CN103193599A - Synthetic method of poly-substituted-5-ethynyl-10,11-dihydro-5H-dibenzyl[a,d]cycloheptane-5-ol - Google Patents
Synthetic method of poly-substituted-5-ethynyl-10,11-dihydro-5H-dibenzyl[a,d]cycloheptane-5-ol Download PDFInfo
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Abstract
The invention relates to a simple synthetic method of poly-substituted-5-ethynyl-10,11-dihydro-5H-dibenzyl[a,d]cycloheptane-5-ol compounds having programmed cell necrosis activities. The structural formula of the compounds is shown in the specification.
Description
Technical field
The present invention relates to the procedural downright bad active polyfunctional group replacement-5-ethynyl-10 of the high anti-cell of a kind of tool, the simple synthesis of 11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol.
Background technology
Nec-12 (5-ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol) is that a class is through the newfound micromolecular compound with the procedural necrocytosis of extremely strong inhibition of magnanimity screening.Up-to-date studies show that, though its mechanism is not clear and definite fully as yet, but procedural necrocytosis process and some important diseases, relevant as apoplexy, myocardial infarction even senile dementia, closely bound up for the exploitation of the understanding treatment of these diseases and related drugs lead compound thereof to the further investigation of its mechanism and relevant inhibitor.In the Nec series compound, suitable inhibition activity is arranged all, Nec-12 demonstrates superior physiologically active.But, for synthesizing of Nec-12 series report not being arranged as yet.The alkynyl introducing method of the present invention exploitation is easy this compounds that has synthesized multiple replacement not only, for the lead compound of seeking out later this type of medicine and the deep exploitation of medicine provide solid chemical fundamentals.
Inhibitor of the present invention and other procedural inhibitor of cellular necrosis structural formula of part are as follows:
Above-mentioned polysubstituted Nec-12 synthetic method finds no the pertinent literature report through SciFinder system and the retrieval of other peek-a-boo.
5-ethynyl-10 is arranged, synthetic report (the Chem Ber of 11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol in the document; 96; 1963; 1221-1228; Journal ofMedicinal Chemistry; 6; 1963; 513-516): with corresponding 10,11-dihydro-5H-phenylbenzene [a, d] suberane ketone in the presence of sodium amide or Lithamide, low temperature (40 ℃) down with as acetylene gas react and obtain.Because this reaction has used acetylene gas as introducing reagent, highly basic sodium amide or Lithamide all need on-the-spot by sodium Metal 99.5 or lithium and subcooled liquefied ammonia prepared in reaction under cold condition, there is certain danger when enlarging reaction, so people also wish to obtain more gentle reaction and method.
Summary of the invention
Purpose of the present invention also provide a kind of polysubstituted-simple synthesis of 5-ethynyl-5H-phenylbenzene [a, d] suberane-5-alkylol cpd.
The compounds of this invention synthetic is to utilize acetylene reagent (listing in the table one) with silicon blocking group and butyllithium to form behind the metal lithium salts with after corresponding substituted diphenylamine basic ring heptane ketone (compound 1) addition to form midbody compound 2, obtains corresponding alkynol compound 3 after sloughing protecting group subsequently.Route and method are as follows:
Wherein, R, R
1-4=H, benzo base, C1～C4 alkyl, C1～C4 alkoxyl group, F, Cl or Br; And R
1-4At least one is not H.
Method of the present invention further describes as follows:
1) compound 2 is synthetic
Under-78 ℃～room temperature and in the organic solvent, the acetylene CH ≡ CPG of silicon blocking group and n-Butyl Lithium reaction generated and form the metal lithium salts in 0.1～1 hour, and metal lithium salts and compound 1 reaction obtained compound 2 in 1～8 hour; Recommend water or the cancellation of ammonium chloride saturated solution reaction.The mol ratio 0.9～1 of the acetylene CH ≡ CPG of compound 1, n-Butyl Lithium and silicon blocking group: 1: 1～2; Described PG is silica-based protective material, as trimethyl silicon based (TMS), triethyl silica-based (TES), xenyl dimethyl silica-based (BDMS), dimethyl (1,1,2-trimethylammonium propyl group) silica-based (TDS), triisopropylsilyl (TIPS), tertiary butyl dimethyl silica-based (TBDMS) or xenyl di-isopropyl silica-based (BDIPS); Above-mentioned organic solvent can be tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene or toluene etc.
2) alkynol compound 3 is synthetic
At room temperature with organic solvent in, the reaction of compound 2 substrates and alkali or tetrabutyl ammonium fluoride obtained compound 3 in 0.5～10 hour; The mol ratio of compound 2, alkali or tetrabutyl ammonium fluoride 1: 1～3; Organic solvent can be alcohol, tetrahydrofuran (THF), ether, Chinese named DMF, Chinese named DMSO, acetone, methylene dichloride, chloroform or benzene etc.; Described alkali is oxyhydroxide or the carbonate of monovalence metal, as KOH, NaOH, K
2CO
3Or Na
2CO
3
Experimental technique reaction conditions gentleness of the present invention, the reaction times is short, and productive rate is higher.The present invention adopts the ethynyl lithium of silica-based protecting group protection as the introducing reagent of ethynyl, has the following advantages:
1) it is less that present method is subjected to the influence of functional group, is applicable to the synthetic of synthetic single, double, polysubstituted compound;
2) the ethynyl lithium of the silica-based protecting group protection of reaction intermediate easily forms, and adds the back at n-Butyl Lithium usually and can transform fully after 15 to 30 minutes;
Keep low temperature when 3) the ethynyl lithium of silica-based protecting group protection is with corresponding substituted diphenylamine basic ring heptane ketone compound addition, for example-60 ℃, but only need for example about two hours.With traditional acetylene gas as ethynyl introduce reagent, amino is received or Lithamide is made alkali and introduced the classical way of ethynyl and compare, and has not both had the acetylene gas steel cylinder and also need not the ammonia steel cylinder, do not have fire-hazardous sodium Metal 99.5 and metallic lithium yet and participate in.Foreshorten to relatively in the time of low-temp reaction simultaneously, for example 2 hours, and do not have the side reaction problem, productive rate is higher (70～＞=90%) also.And the method in the document has the by product that two additions take place to generate;
4) the ethynyl lithium of the silica-based protecting group protection of intermediate, corresponding substituted diphenylamine basic ring heptane ketone compound all are dissolved in solvent, and intermediate 2 need not to purify and can directly remove the reaction of silica-based protecting group;
5) the silica-based protecting group that adopts of this reaction is owing to have specific removal methods (as weak base, F
-, or H
+Exist down), be difficult for reversible reaction takes place, shown in example 2, adopt 2-(2-hydroxypropyl)-acetylene to introduce generation reversible reaction when in the presence of sodium hydroxide, removing protecting group after the ethynyl, what obtain is phenylbenzene suberane ketone.
6) as shown in Table 1, blocking group removes easy, mild condition;
7) as shown in Table 1, qualified silica-based protecting group acetylene reagent is more, and shown in example 1, two step productive rates are all good;
8) as shown in Table 1, used silica-based protecting group is common blocking group.
The detailed experimental implementation of the present invention is recommended as follows: under 0 ℃; n-butyllithium solution is splashed into the organic solution of silica-based protecting group acetylene; mol ratio is that 1: 1～1.5 recommendation mol ratios are in 1: 1～1.1; keep thermotonus after half an hour reaction system to be cooled to subzero about 60 ℃; the organic solution of dropwise reaction substrate ketone 1, with ethynyl lithium mol ratio be 0.9: 1.Dripping off the back keeps low-temp reaction after two hours; be warming up to room temperature gradually and continue reaction water (or ammonium chloride saturated solution) cancellation reaction after six to eight hours; methylene dichloride (or chloroform; ethyl acetate) gets intermediate 2 after the direct rotary evaporation in extraction back concentrates; but column chromatographic isolation and purification also can directly remove the reaction of protecting group.If protecting group is TMS, TES, BDMS, then add methyl alcohol, and the reaction of the salt of wormwood stirring at room of two equivalents got pure product compound 3 after six to 12 hours behind rapid column chromatography; If protecting group is TBDMS, TDS, TIPS, BDIPS, then add tetrahydrofuran (THF), and the reaction of the tetrabutyl ammonium fluoride stirring at room of equivalent got pure product compound 3 after two hours behind rapid column chromatography.
Table one, ethynyl are introduced the reagent table look-up
*A:K
2CO
3, MeOH, r.t.; B: tetrabutyl ammonium fluoride (TABF), THF, H
2O, r.t..
Adopt typical consequence and the relevant bioassay of the synthetic part of compounds of method of the present invention to the results are shown in the table two.Its biological activity has improved nearly 200 times, and (compound 3m, the structure of lead compound is the alcohol of unsubstituted, EC
50Value is 590nM).
Table two, compound structure and biologically active data
Compound of the present invention can be used for the mechanism of programmed cell death (PCD) and understanding in depth and exploring of process, and the medicine that helps research and development and the procedural necrosis of preparation anti-cell, for example is used for the treatment of the medicine of apoplexy, cancer.
Embodiment
Following embodiment will help further to understand the present invention, but can not limit content of the present invention.
The preparation of embodiment 13-fluoro-5-ethynyl-5H-phenylbenzene [a, d] suberene-5-alcohol (3a) compound
PG=TMS (compound 2a), TES (compound 2b), TIPS (compound 2c).
General experimental implementation:
In the there-necked flask of dry 25mL; under 0 ℃; Dropwise 5 mL concentration is the n-butyllithium solution of 1.6M in the 10mL tetrahydrofuran solution of the acetylene of the silica-based protection of 3mmol; keep thermotonus to be cooled to subzero 60 ℃ after 30 minutes, drip the 5mL tetrahydrofuran solution of phenylbenzene suberene ketone 1 (2.7mmo1).Continued low-temp reaction two hours after being added dropwise to complete, make temperature of reaction rise to room temperature gradually and continue to react six to eight hours until the disappearance of TLC demonstration raw material.Add an amount of distilled water cancellation reaction, get intermediate 2 crude products, column chromatography (eluent: ethyl acetate/petroleum ether=1: 20～1: 15) can get intermediate 2a-c after concentrating behind the dichloromethane extraction.For compound 2a and 2b, directly add the K of 2eq
2CO
3, and 20mL methyl alcohol stirring at room reaction six to 12 hours shows that to TLC intermediate transforms fully.The direct rapid column chromatography of concentration of reaction solution gets pure products 3a, and (eluent: ethyl acetate/petroleum ether=1: 10～1: 8), protecting group removes productive rate and is respectively 94% and 85%; For compound 2c, the tetrabutyl ammonium fluoride and the reaction of 20mL tetrahydrofuran (THF) that then add equivalent showed that to TLC intermediate transforms fully after two hours.The direct rapid column chromatography of concentration of reaction solution gets pure products 3a, and (eluent: ethyl acetate/petroleum ether=1: 10～1: 8), it is 85% that protecting group removes productive rate.
2-fluoro-5-(trimethyl silicon based) ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (2a)
Productive rate 96%, yellow oil.
1H?NMR(400MHz?CDCl
3)：δ0.11-0.16(m，9H)，2.83(s，1H)，3.10-3.31(m，2H)，3.36-3.47(m，2H)，6.72-6.78(m，2H)，7.03-7.05(m，1H)，7.09-7.13(m，2H)7.86-7.89(m，2H)；
19F?NMR(376MHz，CDCl
3)：δ-115.84(s，1F)；
MS(EI)m/z(％)：324(M
++1，39)，306(23)，233(57)，226(86)，225(28)，198(100)，197(87)，73(88)；
2-fluoro-5-(triethyl is silica-based) ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (2b)
Productive rate 96%, yellow oil.
1H?NMR(400MHz?CDCl
3)：δ0.63-0.70(m，6H)，0.97-1.03(m，9H)，2.87(s，1H)，3.39-3.47(m，4H)，6.79-6.85(m，2H)，7.10-7.12(m，1H)，7.15-7.22(m，2H)?7.99-8.02(m，2H)；
19F?NMR(376MHz，CDCl
3)：δ-115.81(s，1F)；
MS(EI)m/z(％)：366(M
++1，22)，337(17)，324(31)，291(25)，233(88)，226(77)，199(99)，198(100)，183(58)；
2-fluoro-5-(triisopropylsilyl) ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (2c)
Productive rate 98%, yellow oil.
1H?NMR(400MHz?CDCl
3)：δ1.00-1.19(m，21H)，2.16(s，1H)，3.35-3.50(m，4H)，6.81-6.85(m，2H)，7.11-7.23(m，3H)，8.04-8.08(m，2H)；
19F?NMR(376MHz，CDCl
3)：δ-115.82(s，1F)；
MS(ESI)m/z(％)：407.8(M
++1)
The unsuccessful protecting group that removes after embodiment 22-(2-hydroxypropyl)-acetylene is introduced
5-(3-hydroxy-3-methyl butynyl)-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (5)
Productive rate 70%, light yellow oil.
1H?NMR(300MHz?CDCl
3)：δ1.46(s，6H)，3.25-3.33(m，2H)，3.42-3.47(m，2H)，3.97(s，1H)，7.06-7.15(m，6H)，7.89(d，2H)；
MS(ESI)m/z(％)：347.2(M
++MeOH+Na
+，80)，315.2(100)。
Cited compound data in embodiment 3 tables two
2-fluoro-5-ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3a)
Productive rate 78%, white solid, m.p.92-93 ℃.
1H?NMR(300MHz?CDCl
3)：δ2.93(s，1H)，2.96(s，1H)，3.29-3.56(m，4H)，6.83-6.88(m，2H)，7.13-7.25(m，3H)，7.96-8.01(m，2H)；
19F?NMR(282MHz，CDCl
3)：δ-115(dd，1F)；
MS(EI)m/z(％)：252(M
++1，28)，234(100)，233(62)，232(16)，220(18)，199(40)，196(20)；
IR(KBr)v：3419，3273，1613，1593，1492，1482，1246，1234，1152，1041；
Ultimate analysis C
17H
13FO: calculated value C, 80.93; H, 5.19.Experimental value: C, 80.79; H, 5.29.
2,3-dimethoxy-5-ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3b)
Productive rate 70%, light yellow solid, m.p.135-137 ℃.
1H?NMR(300MHz?CDCl
3)：δ2.93(s，1H)，2.95(s，1H)，3.16-3.47(m，3H)，3.56-3.70(m，1H)，3.84(m，3H)，3.90(m，3H)，6.61(s，1H)，7.15-7.23(m，3H)，7.62(s，1H)，7.95(d，1H)；
MS(EI)m/z(％)：294(M
++1，100)，277(64)，276(70)，268(7)，263(14)，245(18)，233(23)，189(36)，165(34)；
HRMS:C
19H
18O
3Calculated value 294.1256, measured value 294.1259;
IR(KBr)v：3443，3249，3067，2916，2927，2094，1611，1597，1514，1462，1324，1174，1157，1097，1067；
2-methoxyl group-3-fluoro-5-ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3c)
Productive rate 75%, light yellow oil.
1H?NMR(300MHz?CDCl
3)：δ2.93(s，1H)，2.98(s，1H)，3.25-3.59(m，4H)，6.69(d，1H)，7.13-7.24(m，3H)，7.78(d，1H)，7.95(t，1H)；
19F?NMR(282MHz，CDCl
3)：δ-139(dd，1F)；
MS(EI)m/z(％)：282(M
++1，100)，264(94)，262(32)，232(16)，251(25)，229(46)，221(61)；
IR(KBr)v：3471，3283，2931，2113，1615，1541，1453，1267，1124，1094；
Ultimate analysis C
18H
15FO
2: calculated value C, 76.58; H, 5.36 experimental value C, 76.46; H, 5.64.
2,3-, two fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3d)
Productive rate 68%, white solid, m.p.84-86 ℃.
1H?NMR(300MHz?CDCl
3)：δ2.94(s，1H)，2.98(s，1H)，3.17-3.31(m，2H)，3.42-3.63(m，2H)，6.91(t，1H)，7.13-7.26(m，3H)，7.81-7.95(m，2H)；
19F?NMR(282MHz，CDCl
3)：δ-140(m，1F)，-141(m，1F)；
MS(EI)m/z(％)：270(M
++1，16)，253(23)，252(100)，251(52)，233(11)，217(20)，201(13)；
IR(KBr)v：3392，3273，2912，1604，1508，1483，1304，1272，1107，1087；
Ultimate analysis C
17H
12F
2O: calculated value C, 75.55; H, 4.48.Experimental value C, 75.39; H, 4.54.
1,2-, two fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3e)
Productive rate 78%, white solid, m.p.92-94 ℃.
1H?NMR(400MHz?CDCl
3)：δ2.96(s，1H)，2.99(s，1H)，3.21-3.46(m，3H)，?3.62-3.71(m，1H)，6.93-7.00(m，1H)，7.17-7.27(m，3H)，7.80-7.90(m，2H)；
19F?NMR(282MHz，CDCl
3)：δ-134(q，1F)，-135(d，1F)；
MS(EI)m/z(％)：270(M
++1，15)，252(100)，253(24)，251(52)，217(23)，201(16)，197(12)，115(11)；
HRMS:C
17H
12OF
2Calculated value 270.0856, experimental value 270.2853;
2,4-, two fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3f)
Productive rate 82%, light yellow oil.
1H?NMR(400MHz?CDCl
3)：δ2.75(s，1H)，2.97-3.01(m，1H)，3.12-3.27(m，2H)，3.07-3.11(m，1H)，6.61-6.72(m，2H)，7.12(s，1H)，7.24-7.26(m，1H)，8.12(s，1H)；
19F?NMR(282MHz，CDCl
3)：δ-100(d，1F)，-108(s，1F)；
2,3,4-, three fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3g)
Productive rate 57%, white solid, m.p.98-100 ℃.
1H?NMR(400MHz?CDCl
3)：δ2.82(s，3H)，3.01-3.07(m，1H)，3.16-3.27(m，2H)，3.77(d，1H)，3.52-3.59(m，1H)，6.73(t，1H)，7.14(d，1H)，7.27-7.29(m，2H)，8.11(t，1H)；
19F?NMR(282MHz，CDCl
3)：δ-125(d，1F)，-132(q，1F)，-158(t，1F)；
MS(EI)m/z(％)：288(M
++1，24)，271(25)，270(100)，269(61)，252(78)，251(58)，238(22)，183(13)，115(26)；
HRMS:C
17H
11OF
3Calculated value 288.0762, experimental value 288.0764;
IR(KBr)v：3309，3242，2906，1614，1506，1455，1367，1334，1245，1097，1069；
1,2,3-, three fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3h)
Productive rate 77%, white solid, m.p.62-64 ℃.
1H?NMR(400MHz?CDCl
3)：δ2.95(s，1H)，2.99(s，1H)，3.11-3.18(m，1H)，3.28-3.33(m，2H)，3.74-3.82(m，1H)，7.18-7.28(m，3H)，7.74(t，1H)，7.87(d，1H)；
19F?NMR(282MHz，CDCl
3)：δ-131(d，1F)，-134(s，1F)，-157(q，1F)；
MS(EI)m/z(％)：288(M
++1，12)，271(23)，270(100)，269(44)，252(34)，251(31)，238(13)，199(6)，115(16)；
HRMS:C
17H
11OF
3Calculated value 288.0762, experimental value 288.0761;
IR(KBr)v：3384，3272，2942，1633，1615，1513，1430，1339，1094，1065；
2-methyl-3-fluoro-5-ethynyl-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3i)
Productive rate 60%, light yellow oil.
1H?NMR(400MHz?CDCl
3)：δ2.19(s，3H)，2.92(d，2H)，3.19-3.32(m，2H)，3.40-3.47(m，1H)，3.52-3.59(m，1H)，6.92(d，1H)，7.12-7.24(m，3H)，7.66(d，1H)，7.95(t，1H)；
19F?NMR(282MHz，CDCl
3)：δ-117(s，1F)；
2,3,8-, three fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3j)
Productive rate 69%, white solid, m.p.60-62 ℃.
1H?NMR(400MHz?CDCl
3)：δ2.96(s，1H)，3.01(s，1H)，3.19-3.29(m，2H)，3.43-3.57(m，2H)，6.84-6.95(m，3H)，7.83(dd，1H)，7.93(dd，1H)；
19F?NMR(282MHz，CDCl
3)：δ-111(s，1F)，-136(q，1F)，-137(q，1F)；
MS(EI)m/z(％)：288(M
++1，21)，271(30)，270(100)，269(60)，252(5)，251(20)，235(20)，199(6)，115(8)；
HRMS:C
17H
11OF
3Calculated value 288.0762, experimental value 288.0764;
IR(KBr)v：3419，3276，2911，1610，1594，1508，1487，1304，1271，1101，1087；
2,8-, two fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3k)
Productive rate 82%, white solid, m.p.77-78 ℃.
1H?NMR(400MHz?CDCl
3)：δ2.93(s，1H)，2.97(s，1H)，3.30-3.38(m，2H)，3.42-3.50(m，2H)，6.83-6.89(m，4H)，7.97(dd，2H)；
19F?NMR(282MHz，CDCl
3)：δ-111(s，2F)；
MS(EI)m/z(％)：270(M
++1，38)，271(9)，253(43)，252(100)，251(84)，250(52)，233(28)，230(34)，217(49)，197(33)，133(26)，109(29)；
HRMS:C
17H
12OF
2Calculated value 270.0856, experimental value 270.0854;
IR(KBr)v：3377，3273，2930，1609，1593，1492，1434，1352，1232，1148，1048；
3,8-, two fluoro-2-methyl-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3l)
Productive rate 52%, light yellow oil.
1H?NMR(400MHz?CDCl
3)：δ2.13(s，3H)，2.86(d，2H)，3.14-3.23(m，2H)，3.33-3.44(m，2H)，6.75-6.87(m，3H)，7.57(d，1H)，7.87(dd，1H)；
19F?NMR(282MHz，CDCl
3)：δ-111(s，1F)，-117(s，1F)；
1,2,8-, three fluoro-5-ethynyls-10,11-dihydro-5H-phenylbenzene [a, d] suberane-5-alcohol (3m)
Productive rate 54%, white solid, m.p.99-101 ℃.
1H?NMR(400MHz?CDCl
3)：δ2.94(s，1H)，2.99(s，1H)，3.27-3.45(m，3H)，3.59-3.66(m，1H)，6.87-6.91(m，2H)，6.96-7.02(m，1H)，7.79-7.83(m，1H)，7.90-7.93(m，1H)；
19F?NMR(282MHz，CDCl
3)：δ-111(s，1F)，-134(d，1F)，-135(t，1F)；
MS(EI)m/z(％)：288(M
++1，33)，271(36)，270(100)，269(68)，268(43)，251(36)，238(18)，235(40)，215(37)，133(17)，109(19)；
HRMS:C
17H
11OF
3Calculated value 288.0762, experimental value 288.0767
IR(KBr)v：3396，3278，2900，1610，1593，1493，1426，1364，1290，1252，1053；
7-ethynyl-12,13-dihydro-7H-phenylbenzene [4,5] suberane [1,2 α] naphthalene-7-alcohol (4)
Productive rate 81%, white solid, m.p.30-31 ℃.
1H?NMR(300MHz?CDCl
3)：δ2.88(s，1H)，3.13(s，1H)，3.30-3.40(m，1H)，3.59-3.71(m，1H)，3.83-3.94(m，2H)，7.14-7.23(m，3H)，7.38-7.48(m，2H)，7.67-7.77(m，2H)，7.93-7.96(m，1H)，8.10(d，1H)，8.23(d，1H)；
MS(EI)m/z(％)：284(M
++1，5)，266(14)，265(13)，253(3)，231(9)，43(100)，45(15)；
IR(KBr)v：3533，3290，3059，2903，1708，1596，1509，1486，1456，1317，1265，1044；
Ultimate analysis C
21H
16O: calculated value C, 88.70; H, 5.67.Experimental value: C, 88.43; H, 5.75.
The determination of activity of the procedural necrosis of embodiment 4 anti-cells
Activity (the EC of the procedural necrosis of anti-cell of listed compound in the table two
50Value) all in mouse L929 cell, records.The L929 cell mixes the one hour survival mensuration of handling to carry out in back 15 hours based on ATP by 20uM zVAD with the survey compound derivatives.Cell based on the survival of ATP measure the ATP-based assay kit that platform be commercialization (CellTiter-Glo, Promega, Madison, WI).EC
50Value is to get non-linear regression S shape onset dosage from the logarithmic value of inhibition concentration than the curve of survival value.
Claims (6)
1. the synthetic method of polysubstituted-5-ethynyl-5H-phenylbenzene [a, d] suberane-5-alkylol cpd is characterized in that by following step 1) and 2) obtain:
Wherein, R, R
1-4=H, benzo base, C1～C4 alkyl, C1～C4 alkoxyl group, F, Cl or Br; And R
1-4At least one is not H.
1) compound 2 is synthetic
Under-78 ℃～room temperature and in the organic solvent, the acetylene CH ≡ CPG of silicon blocking group and n-Butyl Lithium reaction generated and form the metal lithium salts in 0.1～1 hour, and metal lithium salts and compound 1 reaction obtained compound 2 in 1～8 hour; The mol ratio 0.9～1 of the acetylene CH ≡ CPG of compound 1, n-Butyl Lithium and silicon blocking group: 1: 1～2; Described PG is silica-based protective material;
2) alkynol compound 3 is synthetic
At room temperature with organic solvent in, the reaction of compound 2 substrates and alkali or tetrabutyl ammonium fluoride obtained compound 3 in 0.5～10 hour; The mol ratio of compound 2, alkali or tetrabutyl ammonium fluoride 1: 1～3; Described alkali is oxyhydroxide or the carbonate of monovalence metal, as KOH, NaOH, K
2CO
3Or Na
2CO
3
2. synthetic method as claimed in claim 1; it is characterized in that the PG described in the step 1) be silica-based protective material be trimethyl silicon based, triethyl is silica-based, the xenyl dimethyl is silica-based,, dimethyl (1; 1,2-trimethylammonium propyl group) silica-based, triisopropylsilyl, tertiary butyl dimethyl is silica-based or the xenyl di-isopropyl is silica-based.
3. synthetic method as claimed in claim 1 is characterized in that the reaction employing water described in the step 1) or ammonium chloride saturated solution cancellation reaction.
4. synthetic method as claimed in claim 1 is characterized in that step 2) described in described alkali be K
2CO
3Or Na
2CO
3
5. synthetic method as claimed in claim 1 is characterized in that the organic solvent described in the step 1) is tetrahydrofuran (THF), ether, methylene dichloride, chloroform, benzene or toluene.
6. synthetic method as claimed in claim 1 is characterized in that step 2) described in organic solvent be alcohol, tetrahydrofuran (THF), ether, Chinese named DMF, Chinese named DMSO, acetone, methylene dichloride, chloroform or benzene.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1531528A (en) * | 2001-06-27 | 2004-09-22 | ��˲���ʽ���� | Dibenzocycloheptene compound |
| CN101531570A (en) * | 2009-04-17 | 2009-09-16 | 中国科学院上海有机化学研究所 | 1,2,3-substituted-5-acetylenyl-(or 10,11-dihydro)-5H-diphenyl[a,d] suberne (alkyl)-5-alcohol, synthesizing method and application |
| WO2010007556A1 (en) * | 2008-07-18 | 2010-01-21 | Telefonaktiebolaget Lm Ericsson (Publ) | Access network selection |
-
2012
- 2012-01-06 CN CN2012100041036A patent/CN103193599A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1531528A (en) * | 2001-06-27 | 2004-09-22 | ��˲���ʽ���� | Dibenzocycloheptene compound |
| WO2010007556A1 (en) * | 2008-07-18 | 2010-01-21 | Telefonaktiebolaget Lm Ericsson (Publ) | Access network selection |
| CN101531570A (en) * | 2009-04-17 | 2009-09-16 | 中国科学院上海有机化学研究所 | 1,2,3-substituted-5-acetylenyl-(or 10,11-dihydro)-5H-diphenyl[a,d] suberne (alkyl)-5-alcohol, synthesizing method and application |
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| Title |
|---|
| VICTORIO CADIERNO等: "Isomerization of Propargylic Alcohols into a,b-Unsaturated Carbonyl Compounds Catalyzed by the Sixteen-Electron Allyl-Ruthenium(II) Complex [Ru(h3-2-C3H4Me)(CO)(dppf)][SbF6]", 《ADV. SYNTH. CATAL.》 * |
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