JPH0211574B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 1-phenyl-2,2-dialkoxypropanes. 1-Phenyl-2,2-dialkoxypropanes are compounds used as intermediate raw materials for various concentrated drugs and pharmaceuticals, for example, as an intermediate for producing L-α-methyldopa. A manufacturing method is used in which a mol of a phenylacetylene compound is reacted with 2 mol of an alcohol. However, this production method had problems such as difficulty in obtaining the phenylacetylene compound used as a raw material. The present inventors have developed a method by first contacting 3-phenylpropylene, which may have a substituent on the benzene ring, with an alkyl nitrite ester in the presence of a catalyst of alcohol and palladium salt. A method for producing 1-phenyl-2,2-dialkoxypropanes using readily available raw materials 3-phenylpropylene and nitrite alkyl ester. Developed a manufacturing method and filed a patent application in 1982.
A patent application was filed as No. 108526. As a result of subsequent research, the present inventors found that in this production method, if amines are present in the reaction system, the amount of the target product produced per unit amount of palladium salt catalyst will further increase. The inventors have discovered that the amount of expensive palladium salts used can be reduced and have arrived at the present invention. The present invention is characterized by contacting 3-phenylpropylene, which may have a substituent on the benzene ring, with an alkyl nitrite ester in the presence of an alcohol and palladium salt catalyst and an amine. A method for producing 1-phenyl-2,2-dialkoxypropanes is provided. Next, the present invention will be explained in detail. One of the raw materials of the present invention is 3-phenylpropylene, and the benzene ring of this 3-phenylpropylene may have a substituent. Examples of the substituent include a hydroxyl group, a lower alkyl group having up to 6 carbon atoms, a lower alkoxy group having up to 6 carbon atoms, and a benzyloxy group. These substituents can be attached to the benzene ring in a total number of up to three. Therefore, the 3-phenylpropylene used in the present invention can be represented by the following formula (). (X, Y, and Z are each a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, and a benzyloxy group,
Y and Z may be the same or different; alternatively, 5-7 in which any two of X, Y, and Z contain 1 to 2 oxygen atoms together with a part of the benzene ring; The 3-phenylpropylenes represented by the above formula () can be extracted from naturally occurring vegetable oils, or can be extracted from the corresponding benzene or substituted benzene compound and a halogen It can be easily obtained by reacting a compound with an allyl halide ( _CH2 =CH- _CH2Br , etc.). Another raw material of the present invention is an alkyl nitrite ester, which can be represented by the formula (). RONO () (Here, R is an aliphatic, aromatic, or alicyclic saturated or unsaturated alkyl group, preferably an alkyl group having 1 to 10 carbon atoms or a benzyl group). In the above formula (), R is preferably an aliphatic group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or an aralkyl group such as benzyl. Saturated aliphatic alkyl groups of numbers 1 to 4, i.e. methyl, ethyl, n-
Propyl, isopropyl, n-butyl, sec-butyl and the like are preferred. The reaction on which the production method of the present invention is based can be expressed as follows. As can be seen from the above reaction formula, it is necessary to use at least 2 mol of nitrite alkyl ester per 1 mol of 3-phenylpropylene, and in actual reaction, the amount of nitrite alkyl ester is 2 to 5 mol, preferably 2.1 to 3.5 mol. The above reaction advantageously proceeds in the presence of a catalyst of alcohol and palladium salt. Examples of alcohols used here include alkyl alcohols having 1 to 10 carbon atoms such as methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, and benzyl alcohol. An alcohol having a benzyl group or a benzyl group is preferable. In addition, using an alcohol that has the same alkyl group as the alkyl group of the nitrite alkyl ester used in the reaction has the advantage of making it easier to recover and reuse the alcohol from the reaction solution, so it is recommended to select such an alcohol. preferable. Such alcohol is usually used in an amount of 1 to 10% per mole of 3-phenylpropylene used.
use Note that the above alcohols also act as reaction solvents, so there is no need to use any other solvent, but
Other solvents can be used if desired. Such a solvent is not particularly limited as long as it is substantially inert to the reaction utilized in the present invention, but examples of suitable solvents include lower fatty acid esters such as ethyl acetate and butyl acetate; Examples include ethers such as dioxane, dibutyl ether, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, alicyclic hydrocarbons such as cyclohexane, and aliphatic hydrocarbons such as n-hexane. Examples of palladium salts used as catalysts in the present invention include palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium sulfate, palladium nitrate, and the like. Particularly preferable palladium salts as catalysts in the production method of the present invention include palladium chloride, palladium chloride,
Palladium halides such as palladium bromide. The amount of palladium salts used as a catalyst is generally 0.0001 to 1 mole of 3-phenylpropylene.
0.02 mol, and preferably 0.0005 to 0.005 mol is used. If the amount of catalyst used is less than the lower limit of this range, the reaction will not proceed sufficiently, and even if the amount of catalyst used is more than the upper limit of the above range, it will hardly contribute to improving the reaction rate; This is not preferable because it becomes time consuming to recover the catalyst and also increases the loss of the catalyst during catalyst recovery. The amines used in the present invention can be represented by the following formula (). (However, in the formula, R ¹ , R ² , and R ³ are the same or different and represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and two of R ¹ , R ² , and R ³ are alkylene groups. (can also be combined with each other to form a ring). Examples of such amines include tertiary amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine, trihexylamine; dimethylamine, diethylamine, dipropylamine, dibutylamine, dipentylamine, Secondary amines such as dihexylamine; primary amines such as methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine;
Piperidine, N-methylpiperidine, N-ethylpiperidine, N-propylpiperidine, N-butylpiperidine, N-pentylpiperidine, N-hexylpiperidine, pyrrolidine, N-methylpyrrolidine, N-ethylpyrrolidine, N-propylpyrrolidine, N - Cyclic amines such as butylpyrrolidine, N-pentylpyrrolidine, and N-hexylpyrrolidine; and the like. These amines are used in an amount of 0.1 to 2 moles, preferably 0.2 to 1 mole, per mole of the palladium salt catalyst. If the amount used is less than the lower limit of this range, no co-catalyst effect is expected, and if it is used more than the upper limit, no particular effect will be obtained, and recovery loss will increase, which is undesirable. The above reaction is carried out at a temperature of 0 to 150°C. 150
At temperatures higher than 0.degree. C., side reactions such as isomerization reactions tend to proceed, and at temperatures lower than 0.degree. C., the reaction rate decreases and is not practical. Incidentally, a particularly preferred reaction temperature for practical purposes is a temperature within the range of 10 to 90°C. Although the reaction time varies depending on reaction conditions such as reaction temperature, it is generally selected from a range of 10 minutes to 5 hours. There are no particular restrictions on the pressure of the reaction system during the reaction, but
Usually, a pressure in the range of normal pressure to 200 kg/cm ² (gauge pressure) is selected. The present invention can be implemented, for example, by the following method. The raw materials 3-phenylpropylene, alcohol, amines, and catalyst are placed in a reaction vessel, and a nitrite alkyl ester is added thereto to allow the reaction to proceed under predetermined conditions. However, there is no particular restriction on the order in which these raw materials, catalysts, etc. are added. After the reaction is complete,
The reaction solution is distilled under reduced pressure to separate and obtain the generated NO gas, unreacted raw materials, alcohol, amines, and the desired reaction product (1-phenyl-2,2-dialkoxypropanes). The unreacted raw materials, alcohol, and amines recovered here can be recycled, and the NO gas recovered can also be used for the production of nitrite ester. Next, examples of the present invention will be shown. Example 1 0.10 mol of raw materials 3-phenylpropylene, 0.25 mol of methyl nitrite, 0.5 mol of methyl alcohol, 0.00025 mol of trimethylamine, and 0.0005 mol of palladium chloride as a catalyst were charged into a reaction vessel, and the reaction temperature was increased.
The reaction was carried out at 20°C for a reaction time of 1.5 hours. After the reaction, the reaction solution was subjected to gas chromatography to quantify the unreacted raw materials in the reaction solution and the target product, 1-phenyl-2,2-dimethoxypropane. A yield of 85% and a Pd turnover number of 170 were obtained. Note that the reaction rate of the raw material and the yield of the target product are values calculated according to the following formula (the same applies to each example hereinafter). Reaction rate (%) of raw material [3-phenylpropylenes] = [
Reacted amount of raw material (mol) ÷ Amount of raw material charged (mol)] × 100 Yield (%) of target product [1-phenyl-2,2-dialkoxypropanes] = [Amount of target product produced (mol) ) ÷ Amount of raw material charged (moles)] × 100 In addition, the "Pd turnover number" is a measure of the activity of the palladium salt catalyst, and is a value calculated using the following formula (the same applies to each subsequent example). . Pd turnover number=amount of target product produced (moles)/amount of palladium salt catalyst charged (moles) Comparative Example 1 An experiment was conducted in the same manner as in Example 1, except that trimethylamine was not used. As a result, the reaction rate of the raw material was 13%, the yield of the target product was 11%, and the Pd turnover number was 22. Example 2 0.10 mol of 3-(3,4-dimethoxyphenyl)propylene as raw materials, 0.25 mol of methyl nitrite, 0.5 mol of methyl alcohol, 0.00025 mol of triethylamine, and 0.0005 mol of palladium chloride as a catalyst were charged into a reaction vessel, and the reaction temperature was set at 20°C. The reaction was carried out under the following conditions: 1.5 hours reaction time. After the reaction is completed, the reaction solution is subjected to gas chromatography to separate the unreacted raw materials in the reaction solution and the target product 1-(3,4-dimethoxyphenyl)-
Determination of 2,2-dimethoxypropane and Pd
We calculated the number of turnovers. The results are shown in Table 1. Examples 3 to 11 Experiments were conducted in the same manner as in Example 2, except that 0.00025 mol of each of the various amines shown in Table 1 was used in place of triethylamine. The result is the first
Shown in the table. Comparative Example 2 An experiment was conducted in the same manner as in Example 2, except that triethylamine was not used. The result is the first
Shown in the table.

[Table] Example 12 An experiment was conducted in the same manner as in Example 1, except that 3-phenylpropylene was replaced with 3-(4-hydroxy-3-methoxyphenyl)propylene.
As a result, the reaction rate of the raw material 3-(4-hydroxy-3-methoxyphenyl)propylene was 90%, and the yield of the target product 1-(4-hydroxy-3-methoxyphenyl)-2,2-dimethoxypropane was 90%. rate 78%,
and the number of Pd turnovers was 156. Example 13 An experiment was conducted in the same manner as in Example 1 except that 3-phenylpropylene was replaced with 3-(3,4-methylenedioxyphenyl)propylene. As a result, the reaction rate of the raw material 3-(3,4-methylenedioxyphenyl)propylene was 95%, and the target product 1-
(3,4-methylenedioxyphenyl)-2,2-
The yield of dimethoxypropane was 88% and the Pd turnover number was 176. Examples 14 to 20 Example 2 except that 0.10 mol of each of the various 3-phenylpropylenes shown in Table 2 was used in place of 3-(3,4-dimethoxyphenyl)propylene.
The experiment was carried out using the same procedure. The results are shown in Table 2.

[Table] Examples 21 to 23 Using 0.10 mol each of the various 3-phenylpropylenes shown in Table 3, using 0.00025 mol each of the various amines shown in Table 3, and using bromide instead of palladium chloride. An experiment was conducted in the same manner as in Example 1, except that 0.0005 mol of palladium was used. The results are shown in Table 3.

[Table] Examples 24 to 26 0.10 mol each of the various 3-phenylpropylenes shown in Table 4, 0.25 mol n-butyl nitrite, n
-Butyl alcohol 0.5, triethylamine
0.00025 mol and catalyst palladium chloride 0.0005
A mol was charged into a reaction vessel, and the reaction was carried out at a reaction temperature of 60°C and a reaction time of 1.5 hours. After the reaction is completed, the reaction solution is subjected to gas chromatography to separate the unreacted raw materials in the reaction solution and the generated 1-
The phenyl-2,2-dialkoxypropanes were quantified and the Pd turnover number was calculated.
The results are shown in Table 4.

【table】

Claims (1)

[Claims] 1. 3- which may have a substituent on the benzene ring
A method for producing 1-phenyl-2,2-dialkoxypropanes, which comprises contacting phenylpropylenes with an alkyl nitrite ester in the presence of an alcohol and palladium salt catalyst and an amine. 2. The method for producing 1-phenyl-2,2-dialkoxypropanes according to claim 1, characterized in that no substituent is present on the benzene ring of the 3-phenylpropylenes. 3 In the benzene ring of 3-phenylpropylenes,
1 to 1 selected from the group consisting of hydroxyl group, lower alkyl group, lower alkoxy group, and benzyloxy group
1-phenyl-2,2 according to claim 1, characterized in that three substituents are present.
- A method for producing dialkoxypropanes. 4 In the benzene ring of 3-phenylpropylenes,
In cooperation with a part of the benzene ring, 1 to 1 oxygen atoms are
2. The method for producing 1-phenyl-2,2-dialkoxypropanes according to claim 1, wherein the substituent is present to form a 5- to 7-membered heterocycle containing two substituents. 5. Production of 1-phenyl-2,2-dialkoxypropanes according to claim 1, wherein the alkyl moiety of the nitrite alkyl ester is an alkyl group having 1 to 10 carbon atoms or a benzyl group. Method. 6. 1- of Claim 5, wherein the alkyl moiety constituting the alcohol is the same as the alkyl moiety of the nitrite alkyl ester.
A method for producing phenyl-2,2-dialkoxypropanes. 7. The method for producing 1-phenyl-2,2-dialkoxypropanes according to claim 1, wherein the palladium salt of the catalyst is a palladium halide. 8 Amines have general formula (However, in the formula, R ¹ , R ² , and R ³ are the same or different and represent a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and two of R ¹ , R ² , and R ³ are alkylene groups. 1-phenyl-2,2- according to claim 1, which is a compound represented by:
A method for producing dialkoxypropanes.