hz,?1H),?7.18-7.50(m,?15H)。EI-MS?(
m/z)?:?446?(M
+)。Ultimate analysis (C
31H
30N
2O) measured value (theoretical value, %): C 83.37 (83.41), H 6.77 (6.79), N 6.27 (6.29).
Embodiment 15: compound (
13) preparation
Under the argon shield, to compound
5(515mg, (0.75ml, 10.6mmol) (0.23ml 7.6mmol), stirs 12h with 37% concentrated hydrochloric acid to add DMSO in acetic acid soln 1.51mmol) under the room temperature.In reaction solution, add extracted with diethyl ether after the entry.Organic phase is with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, and anhydrous sodium sulfate drying, concentrating under reduced pressure get yellow bullion.With ether (10ml) dissolving bullion, add sodium hydrogencarbonate (381mg, 4.53mmol), (323 μ l 2.27mmol) and water (5ml), stir 2h to Cbz-Cl then.In reaction solution, add extracted with diethyl ether after the entry.Organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue through column chromatography refining (hexane:EtOAc=3:1～1:1) white crystal
13(430mg, 58%).mp?93～94℃,IR(KBr)?ν(cm
-1)：3031,?1694,?1614,?1467,?1357,?1192,?1118,?760,?733,?694。
1HNMR?(200?MHz)?(CDCl
3)?δ：2.11-2.30(m,?2H),?3.10-3.73(m,?3H),?4.37,?4.65(ABq,?
J?=?16.1?Hz,?2H),?4.83-4.96(m,?2H),?5.12,?5.20(ABq,?
J?=?12.4?Hz,?2H),?6.68(d,?J=?8.0?Hz,?1H),?6.91-7.40(m,?18H)。EI-MS?(
m/z)?:?490?(M
+)。Ultimate analysis (C
32H
30N
2O
3) measured value (theoretical value, %): C 78.28 (78.34), and H 6.11 (6.16), and N 5.68 (5.71).
Embodiment 16: compound (
21) preparation
Use compound
12(90mg, 0.20mmol), n-Butyl Lithium (1.56 M hexane solution, 129 μ l, 0.20mmol) and
1(61mg, 0.40mmol), according to the method preparation of embodiment 1
21Residue gets colorless oil through preparation TLC refining (hexane:EtOAc=5:1)
21(55mg, 52%).IR(KBr)?ν(cm
-1)：2925,?1714,?1611,?1488,?1362,?1174,?747,?699。
1HNMR?(200?MHz)?(CDCl
3)?δ：2.12-2.45(m,?4H),?3.44,?3.65(ABq,?
J?=?13.6?Hz,?2H),?3.71(s,?3H),?4.83(s,?2H),?5.81,?7.07(ABq,?
J?=?15.8?Hz,?2H),?6.66(d,?
J?=?7.7?Hz,?1H),?6.93-7.27(m,?20H)。EI-MS?(
m/z)?:?530(M
+)。
Embodiment 17: compound (
22) preparation
Under the argon shield, (0.87 M THF solution, 512 μ l drip in THF 0.45mmol) (0.5ml) solution to KHMDS at-78 ℃
13(218mg, THF 0.45mmol) (2ml) solution.Uniform temp drips after stirring 30min. down
1(135mg, THF 0.89mmol) (3ml), and then-20 ℃ of stirring 1h.In reaction solution, add ice-cold 0.5 M hydrochloric acid (10ml) back ethyl acetate extraction.Organic phase is with saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate drying.Residue gets colorless oil through preparation TLC refining (hexane:EtOAc=4:1)
22(206mg, 81%).IR(KBr)ν?(cm
-1)：3031,?2949,?1713,?1610,?1469,?1221,?1028,?751,?699。
1HNMR?(200?MHz)?(CDCl
3)δ：2.30-2.39(m,?2H),?2.84-2.94(m,?2H),?3.71(s,?3H),?4.20(d,?
J?=?15.5?Hz,?1H),?4.56(t,?
J?=?15.5?Hz,?1H),?4.65,?4.89(ABq,?
J?=?15.7?Hz,?2H),?5/07,?5.16(ABq,?
J?=?12.5?Hz,?2H),?5.83(t,?
J?=?15.6?Hz,?1H),?6.70(d,?
J?=?7.7?Hz,?1H),?6.87-7.39(m,?19H)。EI-MS?(
m/z)?:?574?(M
+)。Ultimate analysis (C
36H
34N
2O
5) measured value (theoretical value, %): C 75.12 (75.24), and H 6.04 (5.96), and N 4.69 (4.87).
Embodiment 18: compound (
23) preparation
Use
14(154mg, 0.69mmol), n-Butyl Lithium (1.56 M hexane solution, 442 μ l, 0.69mmol) and
1(208mg, 1.38mmol), according to the method preparation of embodiment 1
23Residue gets yellow oil through preparation TLC refining (hexane:EtOAc=4:1)
23(194mg, 92%).Through analyzing is the mixture of two geometrical isomers, and ratio is 59:41.IR(KBr)ν(cm
-1)：2925,?1706,?1610,?1468,?1352,?1170,?750,?698。
1HNMR?(200?MHz)?(CDCl
3)δ：3.73,?4.96(2d,?
J?=?7.3,?7.1?Hz,?2H,?ratio?49:51),?3.77(2s,?3H,?ratio?49:51),?4.94,?4.96(2s,?2H,?ratio?49:51),?6.68-7.53(m,?10H)。EI-MS?(
m/z)?:?307(M
+)。
Comprehensively said, with
6-12Under the situation for substrate, be to be alkali with the n-Butyl Lithium, with
1Reaction.The result shows that reaction yield is good, but if the nitrogen-atoms on the Oxoindole ring is not protected, the Wasserstoffatoms on the amino also can react with n-Butyl Lithium, so the amount of alkali should consume 2 equivalents.Substrate
13On cbz protection base is arranged, n-Butyl Lithium has nucleophilicity to the carbonyl of cbz protection base, therefore substitutes with KHMDS ,-78
oAfter the coldcondition of C prepares enolate ion down ,-20
oC reacts.Substrate
143 two active Wasserstoffatomss are arranged, after addition-elimination also isomerizing can take place, generate cis and trans mixture
23(seeing embodiment 18).
Compound (3) 1, the 3-dimethyl--5-methoxyl group-2 of the embodiment of the invention 1 said preparation, 3-dihydro-2-oxygen-1
H-indoles-3 acrylic acid methyl esters can pass through palladium/carbon catalytic hydrogenating reduction carbon-to-carbon double bond, becomes acid (the 2N NaOH aqueous solution), Curtius rearrangement (diphenyl phosphate azide, triethylamine, ethanol or benzylalcohol) and cyclization (lithium aluminum hydride) to be converted into a kind of effective constituent Physostigmine (Physostigmine) and Eserethole synthetic precursor substance of medicinal plant through hydrolysis of ester group again.The in the past natural product extraction that come from of Physostigmine more; Can be used for clinically treating glaucoma, myasthenia gravis, Alzheimer etc., begun to be used to treat postural hypotension (L. J. Thal et al., N. Engl. J. Med. 308 recently; 720,1983; L. J. Thal et al., Ann. Neurol. 13,491,1983; L. Gustafson et al., Psychopharmacology 93,31, and 1987).
The resulting new class Oxoindole of the present invention for the synthetic in a large number Physostigmine of manual work opens up a new way, has the value of practical application.
Claims (10)
1.3-substituted allyl ester Oxoindole, its structure is suc as formula shown in (I) or the formula (II):
Wherein, R
1Be C
1-10Alkyl, C
2-10Thiazolinyl, benzyl, substituted benzyl, alkoxyalkyl or protection aminoalkyl group;
R
2Be hydrogen, C
1-10Alkyl, C
2-10Thiazolinyl, benzyl or substituted benzyl;
R
3Be hydrogen, C
1-5Alkyl or C
1-5Alkoxyl group;
R
4Be C
1-10Alkyl, C
2-10Thiazolinyl, benzyl and substituted benzyl, phenyl or substituted-phenyl.
2. 3-substituted allyl ester Oxoindole according to claim 1 is characterized in that R
3Be hydrogen or methoxyl group; R
2Be hydrogen or benzyl; R
4Be methyl; R
1Be methyl, benzyl, 3-methyl-2-butene base, benzyloxy ethyl, N, N '-dibenzyl amino ethyl or N-benzyl-N-benzyloxycarbonyl amino-ethyl.
3. according to the 3-substituted allyl ester Oxoindole of claim 1, it is characterized in that it is in following any one:
1,3-dimethyl--5-methoxyl group-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1,3-dimethyl--2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
3-methyl-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1,3-benzyl-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
3-(3-methyl-2-butene base)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(3-methyl-2-butene base)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(3-benzyloxy ethyl)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(N, N-dibenzyl amino ethyl)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters,
1-benzyl-3-(N-benzyl-N-benzyloxycarbonyl amino-ethyl)-2,3-dihydro-2-oxo--1
H-indoles-3 acrylic acid methyl esters or
1-benzyl-3-(2-methoxycarbonyl ethylidene)-2,3-dihydro-2-oxo--1
H-indoles.
4. the preparation method of the described 3-substituted allyl of claim 1 an ester Oxoindole is characterized in that carrying out according to following step:
(1) compound shown in the formula (III) forms the enolization compound in-50 ℃ ~ 20 ℃ Wasserstoffatomss of in aprotic solvent, removing the 3-position under the effect of organic bases, more above-mentioned enolization compound is cooled off at-90 ℃～20 ℃;
(2) 3-(1-imidazolyl) methyl acrylate is joined in the cooled enolization compound, be warming up to-40 ℃～20 ℃ generation addition-elimination reactions then and obtain compound shown in formula (I) or the formula (II);
5. the preparation method of 3-substituted allyl ester Oxoindole according to claim 4 is characterized in that organic bases is n-Butyl Lithium or potassium hexamethyldisilazide described in the step (1), and said organic bases and formula (III) mol ratio is 1～2:1.
6. the preparation method of 3-substituted allyl ester Oxoindole according to claim 4 is characterized in that temperature of reaction is-20 ℃ ~ 0 ℃ in the step (1).
7. the preparation method of 3-substituted allyl ester Oxoindole according to claim 4 is characterized in that aprotic solvent is THF, toluene, ether or glycol dimethyl ether described in the step (1).
8. the preparation method of 3-substituted allyl ester Oxoindole according to claim 4 is characterized in that the reaction times is 30min ~ 12h in the step (1).
9. the preparation method of 3-substituted allyl ester Oxoindole according to claim 4 is characterized in that step (2) adds the diluted acid termination reaction, and said diluted acid is Hydrogen chloride, dilute sulphuric acid or dilute acetic acid.
10. the preparation method of 3-substituted allyl ester Oxoindole according to claim 4 is characterized in that the consumption of 3-(1-imidazolyl) methyl acrylate in the step (2) and the mol ratio of formula (III) are 1～2:1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936649A (en) * | 2014-03-29 | 2014-07-23 | 贵州大学 | 3-(2-acrylate)-3-thio oxindole compound and preparation method thereof |
| CN108329255A (en) * | 2018-03-19 | 2018-07-27 | 华南理工大学 | A kind of synthetic method of hexahydro carbazolone derivative |
-
2011
- 2011-08-16 CN CN 201110234362 patent/CN102382031A/en active Pending
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| Title |
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| 《Chemical Abstract》 19840512 Preobrazhenskaya等 Anionotropic rearrangement in the indole series AN 69:86745，CAS：19611-83-7 1-2 , * |
| 《Journal of the American Chemical Society》 19531231 PERCY等 Studies in the Indole Series. XIII. Oxindole-3-propionic Acid 5301-5页，特别是5302页化合物X 1 第75卷, * |
| 《中国医药工业杂志》 20101231 尚慕宏等 1，3-二甲基-5-甲氧基-2，3-二氢-2-氧-1H-吲哚-3-丙烯酸甲酯的制备 807-808页,特别是807-808页实验部分，807页，图1 1-10 第11卷, 第41期 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936649A (en) * | 2014-03-29 | 2014-07-23 | 贵州大学 | 3-(2-acrylate)-3-thio oxindole compound and preparation method thereof |
| CN103936649B (en) * | 2014-03-29 | 2016-05-04 | 贵州大学 | 3-(2-acrylate)-3-sulfo-Oxoindole compound and preparation method thereof |
| CN108329255A (en) * | 2018-03-19 | 2018-07-27 | 华南理工大学 | A kind of synthetic method of hexahydro carbazolone derivative |
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