CH622012A5 - Process for the preparation of isochromanes - Google Patents

Description

The invention relates to a method for producing isochromanes according to the preamble of patent claim 1.

Such a method is described in Patent No. 610,319.

The object of the invention is to provide a method for isochroman production which is improved in relation to the cited patent in terms of economy and simplicity.

This object is achieved according to the invention by a method of the type mentioned with the features specified in claim 1.

It has been found that the secondary alcohol isopropanol can advantageously be used as the carrier alcohol,

if an azeotroping agent such as hexane is also added. The azeotroping agent is required to enable the water formed during the reaction to be removed by azeotropic distillation and to cause the distillate to separate into an aqueous and an organic phase which can be fed back into the reaction vessel. In the absence of the added azeotroping agent, the water and isopropanol distill over as a single phase. Although the reaction could be carried out without an added azeotroping agent if fresh isopropanol were added to replace the isopropanol distilled off with the water, this would require the use of considerably more isopropanol than when working with hexane, and moreover, at most Isopropanol to be reused in the process should be dried in any way.

The azeotroping agent should generally be inert to the reaction conditions and effectively separate isopropanol from water. In addition to hexane, other substances can be used in this way, e.g. Cyclohexane, benzene, toluene and methylcyclohexane.

The amount of hexane or other azeotroping agent used is usually 5-50%, based on the weight of the arylalkanol submitted. The preferred range is 5-15%.

The use of isopropanol and an azeotroping agent (e.g. n-hexane) has the following advantages over the use of n-hexanol:

1. Isopropanol is less expensive than n-hexanol.

2. A smaller amount by weight of isopropanol than n-hexanol is required to supply the same number of moles of carrier alcohol, which enables an increased throughput during the reaction and

3. A lower reaction temperature is sufficient: 80-95 ° when using isopropanol compared to 140 ° C when using n-hexanol.

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The above-mentioned acetal can be prepared before use in the reaction or formed in situ.

The acid concentration during the reaction is in the range of 1-100% by weight, based on the total weight of the other reaction components presented. The preferred range depends on the acid used. When using 85% phosphoric acid, the preferred concentration is 1-50% by weight, based on the total weight of the other reaction components used.

When the acetal is formed in situ, it is formed by reacting an aldehyde and 2-propanol. The concentration of the aldehyde can range from 0.1 to 100 moles or more, based on the moles of arylalkanol. The preferred range is 1-5 moles of aldehyde per mole of arylalkanol. The alcohol used in the reaction with the aldehyde to form the acetal can be used in concentrations of 0.1 to 100 moles per mole of arylalkanol. If the aldehyde is used in amounts less than 0.5 mole per mole of arylalkanol, it is likely not necessary to use more than 0.1 mole of isopropanol per mole of arylalkanol. If the aldehyde is used in an amount of more than 0.5 mole per mole of arylalkanol, the isopropanol should be used in an amount which is at least twice the difference between the number of moles of aldehyde and half the number of moles of arylalkanol, thereby ensuring that all of the aldehyde is converted to acetal and self-condensation of the aldehyde is avoided under acidic reaction conditions. Isopropanol is preferably used in excess of the amount required for the complete conversion of the aldehyde to acetal. If desired, the isopropanol can also be used as a reaction solvent.

The reaction temperature is between 80 and 95 ° C, with the range of 80-85 ° C being particularly preferred.

The reaction can be carried out at atmospheric pressure, at elevated pressure or at reduced pressure, provided that the reaction temperature required for a usable rate of conversion to form isochroman is achieved. With appropriate selection of the reaction components, the reaction can be carried out smoothly under atmospheric pressure, which avoids the need to use expensive pressure or vacuum systems.

It should be emphasized that the reaction mixture using phosphoric acid or p-toluenesulphonic acid is considerably less corrosive than the reaction mixture of the known method which supplies aqueous hydrogen chloride and releases hydrogen chloride vapor. Accordingly, less expensive steel reactors can be used instead of the more complex glass-lined reaction vessels that were required for the more corrosive mixtures. Furthermore, no chloromethyl methyl ether is present in the present process, neither as reaction components nor as intermediate compounds. This group of compounds has proven to be a significant health hazard that requires special precautions when handling.

According to the invention, the reactions can be represented as follows: compound (2) + compound (3) - »compound (1). The acetal reaction component can be previously or in situ according to the reaction equation

O

II

R3CH (Compound 4) + R5OH + R0OH - »Compound (3)

be formed.

Examples of arylalkanols which can be used for the process according to the invention are the following:

Phenylethyl alcohol, 2- (1 ', 1', 2 ', 3', 3'-pentamethylindan-5'-yl) -1-propanol (prepared according to Example 15b of U.S. Patent 3,360,530), l- (2nd -Hydroxyethyl) -3,5-diethylbenzene, l- (2-hydroxyethyl) -2-methoxy-4-methylbenzene, 2- (l ', 1', 2 ', 3', 3'-pentamethylindane 5'-yl) ethanol, 2-phenyl-l-propanol, 2- (r, l ', 2', 3) -3'-pentamethylindan-5'-yl) -pentanol-l-.

Examples of aldehydes which are suitable for forming the acetal reaction components for the process according to the invention are formaldehyde, acetaldehyde and propionaldehyde.

Instead of the aldehydes themselves, easily decomposable precursors of these aldehydes can be used, e.g. Paraform aldehyde (for the production of formaldehyde) and paraldehyde (for the production of acetaldehyde).

In the above reactions, Ri and R2 are each selected (i) separately from the group: hydrogen, lower alkoxy, lower alkyl or (ii) taken together from the group: benzo, cyclopentano, cyclohexano,

Naphtho, monoalkylcyclopentano, polyalkylcyclohexano. R3 and R4 are the same or different and selected from the group: hydrogen and lower alkyl. R5 and R0 are each isopropyl. A specific example of one of the reactions according to the process according to the invention is the reaction of the 2-propyl alcohol acetal of formaldehyde (formula 6) with 2- (r, r, 2 ', 3', 3'-pentamethylindan-5! -Yl) propanol -l (formula 5), whereby 6-oxa-l, l, 2,3,3,8-hexamethyl-2,3,5,6,7,8-hexa-hydro-lH-benz- (f) - inden (formula 7) according to reaction scheme A (see formula sheets). Another example of the method according to the invention is the formation of 2-oxa-4,5,5,8,8-pentamethyl-l, 2,3,4,5,6,7,8-octahydroanthracene (formula 9) (8) and (6) according to scheme B (see formula sheets).

The same reaction with formation of the acetal reaction component in situ proceeds according to scheme C. The same material can also be produced according to a different reaction sequence which comprises a reaction according to an embodiment of the invention according to scheme D.

After the reaction according to the invention to form the isochromane, the reaction mass can be neutralized with aqueous base, such as aqueous sodium hydroxide or potassium hydroxide solution, and the washed mixture can then be worked up by customary methods, for example by distillation, extraction, preparative chromatography and the like, so that a high-purity isochroman is obtained. Fractional distillation is a preferred method for isolating the isochromane.

Preferred embodiments of the method according to the invention are explained in the following examples.

example 1

A 5 liter flask is made with 1935 g of 2- (l ', r, 2', 3 ', 3'-pentamethylindan-5'-yl) -l-propanol (prepared by the process according to Example 15b of the US -PS 3 360 530, structure see formula 5), 233 g of paraformaldehyde, 370 g of isopropanol and 126 g of p-toluenesulfonic acid. The stirred mixture is heated to reflux (94-95 ° C) for a period of approximately 4 hours and then stirred at reflux for a further 10 hours. The analysis at this point shows an incomplete conversion into the desired compound.

200 g of n-hexane are added and the mixture is stirred under reflux while water is removed by azeotropic distillation. The reflux temperature rises from 81 ° C to 94 ° C within 8 hours. After a further 3 hours, a total of 213 ml of an aqueous solution have passed over azeotropically and the analysis of the reaction mixture shows an essentially complete conversion into the desired product. The main amount of isopropanol is distilled at flask temperatures from to

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recovered to 120 ° C and the remaining material in the reaction vessel at 80 ° C with 515 g of 20% sodium hydroxide solution. After adding 70 g "Primol" (registered trademark for hydrocarbon mineral oil from Exxon Corp., Linden, NJ, USA), 70 g 20% sodium methylate in methanol and 3 g "Ionol" (registered trademark for 2.6 -Di-t-butyl-4-methylphenol) provides the distillation of the washed organic material 6-oxa - 1,1,2,3,3,8-hexamethyl-2,3,5,6,7,8-hexahydro -lH-benz- (f) - inden according to the formula (7) in a yield of 5 85%. The structure is confirmed by gas chromatography, mass spectroscopy, IR and nuclear magnetic resonance analysis.

FORMULA SHEETS R

(2)

0

r,

H

(3)

(4)

Scheme A

O

(5)

(6)

(7)

Scheme B

(8th)

(6)

(9)

Scheme C

+ hc

Oh

\H

(8th)

(9)

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(12)

(13)

Claims (3)

622012 (1) an acetal of the formula (3) as cyclizing agent H or5 (3) r3 org is used in which R5 and R0 each represent the 2-propylene group, 2. The method according to claim 1, characterized in that R3 is hydrogen. 3. The method according to claim 1, characterized in that R3 represents the methyl group. 4. The method according to claim 1, characterized in that n-hexane, cyclo-hexane, methylcyclohexane, benzene or toluene is used as the azeotroping agent. 5. The method according to claim 4, characterized in that n-hexane is used as an azeotroping agent. 6. Application of the method according to claim 1 to acetals, which are mixed in situ by mixing an aldehyde of the formula (4) 0 r (2) one of the protonic acids p-toluenesulfonic acid or phosphoric acid is used as catalyst, (3) the reaction mass does not contain any hydrogen chloride or corrosive halide salts or chloromethyl methyl ether, even after the reaction, (4) the reaction temperature is kept in the range of 80-95 ° C, (5) the acid concentration is between 1 and 100% by weight, based on the weight of the rest of the reaction mass, (6) the ratio of acetal to arylalkanol is at least 0.1: 1, and (7) the reaction is carried out in the presence of an azeotroping agent which brings about the azeotropic removal of water of reaction. 2nd PATENT CLAIMS 1. Process for the preparation of isochromanes of the formula (1) in which Rj and R2 each individually represent hydrogen atoms, lower alkoxy or lower alkyl groups or taken together in the 2- and 3-positions of the benzene ring a benzo, cyclopentano, cyclohexano, naphtho, mono-lower alkyl-cyclopentano, poly-lower alkylcyclopentano, mono-lower mean alkylcyclohexano or poly-lower alkylcyclohexano group, R3 and R4 are identical or different and are hydrogen atoms or lower alkyl groups, by reaction of arylalkanol of the formula (2) (6) Oh R with a cyclizing agent in the presence of a catalyst, characterized in that 3rd are formed with 2-propanol, where R3 represents the hydrogen atom or a lower alkyl group.