CN108440460B - Preparation method of perillene and analogues thereof - Google Patents
Preparation method of perillene and analogues thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/36—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of perillene and analogues thereof. The preparation method takes the compound of the formula III and the compound of the formula IV as raw materials, and Li2CuCl4And a solvent to generate intermolecular reaction to obtain a compound shown in a formula I; the preparation method solves the problem of low yield of the synthesized perillene in the existing preparation method, can realize large-scale production, and has important significance for exerting the wide medical research value and synthesizing other compounds as reaction substrates.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of perillene and analogues thereof.
Background
Perillane (Perillene) is a structurally typical 3-substituted furan-type terpene compound, and was first isolated in 1919 by Japanese scientist Konda, H.et al (Kondo, H.; Yamaguchi, S.J.Pharm.Soc.Japan.1919,446,263-275) from Perilla plant Perillariodora Makino, and subsequently isolated in vivo from Lasius (Dendrolasus) fuliginosus Latr. ant (Bernardi, R.; Cardani, C.; Ghiringhelli, D.; et al.; Tetrahedron Lett.1967,8,3893-3896) and various plant sites.
So far, there are few reports in the literature concerning the pharmacological activity and application of perillene, which was found by Howse, p.e. to be an pheromone for certain ant species (Longhurst, c.; Baker, r.; Howse, p.e. experientia 1979,35,870-872) and other insects (Moiseenkov, a.m.; Lebedeva, k.v.; Czeskis, b.a. usepekhi Khimii1984,53,1709). The taiji group Chongqing Fuling pharmaceutical factory in 2009 studied and applied for related patents, and a patent with application number 200910104602.0 discloses the use of perillene in preparing anti-inflammatory drugs, wherein the patent discloses that perillene has a remarkable inhibitory effect on inflammation caused by mouse otobasil oil as an anti-inflammatory active ingredient. The patent with the application number of 200910104601.6 discloses the application and the composition of perillene in preparing the medicine for promoting the peristalsis of the intestine, and the medicine composition with the function of promoting the peristalsis of the shoulder comprises the following components in the weight ratio of 3-5: 5-3 of perillene and perillaldehyde. The application number 200910104603.5 discloses the use of perillene in preparing antibacterial drugs, and experiments show that perillene has significant inhibitory effect on staphylococcus aureus and escherichia coli. In 2015, the content of perillene in perilla leaf oil is not less than 20% as one of main components in the oral liquid for strengthening vital qi of wrinkled gianthyssop according to the stipulations in pharmacopoeia of the people's republic of China.
As a volatile oil component widely existing in animals and plants, perillene is low in content and boiling point, and extraction operation is not easy, and chemical synthesis is an important way to effectively obtain perillene. Since the first realization of the chemical synthesis of perillene by Thomas, a.f. et al in the sixties of the last century (j. chem.soc., chem.commun.1968,1657-1659), systematic research literature on the chemical synthesis method thereof has not been abundant. These synthetic methods can be divided into two categories: the first is to synthesize the perillene from the precursor of furan derivative, and the other is to synthesize the perillene by constructing furan ring from the functionalized precursor. In the first method, the synthesis of a C10 structure based on perillene is generally carried out by the block method of C4+ C6 (Tetrahedron 1990,46,1199-1210), the block method of C5+ C5 (J. chem. Soc., chem. Commun.1968, 1657-1659; J. org. chem.1979,44, 2807-2808; Tetrahedron Lett.1982,23, 3115-3118; J. org. chem.1983,48, 1106-1107; J. org. chem.1983,48, 4572-4580; Russ. chem. Bull.1989,38,131-134) or the block method of C7+ C3 (Liebigs Ann. 1849-1853); in the second method, the furan ring is usually constructed by a tandem rearrangement reaction of a conjugated ketene thioaldehyde (J.chem.Soc., chem.Commun.1982, 1055-1056; J.Org.chem.1984,49, 3819-plus 3824) or a conjugated ketene thioether (J.Am.Soc.chem.1973,95, 250-plus 252) with a thioylide, a 1, 3-conjugated diene with a singlet O2The photocyclization reaction (Tetrahedron Lett.1976,17,391-394), intramolecular esterification re-reduction (Synth. Commun.1976,6, 331-337; Tetrahedron Lett.1977,18, 2869-2872; Liebigs Ann.1986,226-233), intramolecular acetalization re-dehydration (biosci.Biotech.biochem.1992,56,1888-1889), intramolecular free radical cyclization (chem.Lett.1988,371-372), oxidative recyclization of dienol ester anions (Heterocycles 1978,10,87-91.), or reductive cyclization reaction of trichloroethylpropynyl ether (org.Lett.2002,4, 1387-1389). Compared with the complexity of the furan ring synthesis process, the synthesis method for developing the perillene based on the furan structure has the characteristics of simplicity, high efficiency and easily obtained raw materials. Nevertheless, the side chain of perillene C6 has been constructedThe method has the defects of low yield, complex process, low selectivity and the like.
Therefore, in view of the abundant pharmacological activity and important application of perillene in medicines, the development of a convenient and efficient chemical synthesis method for the compound has important commercial value.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing perillene and its analogues. The preparation method solves the problem of low yield of the synthesized perillene in the existing preparation method, and has important significance for exerting the wide medical research value and synthesizing other compounds as reaction substrates.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for preparing perillene and its analog I from the compound of formula III and the compound of formula IV2CuCl4And a solvent to generate intermolecular reaction to obtain a compound shown in a formula I;
the reaction formula is as follows:
in the formula I, R1And R2Each independently selected from: h, C1-C10 alkyl, C2-C15 alkenyl, substituted or unsubstituted phenyl; the substituent group is selected from OR4，R4Selected from: h or C1-C6 alkyl; r3Selected from: C1-C6 alkyl and benzyl.
Preferably, R1And R2Each independently selected from: h, one of C1-C6 alkyl, 4-methylpent-3-enyl, 4, 8-dimethylnon-3, 7-dienyl or phenyl; r3Selected from: methyl or benzyl.
Further, compounds of formula IV with Li2CuCl4Reacting in a solvent at 0 ℃ for 0.5-1.2 h, and then reacting with a compound shown in a formula III to obtain the compound shown in the formula I.
Further, compounds of formula IV with Li2CuCl4In a molar ratio of 1: 0.06 to 0.12.
Preferably, the compound of formula IV is reacted with Li2CuCl4In a molar ratio of 1: 0.1.
preferably, the compound of formula III is prepared by reacting a compound of formula II with magnesium turnings in THF.
Specifically, the preparation method comprises the following steps:
1) preparing a reaction solution containing a compound shown in a formula III by taking a compound shown in a formula II and magnesium chips as raw materials in the presence of a solvent;
2) li in the reaction liquid obtained in the step 1) of the compound shown in the formula III and the compound shown in the formula IV2CuCl4And carrying out intermolecular reaction in the presence of the catalyst to obtain the compound shown in the formula I.
Further, the preparation method of the compound of formula III in the step 1) comprises the following steps: the compound of the formula II and magnesium chips react in the presence of elemental iodine, 1, 2-dibromoethane and a solvent to generate a reaction solution containing the compound of the formula III.
Further, the molar ratio of the compound of formula II to the compound of formula IV is 1: 0.65 to 0.85.
Preferably, the molar ratio of the compound of formula II to the compound of formula IV is 1: 0.65 to 0.75.
Further, the solvent is THF.
The factor affecting the yield of perillene is mainly the presence of self-coupling side reaction of Grignard reagent, and the applicant has studied the solvent and reaction system temperature in the preparation of Grignard reagent, in which Et is included in the solvent2O, DME and THF as reaction solvent. Et for try2The boiling point of the ether as the solvent of the reaction system is about 35 ℃, so that the temperature of the reaction system is controlled below 35 ℃, thereby avoiding the generation of the coupling side reaction of the chloride caused by overhigh temperature, but unfortunately, the reaction does not occur when the ether is used as the solvent; DME was attempted to be used as the solvent for the reaction system because it has a boiling point close to that of THF and is ethereal in natureAgents, which may hinder the coupling side reactions of the chloro-compound itself, unfortunately with DME as reaction solvent, the Grignard reagent is not successfully prepared; THF was used as a reaction solvent to successfully produce the Grignard reagent, and therefore, THF was finally used as a reaction solvent.
Further, the reaction temperature in the step 1) is 30-35 ℃.
Preferably, the reaction temperature is 30 ℃.
In the experimental process, the reaction yield is influenced to a certain extent by the difference of the temperature of the reaction system in the process of preparing the Grignard reagent, so that the change of the reaction yield is observed by trying different reaction temperatures. In the experimental process, the reaction yield is reduced when the reaction temperature is higher than 35 ℃, the temperature is lower than 25 ℃, the Grignard reaction is not sufficiently initiated, so the yield is 0, when the reaction temperature is controlled to be about 30 ℃, the Grignard reaction can be initiated, the self-coupling side reaction of the chloro-compound can be controlled, and the reaction yield is improved. Therefore, the temperature of the Grignard reaction is finally controlled to about 30 ℃.
Further, the method also comprises the step 3): step 2) after the reaction is completed, adding saturated NH4Cl solution quenching reaction, Et2And (3) extracting, combining organic phases, washing, filtering, removing the solvent and purifying to obtain the compound shown in the formula I.
As a preference, step 3) is: TLC detects the complete reaction of the raw materials, and saturated NH is added4Cl solution quenching reaction, Et2O extraction (65 mL. times.3), combining the organic phases, washing with brine, anhydrous Na2SO4Drying, filtering, distilling under reduced pressure to remove solvent, and purifying by silica gel column chromatography (eluting with pure petroleum ether) to obtain the compound shown in formula I.
The invention has the beneficial effects that:
1) the invention provides a preparation method of perillene and analogues thereof, which solves the problem of low yield of the perillene synthesized by the existing preparation method, can realize large-scale production, and has important significance for exerting the wide medical research value of the perillene and synthesizing other compounds as reaction substrates.
2) The preparation method of the invention provides a key point for remarkably improving the yield of the perillene and the analogues thereof, and creative labor shows that the compound shown in the formula IV is selected as a raw material, the compound shown in the formula IV is electron donating group substituted carbonate, and the yield of the compound shown in the formula IV is remarkably higher than that of other esters.
3) The preparation method of the invention also solves the problem of self-coupling side reaction of the Grignard reagent, THF can be used as a reaction solvent to successfully prepare the Grignard reagent, the reaction temperature is also given, the Grignard reaction can be initiated, the self-coupling side reaction of the chloro-compound can be controlled, and the reaction yield is improved.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
The compounds of formula II can be prepared using known products or by literature published in the prior art, for example by a two-step reaction starting from 3-furancarboxylic acid according to the literature methods (Costas, T.; Costas-Lago, M.C.; Vila, N.; et al., Eur.J.Med.Chem.2015,94,113. 122; Pevzner, L.M.Russ.J.Gen.Chem.2006,76,1299. 1303).
The compounds of formula IV can be prepared in large amounts by reference to the following literature methods: behloul, c.; guijarro.d.; yus, M.tetrahedron 2005,61, 9319-; corey, e.j.; zhang, J.org.Lett.2001,3, 3211-3214.
Example 1
A compound having the structure of formula Ia is prepared by the following reaction scheme:
mg scraps (5.80g,240mmol,2.0equiv.) and one iodine particle are added into a reaction bottle with a thermometer, after nitrogen gas is replaced, dried tetrahydrofuran (20mL) and a few drops of 1, 2-dibromoethane are added, a dried THF solution (20mL) of chloro compound (14.0g,120mmol,1.0equiv.) shown in the formula II is dropwise added into the reaction system under stirring, the dropwise adding speed is controlled to ensure that the temperature of the reaction system is 30 ℃, and after the addition is finished, the reaction is carried out at room temperature for 2h to obtain a Grignard reagent solution shown in the formula III.
Preparing carbonate ester:
the method comprises the following operation steps: dissolving prenol and Pyr in DCM, dropwise adding a DCM solution of benzyl chloroformate into the reaction system at 0 ℃, recovering the room temperature and stirring to obtain the compound shown in the formula IVa after the addition is finished.
An allyl alcohol compound represented by the formula IVa (18.5g,84.0mmol,0.7equiv.) and Li at 0 deg.C2CuCl4(0.1M,84mL,8.40mmol,0.07equiv.) in dry THF solution (40mL) was stirred for reaction for 1h, then the Grignard reagent prepared above was added dropwise rapidly, and after addition, the reaction was continued at 0 ℃ for 1h and returned to room temperature overnight. TLC detects the complete reaction of the raw materials, and saturated NH is added4Cl solution quenching reaction, Et2O extraction (65 mL. times.3), combining the organic phases, washing with brine, anhydrous Na2SO4Drying, filtering, distilling under reduced pressure to remove solvent, and purifying by silica gel column chromatography (eluting with pure petroleum ether) to obtain 10.1g of compound with structure shown in formula Ia with yield of 80.0%.
A compound Ia: a colorless oily liquid;1H NMR(400MHz,CDCl3,TMS)δ1.60(s,3H),1.70(s,3H),2.25(q,2H,J＝8.0Hz),2.45(t,2H,J＝8.0Hz),5.16(t,1H,J＝8.0Hz),6.28(s,1H),7.22(s,1H),7.24(s,1H)ppm；13C NMR(100MHz,CDCl3,TMS)δ17.8,25.0,25.7,28.5,111.0,123.8,124.9,132.1,138.8,142.5ppm
example 2
A compound having the structure of formula Ib is prepared by the following reaction scheme:
adding Mg scraps (418Mg,17.2mmol,2.0equiv.) and one iodine particle into a reaction bottle with a thermometer, replacing nitrogen, adding dry tetrahydrofuran (6mL) and a few drops of 1, 2-dibromoethane, dropwise adding a dry THF solution (8.6mL) of chloride (1.00g,8.60mmol,1.0equiv.) shown in the formula II into the reaction system under stirring, controlling the dropwise adding speed to ensure that the temperature of the reaction system is about 30 ℃, and reacting for 2 hours at room temperature after the dropwise adding to obtain a Grignard reagent solution shown in the formula III.
Preparing carbonate ester: dissolving (E) -3, 5-dimethylhexane-2, 4-diene-1-ol and Pyr in DCM, dropwise adding a methyl chloroformate DCM solution into the reaction system at 0 ℃, and after the addition is finished, recovering the room temperature and stirring to obtain the compound shown in the formula IVb.
An allyl alcohol compound represented by the formula IVb (1.30g,6.0mmol,0.7equiv.) and Li at 0 deg.C2CuCl4(0.1M,6.0mL,0.6mmol,0.07equiv.) in dry THF solution (6mL) was stirred for reaction for 1h, then the Grignard reagent prepared above was added dropwise rapidly, and after the addition was completed, the reaction was continued at 0 ℃ for 1h, and the reaction was returned to room temperature overnight. TLC detects the complete reaction of the raw materials, and saturated NH is added4Cl solution quenching reaction, Et2O extraction (20mL x 3), combining the organic phases, washing with saturated brine, anhydrous Na2SO4Drying, filtering, distilling under reduced pressure to remove solvent, and purifying by silica gel column chromatography (eluting with pure petroleum ether) to obtain 1.00g of compound with structure shown in formula Ib, with yield of 74.0%.
A compound Ib: a colorless oily liquid;1H NMR(400MHz,CDCl3,TMS)δ1.61(s,3H),1.62(s,3H),1.71(s,3H),2.01(t,2H,J＝8.0Hz),2.09(t,2H,J＝8.0Hz),2.28(q,2H,J＝6.0Hz),2.47(t,2H,J＝8.0Hz),5.11(t,1H,J＝8.0Hz),5.19(t,1H,J＝8.0Hz),6.29(s,1H),7.23(s,1H),7.35(s,1H)ppm；13C NMR(100MHz,CDCl3,TMS)δ6.0,17.7,25.0,25.7,26.7,28.5,39.7,111.1,123.8,124.3,125.0,131.3,135.7,138.8,142.5ppm
EXAMPLE 3 Effect of esters of different substituents on yield
The compounds of formula i were prepared in different esters according to the preparation method of example 1 or example 2, and the yields were calculated as shown in table 1:
TABLE 1
1：1HNMR(400MHz,CDCl3)δ1.76(s,3H),1.80(s,3H),4.83(d,2H,J＝8.0Hz),5.39(t,1H,J＝8.0Hz)ppm
2：1HNMR(400MHz,CDCl3)δ1.77(s,3H),1.79(s,3H),4.87(d,2H,J＝8.0Hz),5.46(t,1H,J＝8.0Hz),8.19(d,2H,J＝8.0Hz),8.25(d,2H,J＝8.0Hz)ppm
3：1HNMR(400MHz,CDCl3)δ1.72(s,3H),1.77(s,3H),4.65(d,2H,J＝8.0Hz),5.16(s,2H),5.39(t,1H,J＝8.0Hz),7.35(m,5H)ppm
4：1HNMR(400MHz,CDCl3)δ4.85(d,2H,J＝8.0Hz),5.20(s,2H),6.45(m,1H),6.73(d,1H,J＝16.0Hz),7.38(m,5H),7.50(d,2H,J＝8.0Hz),8.18(d,2H,J＝12.0Hz)ppm
5：1HNMR(400MHz,CDCl3)δ1.60(s,6H),1.68(s,3H),1.97(m,4H),2.17(m,7H),3.68(s,3H),5.10(m,2H),5.67(s,1H)ppm
6：1HNMR(400MHz,CDCl3)δ1.60(s,6H),1.68(s,3H),1.72(s,3H),2.05(m,8H),3.77(s,3H),4.65(d,2H,J＝4.0Hz),5.09(t,2H,J＝4.0Hz),5.38(t,1H,J＝4.0Hz)ppm
7：1HNMR(400MHz,CDCl3)δ1.61(s,3H),1.69(s,3H),1.72(s,3H),2.07(m,4H),4.68(d,2H,J＝8.0Hz),5.08(t,1H,J＝8.0Hz),5.17(s,2H),5.39(t,1H,J＝4.0Hz),7.37(m,5H)ppm
8：1HNMR(400MHz,CDCl3)δ1.59(s,3H),1.68(s,3H),1.71(s,3H),2.05(m,4H),3.77(s,3H),4.65(d,2H,J＝8.0Hz),5.07(t,1H,J＝4.0Hz),5.37(t,1H,J＝8.0Hz)ppm
9：1HNMR(400MHz,CDCl3)δ1.24(t,1H,J＝4.0Hz),1.59(s,6H),1.67(s,3H),1.71(s,3H),1.97(m,2H),2.08(m,4H),4.11(q,1H,J＝8.0Hz),4.66(d,2H,J＝8.0Hz),5.09(t,2H,J＝8.0Hz),5.14(s,2H),5.38(t,1H,J＝8.0Hz),7.35(m,4H)ppm
The results show that the yield of carbonate is significantly higher than that of other esters, the yield of ester with electron withdrawing group is very low or even 0, and the yield of ester with electron donating group is higher. Therefore, the selection of carbonate as a reaction substrate is a key factor for improving the yield of the perillene, and the yield of the carbonate with the compound of formula IV as an electron donating group substituent is obviously higher than that of other esters.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (8)
1. The preparation method of the perillene compound I is characterized in that a compound shown in a formula III and a compound shown in a formula IV are used as raw materials, and Li is added2CuCl4And a solvent to generate intermolecular reaction to obtain a compound shown in a formula I;
the reaction formula is as follows:
wherein R is1And R2Each of which isIndependently selected from: h, C1-C10 alkyl, C2-C15 alkenyl, substituted or unsubstituted phenyl;
R3selected from: C1-C6 alkyl and benzyl.
2. The method of claim 1, wherein the compound of formula IV is reacted with Li2CuCl4Reacting in a solvent at 0 ℃ for 0.5-1.2 h, and then reacting with a compound shown in a formula III to obtain the compound shown in the formula I.
3. The method of claim 1, wherein the compound of formula IV is reacted with Li2CuCl4In a molar ratio of 1: 0.06 to 0.12.
4. The method of claim 1, comprising the steps of:
1) preparing a reaction solution containing a compound shown in a formula III by taking a compound shown in a formula II and magnesium chips as raw materials in the presence of a solvent;
2) li in the reaction liquid obtained in the step 1) of the compound shown in the formula III and the compound shown in the formula IV2CuCl4Carrying out intermolecular reaction in the presence of the compound to obtain a compound shown as a formula I;
the compound of formula II is shown below:
the solvent is THF; the reaction temperature in the step 1) is 30-35 ℃.
5. The method according to claim 4, wherein the reaction temperature in the step 1) is 30 to 35 ℃.
6. The method according to claim 4, wherein the compound of formula III in step 1) is prepared by: the compound of the formula II and magnesium chips react in the presence of elemental iodine, 1, 2-dibromoethane and a solvent to generate a reaction solution containing the compound of the formula III.
7. The process of claim 4, wherein the molar ratio of the compound of formula II to the compound of formula IV is 1: 0.65 to 0.85.
8. The method according to claim 4, further comprising a step 3): step 2) after the reaction is completed, adding saturated NH4Cl solution quenching reaction, Et2And (3) extracting, combining organic phases, washing, filtering, removing the solvent and purifying to obtain the compound shown in the formula I.
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| Regiocontrol in Copper-Catalyzed Grignard Reactions with Allycic Substrates;Jan-E. Backvall et al.;《J. Am. Chem. Soc.》;19901231;第112卷(第18期);第6615-6621页 * |
| Synthesis of the Hypoxic Signaling Inhibitor Furospongolide;John Boukouvalas et al.;《SYNLETT》;20110927(第17期);第2541-2544页 * |
| 柳珊瑚毒素（Lophotoxin）的全合成研究;孙亚男;《重庆大学硕士学位论文》;20181218;第1-109页 * |
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