RU2458902C1 - Method of producing mirtanol - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing mirtanol which is used in synthesis of organometallic compounds and biologically active substances. The method involves conversion of β-pinene epoxide on a heterogeneous Al₂O₃ catalyst in a supercritical two-component solvent containing CO₂ and isopropyl alcohol. As a rule, the method is realised in a flow-type tubular reactor at temperature 170-190°C and pressure 180-190 atm.

EFFECT: method enables to efficiently obtain the end product with high output in a continuous mode for contact time of several minutes in a single preparative step.

3 cl, 1 ex, 4 dwg

Description

The invention relates to the field of synthesis of organic compounds, and in particular to methods for their preparation in new solvent reaction media with the participation of heterogeneous catalysts, the choice of reaction conditions, in particular the conversion of terpene compounds and their oxygen-containing derivatives.

Mirtanol of formula 1 [6,6-dimethylbicyclo [3.1.1] heptan-2-yl) methanol] (Scheme 1) is used in the synthesis of organometallic compounds and biologically active substances (G. Giacomelli, L. Lardicci, F. Palla, J. Org. Chem., 1984, 49, 310; J. Beckmann, A. Duthie, M. Grassmann, J. Organometal. Chem., 2009, 694, 161; Application US 2009104126, A61K 31/225, C07C 307/02, 04/23/2009).

Compound 1 can be synthesized by reduction of myrtenal 2 or myrtenol 3 (Scheme 1) (VNIpatieff, GJ Czajkowski, H. Pines, J. Am. Chem. Soc., 1951, 73, 4098; GWEigenmann, RTArnold, J. Am .Chem. Soc., 1959, 81, 3440), however, the practical use of this pathway is constrained by the low availability of compounds 2, 3.

Scheme 1

Typically, myrtanol 1 is obtained from β-pinene 4 (Scheme 1). The most common method involves the hydroboration of terpen 4 and further interaction with H ₂ O ₂ leading to compound 1 (WO 011472, 2004; application US 2005/131004, 06.16.2005). The disadvantage of this method is the need to use highly toxic boron hydrides, as well as the need to use absolute solvents and inert gases.

In another way, the synthesis of mirtanol 1 from β-pinene 4 can be carried out through the intermediate preparation of β-pinene 5 epoxide (Scheme 1), followed by the opening of the epoxy group in the presence of lithium diethylamide (RKHill, JWMorgan, RVShetty, M.E. Synerholm , J. Am. Chem. Soc., 1974, 96, 4201). A serious drawback of this route to the preparation of myrtanol 1 is the need to use absolute explosive solvents and conduct the reaction in an inert atmosphere.

A known method of transforming β-pinene 5 epoxide, leading to the formation of myrtanol 1, which we adopted as a prototype (VSJoshi, Sukh Dev, Tetrahedron, 1977, 33, 2955), in which the conversion of β-pinene 5 epoxide to myrtanol 1 is carried out in the presence of activated heterogeneous Al ₂ O ₃ in hexane in one preparative step (Scheme 2). Al ₂ O ₃ (100-250 mesh), activated with NaOH for 48 h, dried for 16 h at 120 ° C and then calcined for 1 h at 450 ° C in nitrogen atmosphere, the ratio of catalyst / substrate was used as a catalyst (25: 1). The reaction was carried out in hexane at room temperature for 24 hours with stirring in a nitrogen atmosphere. The products were washed off the catalyst with a mixture of methanol / diethyl ether (800 ml per 1 g of epoxide), the content of myrtanol 1 was 48%. Individual products were isolated using preparative GLC.

Compound 1, at least in part, is a disproportionation product in the presence of Al ₂ O _{3 of the} intermediate formed aldehyde 6 to alcohol 1 and the corresponding acid 7 (Cannizzaro reaction).

Scheme

Significant disadvantages of the known method for producing myrtanol 1, when carrying out chemical transformations of β-pinene 5 epoxide, include the following: moderate yield of alcohol 1, due to the fact that part of the intermediate formed aldehyde 6 is spent on the formation of acid 7; high ratio of catalyst / substrate; long reaction time.

The invention solves the problem of efficient synthesis of mirtanol 1 from β-pinene 5 epoxide with high productivity in a continuous mode during a contact time of several minutes in one preparative stage.

The problem is solved by the method of producing mirtanol in the reactions of conversion of β-pinene epoxide in a solvent on a heterogeneous catalyst Al ₂ O ₃ , which is carried out in a supercritical two-component solvent, including CO ₂ and isopropyl alcohol at a temperature of 170-190 ° C and a pressure of 180-190 atm .

Those. To solve the problem use:

1) a supercritical two-component solvent comprising CO ₂ and isopropyl alcohol;

2) granular Al ₂ O ₃ as a catalyst, providing both isomerization of β-pinene 5 epoxide to myrtanal 6 and reduction of aldehyde 6 to myrtanol 1;

3) a flow-type tubular reactor, which allows conversion in a short contact time.

The method of producing mirtanol 1 from β-pinene epoxide 5 is carried out in a supercritical solvent using an experimental setup based on a flow-type tube reactor containing a granular heterogeneous catalyst Al ₂ O ₃ . The initial mixture is fed into the reactor in two streams. The first stream - supercritical CO ₂ (flow rate 5.0 ml / min) - is fed through a syringe pump to the mixer located at the inlet of the reactor through a heat exchanger, where it is heated to the reaction temperature. The second stream (flow rate 2.0 ml / min) - a solution of β-pinene 5 epoxide in isopropyl alcohol is fed into the same mixer using a piston pump. The use of supercritical CO ₂ as a component of a complex solvent can significantly reduce the critical temperature, thereby avoiding undesirable secondary transformations of products formed during the reaction.

The reaction is carried out in the temperature range T = 170-190 ° C and pressure P = 180-190 atm. Contact time is ~ 4 min. The reaction mixture at the outlet of the reactor is cooled and collected. Get the reaction mixture containing mirtanol 1 (63%), cis-mirtanol 1a (9%), myrtenol 3 (9%) and perilyl alcohol 8 (6%) (scheme 3). Compound 3 can also be subsequently converted to myrtanol 1 by a known method (G.W. Eigenmann, R.T. Arnold, J. Am. Chem. Soc., 1959, 81, 3440).

Scheme 3

Obviously, the reaction begins with the isomerization of epoxide 5 into products 3, 6, and 8. The use of the chosen heterogeneous catalyst allows isomerization of compound 5 with 100% conversion over a contact time of less than 4 minutes.

Further transformations of aldehyde 6 are associated with its reduction to myrtanol 1 (Scheme 4), apparently according to the Meerwein-Pondorf-Verley reaction, isopropyl alcohol, which turns into acetone, acts as a reducing agent. Note that in the literature we have not found examples of the use of the Meerwein-Pondorf-Verley reaction to obtain compound 1.

Scheme

Thus, the proposed method allows to obtain myrtanol 1 from β-pinene 5 epoxide with an acceptable yield in one preparative stage within a contact time of less than 4 minutes without the use of expensive reagents and explosive solvents.

The invention is illustrated by the following example.

Example 1. Synthesis of mirtanol 1

The conversion of β-pinene 5 epoxide to myrtanol 1 is carried out using an experimental setup using a 3 m long tubular reactor with an inner diameter of 1.75 mm, into which 22.1 cm ³ (20.6 g) of a granular heterogeneous catalyst Al ₂ O ₃ is placed. Al ₂ O ₃ (Macherey-Nagel, pH 7 ± 0.5, BET free surface ~ 130 m ² / g) with a grain size of 50-200 μm was charged into the reactor.

The initial mixture is fed into the reactor in two streams. The first stream - supercritical CO ₂ (flow rate 5.0 ml / min) - is fed through a syringe pump to the mixer located at the inlet of the reactor through a heat exchanger, where it is heated to the reaction temperature. The second stream (flow rate 2.0 ml / min) - a 1% solution of β-pinene 5 epoxide in isopropyl alcohol is fed into the same mixer using a piston pump.

The reaction is carried out in the temperature range T = 170-190 ° C and pressure P = 180-190 atm. Contact time is ~ 4 min. The reaction mixture at the outlet of the reactor is cooled and collected. Get the reaction mixture containing mirtanol 1 (63%), cis-mirtanol 1a (9%), myrtenol 3 (9%) and perilyl alcohol 8 (6%) (scheme 3).

As can be seen from the description, the invention solves the problem of the controlled one-step production of myrtanol 1 in the reactions of β-pinene 5 epoxide conversion in the selected supercritical solvent on a heterogeneous Al ₂ O ₃ catalyst and is aimed at obtaining a valuable compound for perfumery-cosmetic and pharmaceutical applications.

The implementation of chemical transformations in supercritical fluid-solvents can be the basis of modern technologies for the production of a wide class of industrially important organic compounds, medicinal and aromatic substances.

Claims (3)

1. The method of producing mirtanol in the conversion reactions of β-pinene epoxide in a solvent on a heterogeneous Al ₂ O ₃ catalyst, characterized in that the conversion reaction of β-pinene epoxide is carried out in a supercritical two-component solvent that includes CO ₂ and isopropyl alcohol. 2. The method according to claim 1, characterized in that it is carried out at a temperature of 170-190 ° C and a pressure of 180-190 atm. 3. The method according to claim 1, characterized in that it is carried out in a flow-through tube reactor.