CN102146020B - Method for synthesizing 1,3-diphenyl-1-propanol compound - Google Patents

Abstract

The invention relates to a synthesis method of 1,3-diphenyl-1-propanol compounds, belonging to a compound synthesis method. Use p-substituted 1-phenylethanol and p-substituted benzyl alcohol as raw materials, wherein R and R' are hydrogen atoms, halogen atoms Cl, Br, alkyl and alkoxy groups, and the feeding ratio is 1:1~2 ; Under nitrogen, add dry catalyst, alkali, p-substituted 1-phenylethanol and p-substituted benzyl alcohol to anhydrous solvent in sequence, place the reactor in an oil bath at 125-135°C, and stir 8-24 hours; cooling, neutralizing the reaction solution, extracting with ethyl acetate, and vacuum concentrating the extract until there is no ethyl acetate odor; purifying with 100-200 mesh forward silica gel column chromatography. The invention has the advantages that the method is simple and easy, the production cost is low, the difficulty of purification and post-treatment is reduced, and the impact on the environment is weakened.

Description

A kind of synthetic method of 1,3-diphenyl-1-propanol compound

technical field

The invention belongs to a compound synthesis method, specifically refers to the cross-coupling reaction of secondary alcohols and primary alcohols. the

Background technique

1,3-diphenyl-1-propanol compounds are as follows formula A, wherein Ar ₁ and Ar ₂ are respectively substituted phenyl groups, and derivative B thereof, which are important pharmaceutical and chemical raw materials, and are used in immunosuppression (U.S. Journal of Chemical Society J.Am.Chem.SOC.1993, 115, 9925-9938), prevention and treatment of neurodegenerative diseases (WO03048142A1), anticoagulation (WO9810763A1), anti-abnormal proliferation (US20030191279), inhibition of β-secretase (US2005119329A1), antibacterial (WO2007014885A1), inhibition of HIV-1 protease (Journal of Medicinal Chemistry, 1997, Vol.40, No.23, 3707-3711) and other fields are widely used in the synthesis of drugs and intermediates. Therefore, the development of its convenient, economical and environmentally friendly synthetic methods has attracted great attention.

Studies in recent years have shown that 1,3-diphenyl-1-propanol compounds can be directly produced through a one-step reaction based on certain metal catalysis, using secondary alcohols and primary alcohols as raw materials, as shown in Reaction Formula 1. Because alcohol compounds are widely distributed, cheap and easy to obtain, and the reaction can be catalyzed, the desired product can be generated in only one step, thus stimulating the research enthusiasm of organic chemists. the

(Reaction 1)

Currently, various synthetic methods based on metal catalysis have been developed to achieve this transformation (a) C.S.Cho, B.T.Kim, H.-S.Kim, T.-J.Kim, S.C.Shim, Organometallics2003, 22 , 3608-3610; b) Shu-Yu Zhang, Yong-Qiang Tu, Chun-An Fan, Yi-Jun Jiang, Lei Shi, Ke Cao, En Zhang, Chem.Eur.J.2008, 14, 10201-10205; c) R.MartNnez, D.J.RamOn, M.Yus, Tetrahedron 2006, 62, 8982-8987; d) K.-i.Fujita, C.Asai, T.Yamaguchi, F.Hanasaka, R .Yamaguchi, Org.Lett.2005, 7, 4017-4019; e) C.S.Cho, W.X.Ren, S.C.Shim, Bull. Korean Chem.Soc.2005, 26, 1611-1613; f) Mnica Viciano, Mercedes Sana, Eduardo Peris, Organometallics 2007, 26, 6050-6054; g) Amparo Prades, Mo′nica Viciano, Mercedes Sanau′, Eduardo Peris; Organometallics 2008, 27, 4254-4259; h) Dinakar Gnanamgari, Chin Hin Leung, Nathan D. Schley, Sheena T. Hilton, Robert H. Crabtree, Organic and Biomolecular Chemistry Org. Biomol. Chem., 2008, 6, 4442-4445; i) Dinakar Gnanamgari, Effiette L.O. Sauer, Nathan D. Schley, Chase Butler, Christopher D. Incarvito, Robert H. Crabtree, Organometallics 2009, 28, 321-325; j) André Pontes da Costa, Mónica Viciano, Mercedes Sanaú, Sonia Merino, Juan Tejeda, Eduardo Peris , Beatriz Royo, Organometallics 2008, 27, 1305-1309.k) Shimizu K, Sato R, Satsuma A, Applied Chemistry International Edition Angew.Chem.Int.Ed.2009, 48(22), 3982-3986). But in spite of this, there are still following problems that limit the application of this method in the industrial production of 1,3-diphenyl-1-propanol compounds:

1) At present, this type of reaction uses ruthenium (Ru), iridium (Ir), palladium (Pd) and silver (Ag) metals as catalysts, which are expensive and increase the reaction cost;

2) Some reactions need to add hydrogen acceptors (such as 1-dodecene) to promote the reaction, which reduces the atomic efficiency of the reaction and brings great difficulties to the subsequent separation and purification of the reaction;

3) Some catalysts (such as RuCl2(DMSO)4, etc.) are not commercialized and require special preparation, which is not suitable for industrial production;

4) Most reactions need to add special ligands (such as azacarbene ligands, etc.) to enable the reaction to proceed smoothly and achieve better selectivity, and these ligands are often not suitable for obtaining, and the production cost is quite high;

5) For some reactions, it is necessary to add an excessive amount of primary alcohol to ensure better product selectivity, resulting in waste and loss of raw materials;

6) Most reactions must add stoichiometric alkali to receive better results, which not only causes great environmental problems, but also increases the cost of post-treatment due to the large amount of alkaline waste liquid produced. the

Based on the practical problems mentioned above, it is particularly important to develop a synthetic method for 1,3-diphenyl-1-propanol compounds that is easy to implement, low in cost and more suitable for industrialization. the

Contents of the invention

The present invention provides a kind of 1, the synthetic method of 3-diaryl-1-propanol compound, to solve the above-mentioned problem that existing synthetic method exists, this compound structure is as shown in (I), wherein R and R' can be Hydrogen atom, halogen atom (Cl, Br), alkyl and alkoxy. The technical scheme that the present invention takes is:

1. Using p-substituted 1-phenylethanol (II) and p-substituted benzyl alcohol (III) as raw materials, wherein R and R' are hydrogen atoms, halogen atoms Cl, Br, alkyl and alkoxy groups, The feeding ratio is 1:1~2;

2. Under nitrogen conditions, add dry catalyst, alkali, p-substituted 1-phenylethanol and p-substituted benzyl alcohol into anhydrous solvent in sequence, and place the reactor in an oil bath at 125-135°C. Stir for 8-24 hours; cool, neutralize the reaction solution, extract with ethyl acetate, and concentrate the extract in vacuum until there is no ethyl acetate smell; purify with 100-200 mesh forward silica gel column chromatography to obtain the desired product (I). the

One embodiment of the present invention is: the feeding ratio of p-substituted 1-phenylethanol and p-substituted benzyl alcohol is preferably 1:1. the

One embodiment of the present invention is: the catalyst is ferrocene, ferrocene methanol and ferrocene formaldehyde, and the loading amount of the catalyst is 1-10 mol% based on the corresponding moles of 1-phenylethanol. the

One embodiment of the present invention is: the catalyst is preferably ferrocene formaldehyde, and the loading amount of the catalyst is 5 mol% based on the corresponding moles of 1-phenylethanol. the

One embodiment of the present invention is: the base is Cs ₂ CO ₃ , NaOH and KOH, and the loading amount of the base is 10-20 mol% based on the corresponding moles of 1-phenylethanol.

One embodiment of the present invention is: the base is preferably NaOH; based on the moles of the corresponding 1-phenylethanol, preferably 20 mol%. the

One embodiment of the present invention is: the solvent is p-xylene, o-xylene and m-xylene, and the molar concentration is 1.0-2.0. the

One embodiment of the present invention is: the solvent is preferably p-xylene, and the molar concentration is preferably 1.0. the

One embodiment of the present invention is: the temperature is preferably 130°C. the

One embodiment of the present invention is: the optimal reaction time is 12 hours. the

Reaction formula of the present invention is as follows:

(反应式2) 

(Reaction 2)

In order to overcome the above problems, seek to reduce costs, simplify operations, save raw materials, reduce the difficulty of purification and post-processing, especially reduce the impact on the environment as much as possible, in order to comply with the guiding ideology of sustainable development, combined with the laboratory's research on the basis of low-cost Interested in metal-catalyzed organic synthesis and catalytic reactions, we began to explore more economical, simple and effective synthesis methods for 1,3-diphenyl-1-propanol compounds. the

To further improve the yield, we focused on the effects of counterions and different chemical valences on the catalytic activity of iron-based catalysts. In continuing research on FeSO ₄ ·7H ₂ O, FeCl ₃ ·6H ₂ O, anhydrous FeCl ₂ , FeCl ₂ ·4H ₂ O, ferrocene, ferrocenemethanol, and ferroceneformaldehyde, it was found that the The introduction can greatly increase the yield. For example, commercially available ferrocene, ferrocene methanol and ferrocene formaldehyde have better catalytic activity than simple iron salts, and ferrocene formaldehyde is the best, and the yield can reach 96%.

The advantages of the present invention are:

1) Using widely distributed, cheap and easy-to-obtain secondary alcohols and primary alcohols as raw materials, 1,3-diaryl-1-propanol compounds can be obtained in a high yield through a one-step reaction in a catalytic manner, and the method is simple and easy , low production cost;

2) Ferrocene formaldehyde is a commercial product, and compared with the catalysts used in the past, it has obvious price advantages;

3) Without adding ligands and hydrogen acceptors, the reaction can obtain a high yield of 96%, which greatly reduces production costs and reduces the difficulty of purification and post-processing;

4) Only by using a catalytic amount of alkali 10-20mol% NaOH, the reaction can be carried out smoothly, and the impact on the environment is weakened;

5) The two substrates can be reacted at a feed ratio of 1:1, saving raw materials. the

Detailed ways

Example 1

Under nitrogen, ferrocene 0.1mmol, 18.6mg, Cs ₂ CO ₃ 1.0mmol, 32.6mg, 1-phenyl-ethanol 10.0mmol, 1.22g and benzyl alcohol 15.0mmol, 1.62g were added in sequence to 6.7mL of anhydrous In m-xylene; at 125 ° C, stirred for 8h. Cool, neutralize the reaction solution with NH ₄ Cl saturated solution, extract it with ethyl acetate, and concentrate the extract in vacuo until there is no ethyl acetate odor; purify it by 100-200 mesh forward silica gel column chromatography, n-hexane: ethyl acetate Esters = 40:1 elution, the product 1,3-diphenyl-1-propanol 1.55g, 7.3mmol, yield: 73%.

Example 2

Under nitrogen, ferrocene formaldehyde 0.5mmol, 107.0mg, NaOH 2.0mmol, 80.0mg, 1-phenyl-ethanol 10.0mmol, 1.22g and 4-methoxybenzyl alcohol 10.0mmol, 1.38g were added in sequence for 10.0 mL of anhydrous p-xylene; at 130 ° C, stirred for 24h. After cooling, the reaction solution was neutralized with saturated NH ₄ Cl solution, extracted with ethyl acetate, and the extract was concentrated in vacuo until there was no ethyl acetate odor. Purified by 100-200 mesh forward silica gel column chromatography, eluting with n-hexane:ethyl acetate=30:1, the product 1-phenyl-3-(4'-methoxyphenyl)-1-propane can be obtained Alcohol 2.33g, 9.6mmol, yield: 96%.

Example 3

Under nitrogen, ferrocenemethanol 1.0mmol, 216.1mg, KOH 1.5mmol, 84.2mg, 1-(4'-methylphenyl)-ethanol 10.0mmol, 1.36g and 4-chlorobenzyl alcohol 20.0mmol, 2.85 g, successively added to 5.0 mL of anhydrous o-xylene. Stir at 135°C for 12 hours; cool down, neutralize the reaction solution with NH ₄ Cl saturated solution, extract it with ethyl acetate, and concentrate the extract in vacuo until there is no ethyl acetate smell; use a 100-200 mesh forward silica gel column Chromatographic purification, eluting with n-hexane:ethyl acetate=38:1, can obtain the product 1-(4'-methylphenyl)-3-(4'-chlorophenyl)-1-propanol 2.11g, 8.1 mmol, yield: 81%.

Claims (9)

1. a synthetic method of 3-diphenyl-1-propanol compound, is characterized in that comprising the following steps: 1. To contain p-substituted 1-phenylethanol, its structural formula is

and p-substituted benzyl alcohols, whose structural formula is

as raw materials, wherein R and R' are hydrogen atoms, halogen atoms Cl, Br, alkyl and alkoxy groups, and the feeding ratio is 1:1~2; 2. Under nitrogen conditions, add dry catalyst, alkali, p-substituted 1-phenylethanol and p-substituted benzyl alcohol into anhydrous solvent in sequence, and place the reactor in an oil bath at 125-135°C. Stirring for 8-24h, the described catalyst is ferrocene, ferrocene methanol or ferrocene formaldehyde, based on the corresponding moles of 1-phenylethanol, the catalyst loading is 1-10mol%; cooling, Neutralize the reaction solution, extract it with ethyl acetate, and concentrate the extract in vacuo until there is no ethyl acetate smell; purify it with 100-200 mesh forward silica gel column chromatography to obtain the desired product. 2. a kind of 1 according to claim 1, the synthetic method of 3-diphenyl-1-propanol compound is characterized in that: to substituted 1-phenylethanol and to substituted benzyl alcohol charging ratio is 1:1. 3. a kind of 1 according to claim 1, the synthetic method of 3-diphenyl-1-propanol compound is characterized in that: described catalyzer adopts ferrocene formaldehyde, with corresponding 1-phenyl The catalyst loading was 5 mol% based on the number of moles of ethanol. 4. a kind of 1 according to claim 1, the synthetic method of 3-diphenyl-1-propanol compound is characterized in that: alkali is Cs ₂ CO ₃ , NaOH and KOH, with corresponding 1-benzene Based on the number of moles of ethanol, the loading amount of the base is 10-20 mol%. 5. a kind of 1 according to claim 4, the synthetic method of 3-diphenyl-1-propanol compound is characterized in that: alkali adopts NaOH; In the molar number of corresponding 1-phenylethanol, The loading of NaOH was 20 mol%. 6. a kind of 1 according to claim 1, the synthetic method of 3-diphenyl-1-propanol compound is characterized in that: described solvent is p-xylene, o-xylene and m-xylene, mol The concentration is 1.0-2.0. 7. a kind of 1 according to claim 6, the synthetic method of 3-diphenyl-1-propanol compound is characterized in that: alkali adopts NaOH; In the molar number of corresponding 1-phenylethanol, The loading of NaOH was 20 mol%. 8. The synthesis method of a 1,3-diphenyl-1-propanol compound according to claim 1, characterized in that: the reactor is placed in an oil bath at 130°C. 9. The synthetic method of a kind of 1,3-diphenyl-1-propanol compound according to claim 1, characterized in that: the stirring time is 12h.