TW201319046A - Method of producing 3,4-dihydroisoquinoline derivative - Google Patents

Abstract

The invention provides an industrially advantageous method of producing 3, 4-dihydroisoquinoline derivatives. The method of producing a 3, 4-dihydroisoquinoline derivative represented by general formula (1) involves reacting a compound represented by general formula (2) with a compound represented by general formula (3) in the presence of an acid, either within a hydrocarbon-based solvent or in the absence of a solvent. R3-CN (3)

Description

Method for producing 3,4-dihydroisoquinoline derivatives

The present invention relates to a process for producing a 3,4-dihydroisoquinoline derivative.

3,4-Dihydroisoquinoline derivatives are known to be important manufacturing intermediates in a wide variety of fields. For example, the 1,3,3-trimethyl-3,4-dihydroisoquinoline which is one of the derivatives is described in Patent Document 1 and Patent Document 2 as an intermediate for the production of a pharmaceutical agent. Patent Document 3 describes a production intermediate as a laundry detergent composition. Therefore, a method for efficiently producing a 3,4-dihydroisoquinoline derivative is very important.

In the investigation, it is disclosed in the prior art that: (1) a method of reacting a phenethyl chloride derivative with acetonitrile in the presence of tin tetrachloride (Non-Patent Document 1), (2) adding phenylethyl alcohol to acetonitrile containing sulfuric acid and acetic acid A method in which a derivative is cyclized after a reaction for 3 days (Patent Document 3), and (3) a method of reacting ethyl cyanoacetate with a phenylethyl alcohol derivative in the presence of sulfuric acid in a benzene solvent (Patent Document 1) And (4) a method of reacting acetonitrile with a phenylethanol derivative in the presence of sulfuric acid in a benzene solvent (Patent Document 2).

However, these methods have the problems shown below. The method of (1) is a transition metal used as a problem in terms of waste. (2) The method has a long reaction time and requires two steps. The method of (3), the yield is not described, the details are not clear, but the atomic efficiency is not good because the ethoxycarbonyl group of ethyl cyanoacetate needs to be removed. (4) The method can be used in one step because no transition metal is used. The object was obtained as a method in which the atomic efficiency of the starting material was also excellent, but the yield was low.

Judging from the above, although the 3,4-dihydroisoquinoline derivative is a useful manufacturing intermediate, the prior art does not at all satisfy the method provided on an industrial scale.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] European Patent No. 1433789

[Patent Document 2] International Publication No. 2003/64389

[Patent Document 3] International Publication No. 2001/16275

[Non-patent literature]

[Non-Patent Document 1] Mendeleev Communications (Mendeleev Commun.), Vol. 8, No. 4, pp. 153-154 (1998)

An object of the present invention is to provide a production method which is advantageous for industrialization of a 3,4-dihydroisoquinoline derivative.

In an effort to overcome the above problems, it was found that the desired 3,4-dihydroisoquinoline can be produced in a good yield by reacting a phenylethyl alcohol derivative with an alkyl nitrile derivative in the presence of an acid without using a solvent. derivative. Further investigation revealed that the reaction product can be obtained in a better yield than the conventional reaction using a benzene solvent by carrying out the reaction in a hydrocarbon solvent. The reaction in the presence of a solvent makes it easy to control the heat generated during the reaction, and is therefore suitable for mass production.

From the above, the method of the present invention is not only excellent in productivity, but also avoids the use of a solvent such as benzene which is environmentally unsuitable, and is easy to handle, and is therefore an effective means for solving the above problems. in this way, The present invention has been completed.

In other words, the present invention is a method for producing a compound represented by the formula (1), wherein the compound represented by the formula (2) and the compound represented by the formula (3) are used in a hydrocarbon solvent. Or in the absence of a solvent, in the presence of an acid;

(wherein R1 and R2 each independently represent an alkyl group having 1 to 6 carbon atoms which may be substituted, and X represents a halogen atom, an alkyl group which may be substituted with 1 to 6 carbon atoms, or a carbon which may be substituted Number 1 to 6 alkoxy groups, n represents an integer from 0 to 4, and R3 represents an alkyl group having 1 to 3 carbon atoms)

(wherein, R1, R2, X and n have the same meanings as described above.)

R3-CN (3)

(wherein R3 has the same meaning as described above).

[2] The method for producing a compound represented by the formula (1), wherein n = 0.

According to the present invention, it is possible to avoid the use of a solvent having no environmental suitability and to produce a 3,4-dihydroisoquinoline derivative for the purpose of easy handling and high yield. Therefore, the present invention is suitable as an industrial manufacturing method.

[Formation of the Invention]

The form of the present invention will be described in detail below.

The substituent in the alkyl group having 1 to 6 carbon atoms which may be substituted with R1 and R2 in the formula (1) represents a halogen atom and an alkoxy group having 1 to 6 carbon atoms. The halogen atom is fluorine, chlorine, bromine or iodine. An alkoxy group having 1 to 6 carbon atoms, which means, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, Pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1 a linear or branched alkoxy group of 2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy. It is preferably an alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group. The number of the substituents is not particularly limited, and each substituent may be the same or different.

The alkyl group in the alkyl group having 1 to 6 carbon atoms which may be substituted with R1 and R2 in the formula (1), and represents, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group. , second butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2- A linear or branched alkyl group of dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl. It is preferably an alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group.

The halogen atom of X in the formula (1) is fluorine, chlorine, bromine or iodine.

The alkyl group having a carbon number of 1 to 6 which may be substituted by X in the formula (1), and the alkyl group having 1 to 6 carbon atoms which may also be substituted with R1 and R2 in the formula (1) The same meaning.

The substituent in the alkoxy group having 1 to 6 carbon atoms which may be substituted in the formula (1) is a halogen atom and is fluorine, chlorine, bromine or iodine. The number of the substituents is not particularly limited, and each substituent may be the same or different.

The alkoxy group in the alkoxy group having a carbon number of 1 to 6 which may be substituted in the formula (1), and represents an oxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group or a butoxy group. , isobutoxy, second butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, Oxyl, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2- Dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy a linear or branched alkoxy group of 2-ethylbutoxy group. It is preferably an alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.

The alkyl group having 1 to 3 carbon atoms of R3 in the formula (1) is a methyl group, an ethyl group, a propyl group, and an isopropyl group.

n in the formula (1) is an integer of 0 to 4.

When n in the general formula (1) is 2 or more, X may be the same or different.

R1, R2, X and n in the formula (2) have the same meanings as in the formula (1).

The compound represented by the formula (2), for example, 1,1-dimethyl-2-phenylethanol, can be obtained from a commercially available product.

R3 in the formula (3) has the same meaning as in the formula (1).

Regarding the compound represented by the formula (3), for example, acetonitrile can be obtained from a commercially available product.

The compound represented by the formula (1) can be obtained by reacting a compound represented by the formula (2) with a compound represented by the formula (3) in a hydrocarbon solvent or in the absence of a solvent in the presence of an acid.

The hydrocarbon solvent used for the reaction means a linear chain composed of carbon and hydrogen such as pentane, hexane, heptane, octane, 2-methylbutane, isohexane, cyclohexane or methylcyclohexane. A branched or cyclic solvent or a solvent composed of chlorine, carbon and hydrogen such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride. It is preferably a linear or cyclic solvent composed of carbon and hydrogen, and a solvent composed of chlorine, carbon and hydrogen. Preferred are hexane, heptane, cyclohexane, methylcyclohexane, and dichloroethane. Further, these solvents may be used singly or in combination of two or more kinds in any ratio.

In the case of using a hydrocarbon-based solvent, the reaction is usually 20 parts by weight or less based on the compound represented by the formula (2).

The acid to be used is not particularly limited as long as the reaction proceeds, but a sulfonic acid is preferred. The sulfonic acid may, for example, be trifluoromethanesulfonic acid or sulfuric acid, preferably sulfuric acid.

Commercially available sulfuric acid contains about 3 to 5% water, but any sulfuric acid can be used. As described in the examples, the water contained in the commercially available sulfuric acid may be converted into sulfuric acid by fuming sulfuric acid and used in the reaction.

The amount of the acid to be used is not particularly limited, and is usually 3 equivalents to 30 equivalents, preferably 5 equivalents or more and 15 equivalents or less, based on the compound represented by the formula (2).

The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually 0 ° C or more and 80 ° C or less than the boiling point of the solvent, preferably 10 ° C or more and 50 ° C or less or the boiling point of the solvent.

In the embodiment in which the hydrocarbon-based solvent is used, a method in which a compound represented by the formula (2) and a compound represented by the formula (3) are mixed with a hydrocarbon-based solvent and then added to an acid containing a hydrocarbon-based solvent is used. A method in which a compound represented by the formula (2) and a compound represented by the formula (3) are added to a hydrocarbon solvent and then added to an acid, and a compound represented by the formula (2) is mixed with a compound represented by the formula (3). The method of containing the acid of the hydrocarbon solvent, etc., but not limited to these, can be suitably set.

The following is a description of the post-reaction treatment.

After the reaction, water or an aqueous alkali solution may be added. When a large amount of acid is used, a method of neutralizing with an aqueous alkali solution after adding water is preferred in terms of safety. As the aqueous alkali solution to be used, those in which ammonia, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or the like is dissolved in water can be used. When salt is precipitated after the neutralization operation, water may be added to dissolve the salt or the salt may be removed by a filtration operation.

The liquid separation can be performed after the neutralization operation. When a hydrocarbon solvent is used for the reaction, the liquid may be directly separated or an appropriate solvent may be added. In the case where the hydrocarbon solvent is not used in the reaction, a suitable solvent is charged and a liquid separation operation is carried out. Examples of the solvent in this case include a benzene solvent such as toluene, xylene, benzene, chlorobenzene or dichlorobenzene, an ester solvent such as ethyl acetate, isopropyl acetate or butyl acetate, diethyl ether or diisopropyl ether. An ether solvent such as methyl-tert-butyl ether; a chlorinated hydrocarbon solvent such as dichloromethane, dichloroethane or chloroform; or a hydrocarbon solvent such as hexane, heptane, cyclohexane or methylcyclohexane; A solvent that is immiscible with water can be added. The number of liquid separations is not particularly limited and can be carried out in accordance with the purity of the purpose.

The reaction mixture containing the compound (1) obtained as described above can be removed by using a desiccant such as sodium sulfate or magnesium sulfate, but this step is not essential.

The reaction mixture containing the compound (1) obtained as described above can be distilled off. The reaction mixture containing the compound (1) obtained by distilling off the solvent can be further purified according to the purity of the object. When the compound represented by the compound (1) is a solid, it may be washed, reprecipitated or recrystallized by a suitable solvent, and may be distilled in the case of a liquid. Further, both the solid and the liquid can be purified by column chromatography.

As described above, according to the present invention, a 3,4-dihydroisoquinoline derivative can be produced with a simple operation and good efficiency.

[Examples]

The invention will be described in more detail below by way of examples, but the invention is not limited to the examples.

2-methyl-1-phenylpropan-2-ol is called compound (I), and 1,3,3-trimethyl-3,4-dihydroisoquinoline is called compound (II), high-speed liquid layer The analysis is called HPLC.

[Comparative Example 1] Re-inspection of the description example of International Publication No. 2003/64389

7.0 ml of a benzene solution containing 7.0 g of the compound (I) and 1.62 ml of acetonitrile was added dropwise to 10 ml of 97% sulfuric acid at 0 °C. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. The reaction mixture obtained was analyzed by HPLC to give 2.72 g of Compound (II). According to the publication of International Publication No. 2003/64389, 2.53 g of the compound (II) is isolated, and the patent document can be reproduced. The yield was 33.4% based on the compound (I) and 50.6% based on the acetonitrile.

[Example 1] Synthesis of Compound (II) Using Cyclohexane as a Solvent

To 75.41 g of 97% sulfuric acid, 75 ml of cyclohexane was added, and the mixture was cooled to 15 °C. Here, 75 ml of cyclohexane containing 50.00 g of the compound (I) and 23.23 g of acetonitrile was maintained at 20 ° C or lower and added dropwise over a period of 45 minutes. After the completion of the dropwise addition, the mixture was stirred at 20 ° C for 20 hours. Next, the reaction mixture was added dropwise at 50 ° C or less in 375 ml of water cooled to 10 ° C. At this time, the reaction mixture was observed by HPLC, and the compound (II) was obtained with a reaction yield of 89.9%. After dropwise addition of a 25% aqueous ammonia solution at 25 ° C, 350 ml of cyclohexane was added and liquid separation was carried out. The obtained organic layer was concentrated under reduced pressure to give the compound (II) 52.30 g of purity 93.7%. The yield was 85.0%.

As is apparent from the comparative examples, the use of cyclohexane in the solvent can significantly improve the yield.

Further, in order to analyze the obtained compound, distillation was carried out at 5 torr at 82 °C. The analytical values are in agreement with International Publication No. 2003/64389.

Substance data of compound (II)

¹ H-NMR (CDCl ₃ ) δ: 7.48 (1H, d, J = 7.6 Hz), 7.35-7.33 (1H, m), 7.29-7.27 (1H, m), 7.14 (1H, d, J = 7.6 Hz ), 2.69 (2H, s), 2.37 (3H, s), 1.20 (6H, s).

[Example 2] Synthesis of Compound (II) Using Cyclohexane as Solvent

To 103.09 g of 95% sulfuric acid, 30 ml of cyclohexane was added and cooled to 15 °C. Thereto, 30 ml of cyclohexane containing 20.00 g of the compound (I) and 9.29 g of acetonitrile was added dropwise at 20 ° C or lower. After the completion of the dropwise addition, the mixture was stirred at 20 ° C for 20 hours. The obtained reaction mixture was observed by HPLC, and as a result, the compound (II) was obtained in a reaction yield of 87.5%.

[Example 3] Synthesis of Compound (II) Using Cyclohexane as a Solvent

After adding 63.86 g of 25% fuming sulfuric acid to 63.88 g of 97% sulfuric acid, 30 ml of cyclohexane was added and cooled to 15 °C. 30 ml of cyclohexane containing 20.00 g of the compound (I) and 9.29 g of acetonitrile was added dropwise at 20 ° C or lower. After the completion of the dropwise addition, the mixture was stirred at 20 ° C for 20 hours. The obtained reaction mixture was observed by HPLC, and the compound (II) was obtained in a reaction yield of 84.0%.

[Example 4] Synthesis of Compound (II) Using Methylcyclohexane as a Solvent

The reaction was carried out in the same manner as in Example 3 except that the cyclohexane was changed to methylcyclohexane. The obtained reaction mixture was observed by HPLC, and the compound (II) was obtained in a reaction yield of 78.7%.

[Example 5] Synthesis of Compound (II) Using Heptane as Solvent

The reaction was carried out in the same manner as in Example 3 except that the cyclohexane was changed to heptane. The obtained reaction mixture was observed by HPLC, and the compound (II) was obtained in a reaction yield of 84.0%.

[Example 6] Synthesis of Compound (II) in the absence of a solvent

After cooling 67.31 g of 97% sulfuric acid to 10 ° C, 1 kg of the compound (I) and 4.10 g of acetonitrile were mixed and maintained at 15 ° C or lower, followed by dropwise addition. After stirring at 6 to 10 ° C for 3 hours, the temperature was raised to room temperature and stirred for 16 hours. After the completion of the reaction, the reaction mixture was observed by HPLC, and the compound (II) was obtained with a reaction yield of 85.6%.

[Example 7] Synthesis of Compound (II) Using Dichloroethane as a Solvent

After cooling 30 ml of dichloroethane containing 101.0 g of 97% sulfuric acid to 15 ° C, 30 ml of dichloroethane containing 20.00 g of the compound (I) and 9.29 g of acetonitrile was added dropwise at 20 ° C or lower. After the completion of the dropwise addition, the mixture was stirred at 20 ° C for 20 hours. The obtained reaction mixture was observed by HPLC, and the compound (II) was obtained in a reaction yield of 79.0%.

[Reference Example 1]

The reaction was carried out in the same manner as in Example 3 except that the cyclohexane was changed to toluene. The obtained reaction mixture was observed by HPLC, and the compound (II) was obtained in a reaction yield of 18.0%. It is understood that the reaction yield will be significantly reduced if the benzene solvent such as toluene is used.

[Reference Example 2]

The reaction was carried out in the same manner as in Example 3 except that the cyclohexane was changed to xylene. The obtained reaction mixture was observed by HPLC, and the compound (II) was obtained in a reaction yield of 20.2%. It is understood that the reaction yield will be significantly reduced if the benzene solvent such as xylene is used.

[Industry Utilization]

According to the present invention, a 3,4-dihydroisoquinoline derivative can be provided in a simple operation and in a high yield. Further, the present invention can avoid the use of a solvent having no environmental suitability, and can be advantageously produced industrially, so that it is highly utilized in the industry.

Claims (2)

A process for producing a compound represented by the formula (1), comprising: a compound represented by the formula (2) and a compound represented by the formula (3) in a hydrocarbon solvent or in the absence of a solvent in the presence of an acid reaction; (wherein R1 and R2 each independently represent an alkyl group having 1 to 6 carbon atoms which may be substituted, and X represents a halogen atom, an alkyl group which may be substituted with 1 to 6 carbon atoms, or a carbon which may be substituted Number 1 to 6 alkoxy groups, n represents an integer from 0 to 4, and R3 represents an alkyl group having 1 to 3 carbon atoms) (wherein R1, R2, X and n have the same meanings as defined above) R3-CN(3) (wherein R3 has the same meaning as defined above). A method for producing a compound represented by the formula (1) in the first aspect of the patent application, wherein n=0.