CN101544540B - (R)-2-methyl-5,5-diphenyl-4-amylene-1-ol derivatives - Google Patents

(R)-2-methyl-5,5-diphenyl-4-amylene-1-ol derivatives Download PDF

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CN101544540B
CN101544540B CN2009100505984A CN200910050598A CN101544540B CN 101544540 B CN101544540 B CN 101544540B CN 2009100505984 A CN2009100505984 A CN 2009100505984A CN 200910050598 A CN200910050598 A CN 200910050598A CN 101544540 B CN101544540 B CN 101544540B
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amylene
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CN101544540A (en
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田伟生
蔺宇
汪昀
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention relates to (R)-2-methyl-5,5-diphenyl-4-amylene-1-ol derivatives and a method for synthesizing the same. The compounds can be used for synthesizing a plurality of compounds with chiral methyl groups, and the structural formula of (R)-2-methyl-5,5-diphenyl-4-amylene-1-ol compounds the formula. The method for synthesizing the derivatives has simple and convenient operation and is easy to perform large-scale preparation; and simultaneously, the method is advantageous for application of steroid sapogenins to oxidize and degrade waste materials.

Description

One type of (R)-2-methyl-5,5-phenylbenzene-4-amylene-1-ol derivatives
Technical field
The present invention relates to one type of (R)-2-methyl-5; 5-phenylbenzene-4-amylene-1-ol derivatives; The small segment lactone that they can obtain with steroid sapogenin degradation easily is that raw material prepares, and this compounds can be used for synthesizing a plurality of compounds that have the chirality methyl group.The compound method of this analog derivative is easy and simple to handle, prepares in a large number easily.
Technical background
Optically active (R)-2-methyl-5,5-phenylbenzene-4-amylene-1-ol derivatives (1) is important organic synthesis intermediate.As raw material, can synthesize a plurality of compounds that have the chirality methyl group, for example: lipopeptid compound Dragonamide or the like in insect pheromone and corpus allatum hormone, muskone (R)-Muscone, the marine alga.
2008; Tian Weisheng etc. have applied for the patent (CN 200810037533.1) of " (S)-4-methyloctane derivate, compound method and the purposes in synthetic (S)-3-methyl enanthic acid thereof "; This patent utilization (S)-4-methyloctane derivate synthesizes (S)-3-methyl enanthic acid; On this basis, we also can pass through (R)-2-methyl-5, and 5-phenylbenzene-4-amylene-1-ol derivatives synthesizes (S)-3-methyl enanthic acid.
Figure G2009100505984D00021
And (R)-2-methyl-5,5-phenylbenzene-4-amylene-1-ol derivatives can utilize small segment waste (R)-γ-methyl-δ-Wu Neizhi of chirality methyl to synthesize equally easily.The present invention not only helps the utilization of steroid sapogenines oxidative degradation waste;, also be the synthetic important synthesis intermediates that provides that has the compound of chirality methyl group simultaneously also for a large amount of from now on preparation compound (S)-3-methyl enanthic acids provides an other route.
Summary of the invention
The purpose of this invention is to provide one type of (R)-2-methyl-5,5-phenylbenzene-4-amylene-1-ol derivatives, their general structure is:
Figure G2009100505984D00022
Wherein, R=H, TMS, TES, TBS, TBDPS, Bn.
Wherein, TMS is trimethyl silicon based, and TES is that triethyl is silica-based, and TBS is that tertiary butyl dimethyl-is silica-based, and TBDPS is that tert-butyl diphenyl is silica-based, and Bn is a benzyl.
(R)-2-methyl-5 of the present invention, 5-phenylbenzene-4-amylene-1-ol derivatives is through step 1), step 1)～2), step 1)～3) or step 1)～4) synthetic;
The concrete operations step is following:
Figure G2009100505984D00023
Wherein, the R definition as stated.
1) in non-protonic solvent and under the auxiliary catalysis, compound 2 reacted 1～50 hour to reflux temperature at 0 ℃ with hydroxyl protection reagent, obtained the protected compound 3 of hydroxyl; Compound 2 is 1: 1～5: 1～5 with the mol ratio of hydroxyl protection reagent and auxiliary reagent; Described hydroxyl protection reagent is trimethyl silicon based chlorine (TMSCl), the silica-based chlorine of triethyl (TESCl), the silica-based chlorine of tertiary butyl dimethyl-(TBSCl), the silica-based chlorine of tert-butyl diphenyl (TBDPSCl), benzyl chloride (BnBr); Described auxiliary is imidazoles, sodium hydride;
2) in non-protonic solvent, compound 3 reacted 1～20 hour under room temperature to reflux temperature with phenyl grignard reagent, obtained compound 4; Compound 3 is 1: 2～10 with the phenyl grignard reagent mol ratio; Described phenyl grignard reagent is benzene bromine and the formed Grignard reagent of magnesium chips;
3) in non-protonic solvent, compound 4 reacted 1～20 hour to reflux temperature at 0 ℃ with dehydrated reagent, obtained compound 1; Compound 4 is 1: 0.2～5 with the mol ratio of dehydrated reagent; Described dehydrated reagent is trimethylchlorosilane, p-methyl benzenesulfonic acid, the silica gel of living;
4) in methyl alcohol, non-protonic solvent, compound 1 removes reagent with the protection base and under room temperature to reflux temperature, reacted 1～24 hour, obtains compound 5; Compound 1 is 1: 1～15 with the mol ratio that the protection base removes reagent; It is tetrabutyl fluoride amine (TBAF), hydrogen that described protection base removes reagent;
Non-protonic solvent described in the above-mentioned reaction is methylene dichloride, chloroform, ETHYLE ACETATE, THF (THF), nitrogen N (DMF);
The practical implementation method
To help to understand the present invention through following practical implementation method, but not limit content of the present invention.
The method of starting compound 2 reference literatures of the present invention synthetic (Chinese patent, CN200410093257.2).
Embodiment 1 compound 3a's is synthetic
Figure G2009100505984D00031
In the 500mL reaction flask, (101.8g 0.696mol) is dissolved among the 100ml DMF, adds imidazoles (71.1g under the room temperature with thick product lactone polymer 2; 1.04mol), add in batches TBSCl (126.0g, 0.836mol); Stirred overnight at room temperature, TLC detects, and raw material disappears.Add water, ether, separatory, water merges organic phase with ether (100mL * 5) extraction, with saturated common salt washing twice, anhydrous Na SO 4Dry.Filter, revolve dried, underpressure distillation under the 7mmHg pressure, 95～105 ℃ of cuts are collected in 130 ℃ of oil baths, colourless liquid compound 3a, common 173.3g, productive rate 95.4%. 1HNMR(300MHz，CDCl 3)δ(ppm)：3.84(s，2H)，3.60(d，J＝5.7Hz，2H)，2.56～2.45(m，2H)，1.98～1.91(m，1H)，1.82～1.76(m，1H)，1.64～1.57(m，1H)，1.10～1.07(m，12H)，0.19(m，6H). 13CNMR(75MHz，CDCl 3)δ(ppm)：174.3，67.8，51.4，35.2，31.8，28.4，25.8，18.2，16.3，-5.5.IR(KBr，cm -1)：2957，2932，2887，2859，1745，1473，1437，1257，1173，1094，838，776，667.LR-MS(ESI)(m/z)：261.2[M+H] +，283.3[M+Na] +.LR-MS(EI)(m/z)(％)：229([M-OMe] +，18.29)，171(100.0).EA(％)：Calcd：C?59.95，H10.84；Found：C?60.25，H?11.06.
Embodiment 2 compound 3b's is synthetic
Figure G2009100505984D00041
In the 500mL reaction flask, (146g 1mol) is dissolved among the 150ml DMF, and (36g, 1.5mol), add BnBr (256.5g, 1.5mol), ice bath stirred 5 hours, TLC detection, raw material disappearance in batches to add NaH under the room temperature with thick product lactone polymer 2.Add water, ether, separatory, water merges organic phase with ether (100mL * 5) extraction, with saturated common salt washing twice, anhydrous Na SO 4Dry.Filter, revolve dried, underpressure distillation, colourless liquid compound 3b, 220g altogether, productive rate 93.2%.
Embodiment 3 compound 4a's is synthetic
Figure G2009100505984D00042
Anhydrous and oxygen-free is handled the 500mL three-necked bottle, under argon shield, the adding magnesium chips (9.724g, 0.4mol); One granule iodine adds 100mL THF, and slow dropping phenyl-bromide under the room temperature (41.87mL, 0.4mol); Drip the back and stir half a hour, magnesium sheet disappears, and solution is brown, drips compound 3a (26.045g under the room temperature; 0.1mol) 100mLTHF solution, stirred overnight under the room temperature, TLC detects, raw material disappears.Add the dilution of 100mL ether in the reaction system, add saturated NH 4Organic phase is told in Cl solution cancellation reaction, and water merges organic phase, saturated common salt water washing, anhydrous Na with ether (50mL * 3) extraction 2SO 4Drying, decompression is revolved dried, the silica gel column chromatography rapid column chromatography, V (sherwood oil)/V (ETHYLE ACETATE)=100/1 wash-out gets colourless oil liquid 4a 39.334g altogether, productive rate＞99%.[α] D 27＝+2.63(c?0.60，CHCl 3). 1HNMR(300MHz，CDCl 3)δ(ppm)：7.49～7.24(m，10H)，3.47(d，J＝6.0Hz，2H)，2.45～2.32(m，3H)，1.73～1.66(m，1H)，1.53～1.45(m，1H)，0.95～0.93(m，12H)，0.08(s，6H). 13CNMR(75MHz，CDCl 3)δ(ppm)：147.2，147.0，128.0，126.6，126.0，125.9，78.2，68.1，39.2，36.0，27.2，25.9，18.3，16.8，-5.4.IR(KBr，cm -1)：3089，3061，3026，2956，2930，2858，1711，1472，1448，1255，1092，837，775，700.LR-MS(ESI)(m/z)：407.3[M+Na] +.HR-MS(ESI)(m/z)：Calcd：407.2377[M+Na] +；Found：407.2377[M+Na] +.
Embodiment 4 compound 1a's is synthetic
Figure G2009100505984D00051
In the 50mL reaction flask, add compound 4a (0.384g 1.0mmol), adds the 20mL methylene dichloride, drip under the room temperature TMSCl (0.07mL, 0.5mmol), stirred overnight at room temperature, TLC detects, raw material disappears.Decompression is revolved dried, adds saturated sodium bicarbonate solution, tells organic phase, and water merges organic phase, anhydrous Na with methylene dichloride (20mL * 3) extraction 2SO 4Drying, decompression is revolved dried, the silica gel column chromatography rapid column chromatography, the sherwood oil wash-out gets colourless oil liquid 1a 0.371g altogether, productive rate＞99%.[α] D 27＝+8.42(c?0.71，CHCl 3). 1HNMR(300MHz，CDCl 3)δ(ppm)：7.58～7.36(m，10H)，6.32(t，J＝7.8Hz，1H)，3.67～3.54(m，2H)，2.48～2.41(m，1H)，2.17～2.07(m，1H)，2.00～1.95(m，1H)，1.10～1.04(m，12H)，0.21(s，6H). 13CNMR(75MHz，CDCl 3)δ(ppm)：142.9，142.2，140.2，130.0，128.6，128.1，128.0，127.2，126.8，68.0，36.8，33.3，25.9，18.3，16.7，-5.4.IR(KBr，cm -1)：3357，3081，3058，3025，2957，2929，1599，1494，1471，1445，1257，836，772，759，700.LR-MS(EI)(m/z)：205，309.
Synthesizing of embodiment 5 compounds 5
Figure G2009100505984D00052
In the 250mL reaction flask, adding compound 1a (16g 43.6mmol), adds the 150mL THF, and adding tetrabutyl ammonium fluoride TBAF under the room temperature (27.5g, 87.3mmol), stirred overnight at room temperature, TLC detects, and raw material disappears.Decompression is revolved dried, adds entry and ether, tells organic phase, and water merges organic phase, anhydrous Na with ether (50mL * 3) extraction 2SO 4Drying, decompression is revolved dried, the silica gel column chromatography rapid column chromatography, V (sherwood oil)/V (ETHYLE ACETATE)=3: 1 wash-outs gets colourless oil liquid 5 10.6g altogether, productive rate 96.2%.[α] D 27＝+8.35(c?2.17，CHCl 3). 1HNMR(300MHz，CDCl 3)δ(ppm)：7.39～7.15(m，10H)，6.11(t，J＝7.5Hz，1H)，3.49～3.36(m，2H)，2.25～2.18(m，1H)，2.05～1.97(m，1H)，1.82～1.78(m，1H)，1.55(s，1H)，0.92(d，3H). 13CNMR(75MHz，CDCl 3)δ(ppm)：142.7，142.6，140.1，129.9，128.2，128.1，127.8，127.1，126.9，126.8，67.8，36.7，33.2，16.6.IR(KBr，cm -1)：3341，3081，3057，3024，2957，2930，2874，1598，1494，1445，1032，771，759，701.LR-MS(EI)(m/z)：252.
Embodiment 6 compound 4b's is synthetic
Figure G2009100505984D00061
Anhydrous and oxygen-free is handled the 500mL three-necked bottle, under argon shield, the adding magnesium chips (9.724g, 0.4mol); One granule iodine adds 100mL THF, and slow dropping phenyl-bromide under the room temperature (41.87mL, 0.4mol); Drip the back and stir half a hour, magnesium sheet disappears, and solution is brown, drips compound 3b (23.6g under the room temperature; 0.1mol) 100mL THF solution, 50 ℃ of following stirred overnight, TLC detects, raw material disappears.Add the dilution of 100mL ether in the reaction system, add saturated NH 4Organic phase is told in Cl solution cancellation reaction, and water merges organic phase, saturated common salt water washing, anhydrous Na with ether (50mL * 3) extraction 2SO 4Drying, decompression is revolved dried, and the silica gel column chromatography rapid column chromatography gets colourless oil liquid 4b 34.2g altogether, productive rate 95%.
Embodiment 7 compound 1b's is synthetic
Figure G2009100505984D00062
In the 50mL reaction flask, add compound 4b (0.36g 1.0mmol), adds the 20mL methylene dichloride, drip under the room temperature TMSCl (0.112mL, 0.8mmol), stirred overnight at room temperature, TLC detects, raw material disappears.Decompression is revolved dried, adds saturated sodium bicarbonate solution, tells organic phase, and water merges organic phase, anhydrous Na with methylene dichloride (20mL * 3) extraction 2SO 4Drying, decompression is revolved dried, the silica gel column chromatography rapid column chromatography, the sherwood oil wash-out gets colourless oil liquid 1b 0.325g altogether, productive rate 95%.
Synthesizing of embodiment 8 compounds 6
Figure G2009100505984D00071
With compound 5 (5.06g 20mmol) is dissolved in the 50ml methylene dichloride, add Anhydrous potassium carbonate (4.14g, 30mmol, 1.5eq); In the ice-water bath, add again triphenylphosphine (7.86g, 30mmol, 1.5eq); (1.1eq), the 1h reaction finishes gradation adding carbon tetrabromide for 7.28g, 22mmol then.Remove by filter inorganic salt, revolve most of solvent, add sherwood oil 50ml, the solid that filtering produces revolves driedly, adds sherwood oil again, 3-5 time repeatedly, obtains bromination product 5.99g through column chromatography for separation then, productive rate 95%.
Get the 50mL bottle, (0.632g is 26mmol) in wherein to take by weighing MAGNESIUM METAL 99; Argon shield adds the new THF that steams of 20mL down, and reflux conditions drips down and contains positive propyl bromo (2.2mL, 24mmol then; 2.4eq.) the new tetrahydrofuran solution that steams of 20mL, dropwise continued and stir 1h;
Get one of the there-necked flask of 250mL, vacuumize applying argon gas three times, in argon shield downhill reaction bottle, add anhydrous tetrahydro furan 25ml, bromo cpd (3.15g, 10mmol, 1eq.), N-N-methyl-2-2-pyrrolidone N-(NMP) (3.6ml, 20.9mmol, 4eq.), and Li 2CuCl 4THF solution (0.6mL, 1.5mol/L, 1mmol).Add the Grignard reagent of n-propyl bromination magnesium in the constant voltage dropping liquid dropping funnel, slowly splash into system under the room temperature, dropwise the back normal-temperature reaction after about 4 hours; In reaction solution, add saturated ammonium chloride solution quencher reaction, filter the back separatory, water is with extracted with diethyl ether 3 times; Merge organic phase, saturated common salt is washed once, the anhydrous sodium sulfate drying after-filtration; Decompression is revolved and is desolvated, and column chromatography for separation obtains compound 62.53g, productive rate 91%.

Claims (3)

1. one type of (R)-2-methyl-5,5-phenylbenzene-4-amylene-1-ol and verivate thereof is characterized in that having following structure:
Figure FSB00000595840800011
Wherein, R=H, TBS, Bn;
Wherein, TBS is that tertiary butyl dimethyl-is silica-based, and Bn is a benzyl.
2. (R)-2-methyl-5 as claimed in claim 1, the compound method of 5-phenylbenzene-4-amylene-1-ol and verivate thereof is characterized in that through step 1)～3) or step 1)～4) synthetic:
The concrete operations step is following:
Figure FSB00000595840800012
Wherein, the R definition as stated;
1) in non-protonic solvent and under the auxiliary catalysis, compound 2 reacted 1～50 hour to reflux temperature at 0 ℃ with hydroxyl protection reagent, obtained the protected compound 3 of hydroxyl; Compound 2 is 1: 1～5: 1～5 with the mol ratio of hydroxyl protection reagent and auxiliary reagent; Described hydroxyl protection reagent is silica-based chlorine of tertiary butyl dimethyl-or benzyl chloride; Described auxiliary is imidazoles or sodium hydride;
2) in non-protonic solvent, compound 3 reacted 1～20 hour under room temperature to reflux temperature with phenyl grignard reagent, obtained compound 4; Compound 3 is 1: 2～10 with the phenyl grignard reagent mol ratio; Described phenyl grignard reagent is benzene bromine and the formed Grignard reagent of magnesium chips;
3) in non-protonic solvent, compound 4 reacted 1～20 hour to reflux temperature at 0 ℃ with dehydrated reagent, obtained compound 1; Compound 4 is 1: 0.2～5 with the mol ratio of dehydrated reagent; Described dehydrated reagent is trimethylchlorosilane, p-methyl benzenesulfonic acid, the silica gel of living;
4) in methyl alcohol, non-protonic solvent, compound 1 removes reagent with the protection base and under room temperature～reflux temperature, reacted 1～24 hour, obtains compound 5; Compound 1 is 1: 1～15 with the mol ratio that the protection base removes reagent; It is tetrabutyl fluoride amine, hydrogen that described protection base removes reagent.
3. (R)-2-methyl-5 as claimed in claim 2, the compound method of 5-phenylbenzene-4-amylene-1-ol and verivate thereof is characterized in that described non-protonic solvent is methylene dichloride, chloroform, ETHYLE ACETATE, THF, nitrogen N.
CN2009100505984A 2009-05-05 2009-05-05 (R)-2-methyl-5,5-diphenyl-4-amylene-1-ol derivatives Expired - Fee Related CN101544540B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1358203A (en) * 1972-01-07 1974-07-03 Beecham Group Ltd Derivatives of diphenyl alkanols
CN1660741A (en) * 2004-12-21 2005-08-31 中国科学院上海有机化学研究所 2-ramification of methyl alkyl diol in optical purity
CN101274891A (en) * 2008-05-16 2008-10-01 中国科学院上海有机化学研究所 S-4- methyloctane derivate, synthetic method thereof and application thereof to (S)-3-methyl-heptanoate sythesis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1358203A (en) * 1972-01-07 1974-07-03 Beecham Group Ltd Derivatives of diphenyl alkanols
CN1660741A (en) * 2004-12-21 2005-08-31 中国科学院上海有机化学研究所 2-ramification of methyl alkyl diol in optical purity
CN101274891A (en) * 2008-05-16 2008-10-01 中国科学院上海有机化学研究所 S-4- methyloctane derivate, synthetic method thereof and application thereof to (S)-3-methyl-heptanoate sythesis

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