JP5040261B2 - Process for the production of (substituted propylsulfanyl) -alkyl alcohols - Google Patents

Description

  The present invention relates to a process for producing novel (substituted propylsulfanyl) -alkyl alcohols.

  (Substituted propylsulfanyl) -alkyl alcohol is known to be useful as a raw material for medical pesticides and functional substances (see Patent Document 1).

Conventionally, as a method for producing (substituted propylsulfanyl) -alkyl alcohol, for example, in the case of 2- (3-chloropropylsulfanyl) -ethanol, the following methods are known.
(1) A method of reacting 2-mercaptoethanol with dihalopropane in the presence of sodium ethoxide, as shown in the following reaction scheme (see Non-Patent Document 1).

  (2) A method in which an allylamine derivative represented by the following reaction scheme is reacted with 2-mercaptoethanol under an oxygen stream (see Patent Document 1).

  However, the method (1) has poor atomic efficiency, and a large amount of sodium bromide is by-produced as waste. In addition, since the method (2) is a reaction in which oxygen is blown, it is generally difficult to control the reaction. In addition, since oxygen exists in the reaction system, there is a risk of explosion due to some ignition source, which is problematic in terms of safety.

Therefore, the production of (substituted propylsulfanyl) -alkyl alcohols using conventional methods is industrially disadvantageous in terms of environmental problems and safety.
US Pat. No. 5,278,341 Journal of the American Chemical Society, 67th Edition, 1945, p. 1847

  Accordingly, an object of the present invention is to provide a method capable of safely and efficiently producing (substituted propylsulfanyl) -alkyl alcohols useful as raw materials for medical pesticides and functional substances by solving environmental problems. is there.

  As a result of earnestly examining industrially advantageous methods for the above-mentioned problems, the present inventors have reacted an allyl compound with 2-mercaptoethanol in the presence of a catalytic amount of an azo compound to obtain (substituted propylsulfanyl). -The inventors have found that alkyl alcohols can be produced easily, safely and efficiently, and have completed the present invention.

That is, this invention provides the manufacturing method of the (substituted propylsulfanyl) -alkyl alcohol as shown below.
Item 1. The following general formula (1);

(X in the formula represents a halogen, a hydroxyl group, an alkyl ether group, an aromatic ether group, a benzyl ether group, a trialkylsilyl ether group, an alkyl ester group or an alkylamide group.)
In the presence of an azo compound, an allyl compound represented by the following general formula (2):

(A in the formula represents an alkylene group.)
The following general formula (3), characterized by reacting with a hydroxymercapto compound represented by the formula:

(X and A in the formula are as defined above.)
The manufacturing method of (substituted propylsulfanyl) -alkyl alcohol represented by these.
Item 2. Item 2. The method according to Item 1, wherein the hydroxymercapto compound is 2-mercaptoethanol or 4-hydroxythiophenol.
Item 3. Item 3. The method according to Item 1 or 2, wherein the azo compound is 2,2'-azobisisobutyronitrile or dimethyl-2,2'-azobis (2-methylpropionate).
Item 4. The following general formula (1);

(X in the formula is as defined above.)
In the presence of an azo compound, an allyl compound represented by the following general formula (2):

(A in the formula is as defined above.)
The following general formula (3) obtained by reacting with a hydroxymercapto compound represented by:

(X and A in the formula are as defined above.)
(Substituted propylsulfanyl) -alkyl alcohol represented by

  According to the production method of the present invention, (substituted propylsulfanyl) -alkyl alcohol can be efficiently produced easily and safely under mild conditions with high atomic efficiency and less environmental burden.

  Hereinafter, the present invention will be described in detail.

  In the present invention, the allyl compound to be used is represented by the following general formula (1).

  X in the general formula (1) represents a halogen, a hydroxyl group, an alkyl ether group, an aromatic ether group, a benzyl ether group, a trialkylsilyl ether group, an alkyl ester group or an alkylamide group. Examples of the halogen include chlorine, bromine and iodine, and chlorine or bromine is preferable. Further, the alkyl moiety of the alkyl ether group, trialkylsilyl ether group, alkyl ester group and alkylamide group may be linear or branched, and in the case of a branched chain, the branch position and the number of branches are not limited. Preferably, an alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group is used, and a methyl group or an ethyl group is more preferable. Aromatic ether aromatics are not particularly limited, but include phenyl, alkylphenyl, alkoxyphenyl, chlorophenyl, bromophenyl, and iodophenyl groups. Phenyl, alkoxyphenyl or chlorophenyl Groups are preferred. The alkyl moiety of the alkylphenyl group and alkoxyphenyl group may be linear or branched, and in the case of a branched chain, the branch position and the number of branches are not limited. Preferably, an alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group is used, and a methyl group or an ethyl group is more preferable. Preferable specific examples of the allyl compound include 3-chloropropene, 2-propen-1-ol, allyl acetate, allyloxy-trimethylsilane, and allyl benzyl ether.

  In the present invention, the hydroxymercapto compound to be used is represented by the following general formula (2).

  A in the general formula (2) represents an alkylene group. The alkylene group may be linear or branched, and in the case of a branched chain, the branch position and the number of branches are not limited. As an alkylene group, 1-30 are preferable, and 2-10 are especially preferable. Preferable specific examples of the hydroxymercapto compound include mercaptomethanol, 2-mercaptoethanol, 3-mercaptopropanol, and 4-mercaptobutanol, and particularly preferably 2-mercaptoethanol or 3-mercaptopropanol. The usage-amount of a hydroxy mercapto compound is 0.5 mol-3.0 mol with respect to 1 mol of allyl compounds represented by the said General formula (1), Especially 0.7-2.0 mol is preferable.

  Examples of the azo compound used in the present invention include 2,2′-azobisisobutyronitrile, 2,2′-azobis (2-methylbutyronitrile), 2,2′-azobis (2,4-dimethyl- Valeronitrile), 1,1′-azobis (cyclohexane-1-carbonitrile), dimethyl-2,2′-azobis (2-methylpropionate) and 2,2′-azobis (2,4,4-trimethyl) Pentane), preferably 2,2′-azobisisobutyronitrile, 2,2′-azobis (2-methylbutyronitrile) and dimethyl-2,2′-azobis. Those selected from the group consisting of (2-methylpropionate) are particularly preferred. The amount of the azo compound used is preferably 0.1 to 100.0 mmol, particularly preferably 0.5 to 10.0 mmol, with respect to 1 mol of the allyl compound represented by the general formula (1).

  The organic solvent used in the present invention is not particularly limited as long as it does not react with the reaction reagent. For example, aromatic solvents such as benzene, toluene, xylene, diethyl ether, diisopropyl ether, methyl-t-butyl ether, cyclopentyl methyl ether. , Ether solvents such as dimethoxyethane and anisole, hydrocarbon solvents such as hexane, cyclohexane, heptane and octane, and halogen solvents such as dichloromethane and chloroform, among which benzene, toluene, hexane and heptane are preferred. .

  The amount of the organic solvent used for the reaction is preferably 0.5 mL to 10 mL, more preferably 1 mL to 5 mL, with respect to 1 g of the allyl compound represented by the general formula (1).

  The reaction temperature is preferably 20 ° C to 75 ° C, more preferably 30 ° C to 60 ° C. The reaction time is preferably 6 hours to 72 hours, more preferably 12 hours to 48 hours.

  After completion of the reaction, the reaction is stopped by adding water, and after obtaining a crude product by a conventional method such as extraction, washing, dehumidification, concentration, etc., it is purified using a conventional method such as column chromatography. (Substituted propylsulfanyl) -alkyl alcohol represented by

(In the formula, X and A are as defined above.)

  By using the production method of the present invention, it is not necessary to blow oxygen separately, the reaction control is simplified, and there is no risk of explosion due to any ignition source, and the (substituted propylsulfanyl) -alkyl alcohol is safe and efficient. Can be manufactured well.

  The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Production of 2- (3-chloropropylsulfanyl) -ethanol (reaction)
2-mercaptoethanol (9.36 g, 120.0 mmol), 2,2′-azobisisobutyronitrile (0.02 g, 0.12 mmol), and toluene (17 mL) were added to a 50 mL two-necked flask sufficiently purged with nitrogen. After the temperature of the solution was raised to 45 ° C., 7.60 g (100.0 mmol) of 3-chloropropene was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The obtained concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to give 6.99 g of 2- (3-chloropropylsulfanyl) -ethanol, yield 45.2. % As a slightly yellow transparent liquid.
¹ H-NMR (CDCl ₃ ): δ = 3.73 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 6.2 Hz, 2H), 2.69 (t, J = 6) 0.0 Hz, 2H), 2.68 (t, J = 7.0 Hz, 2H), 2.03 (tt, J = 7.0, 6.2 Hz, 2H)

Example 2 Production of 2- (3-chloropropylsulfanyl) -ethanol (reaction)
2-mercaptoethanol (9.36 g, 120.0 mmol), dimethyl-2,2′-azobis (2-methylpropionate) (0.03 g, 0.12 mmol), and toluene (17 mL) were placed in a 50 mL two-necked flask that had been sufficiently purged with nitrogen. added. After the temperature of the solution was raised to 45 ° C., 7.60 g (100.0 mmol) of 3-chloropropene was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The resulting concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to give 6.45 g of 2- (3-chloropropylsulfanyl) -ethanol, yield 41.9. % As a slightly yellow transparent liquid.

Comparative Example 1
(reaction)
To a 50 mL two-necked flask, 9.313 g (120.0 mmol) of 2-mercaptoethanol and 17 mL of toluene were added. The temperature of the solution was raised to 45 ° C., 7.60 g (100.0 mmol) of 3-chloropropene was added, and the mixture was heated and stirred for 72 hours while injecting dry air. However, the reaction did not proceed and 2- (3-chloropropylsulfanyl) -ethanol was not obtained.

Example 3 Production of 3- (3-chloropropylsulfanyl) -propanol (reaction)
To a 50 mL two-necked flask sufficiently purged with nitrogen, 11.06 g (120.0 mmol) of 3-mercaptopropanol, 0.02 g (0.12 mmol) of 2,2′-azobisisobutyronitrile and 17 mL of toluene were added. After the temperature of the solution was raised to 45 ° C., 7.60 g (100.0 mmol) of 3-chloropropene was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The resulting concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to give 9.84 g of 3- (3-chloropropylsulfanyl) -propanol, yield 51.2. % As a slightly yellow transparent liquid.
¹ H-NMR (CDCl ₃ ): δ = 3.75 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.2 Hz, 2H), 2.69-2.60 (m 4H), 2.09-2.01 (m, 2H), 1.89-1.82 (m, 2H)

Comparative Example 2
(reaction)
To a 50 mL two-necked flask, 11.06 g (120.0 mmol) of 3-mercaptopropanol and 17 mL of toluene were added. The temperature of the solution was raised to 45 ° C., 7.60 g (100.0 mmol) of 3-chloropropene was added, and the mixture was heated and stirred for 72 hours while injecting dry air. However, the reaction did not proceed and 3- (3-chloropropylsulfanyl) -propanol was not obtained.

Example 4 Production of 2- (3-acetoxypropylsulfanyl) -ethanol (reaction)
2-mercaptoethanol (9.36 g, 120.0 mmol), 2,2′-azobisisobutyronitrile (0.02 g, 0.12 mmol), and toluene (17 mL) were added to a 50 mL two-necked flask sufficiently purged with nitrogen. After the temperature of the solution was raised to 45 ° C., 10.01 g (100.0 mmol) of allyl acetate was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The obtained concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to give 16.06 g of 2- (3-acetoxypropylsulfanyl) -ethanol, yield 90.1 % As a slightly yellow transparent liquid.
¹ H-NMR (CDCl ₃ ): δ = 3.74 (t, J = 6.4 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6 0.0 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H), 2.13 (s, 3H), 1.83 (tt, J = 7.0, 6.4 Hz, 2H)

Example 5 Production of 3- (3-acetoxypropylsulfanyl) -propanol (reaction)
To a 50 mL two-necked flask sufficiently purged with nitrogen, 11.06 g (120.0 mmol) of 3-mercaptopropanol, 0.02 g (0.12 mmol) of 2,2′-azobisisobutyronitrile and 17 mL of toluene were added. After the temperature of the solution was raised to 45 ° C., 10.01 g (100.0 mmol) of allyl acetate was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The obtained concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to give 17.75 g of 3- (3-acetoxypropylsulfanyl) -propanol, yield 92.3. % As a slightly yellow transparent liquid.
¹ H-NMR (CDCl ₃ ): δ = 4.14 (t, J = 6.4 Hz, 2H), 3.74 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 7 .0 Hz, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.04 (s, 3H), 1.90 (tt, J = 7.0, 6.4 Hz, 2H), 1 .83 (tt, J = 7.0, 6.0 Hz, 2H)

Example 6 Production of 2- (3-hydroxypropylsulfanyl) -ethanol (reaction)
2-mercaptoethanol (9.36 g, 120.0 mmol), 2,2′-azobisisobutyronitrile (0.02 g, 0.12 mmol), and toluene (17 mL) were added to a 50 mL two-necked flask sufficiently purged with nitrogen. After the temperature of the solution was raised to 45 ° C., 5.81 g (100.0 mmol) of 2-propen-1-ol was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The obtained concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to obtain 12.86 g of 2- (3-hydroxypropylsulfanyl) -ethanol, yield 94.4. % As a slightly yellow transparent liquid.
¹ H-NMR (CDCl ₃ ): δ = 3.72 (t, J = 6.0 Hz, 2H), 3.71 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 6) 0.0 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.81 (tt, J = 7.2, 6.0 Hz, 2H)

Example 7 Production of 2- (3-trimethylsilylpropylsulfanyl) -ethanol (reaction)
2-mercaptoethanol (9.36 g, 120.0 mmol), 2,2′-azobisisobutyronitrile (0.02 g, 0.12 mmol), and toluene (17 mL) were added to a 50 mL two-necked flask sufficiently purged with nitrogen. After the temperature of the solution was raised to 45 ° C., 13.03 g (100.0 mmol) of allyloxy-trimethylsilane was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The obtained concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to obtain 13.55 g of 2- (3-trimethylsilylpropylsulfanyl) -ethanol, yield 65.0. % As a slightly yellow transparent liquid.
¹ H-NMR (CDCl ₃ ): δ = 3.61 (t, J = 5.8 Hz, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 5 .8 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 1.69 (tt, J = 7.2, 6.0 Hz, 2H), 0.01 (s, 9H)

Example 8 Production of 2- (3-benzyloxypropylsulfanyl) -ethanol (reaction)
2-mercaptoethanol (9.36 g, 120.0 mmol), 2,2′-azobisisobutyronitrile (0.02 g, 0.12 mmol), and toluene (17 mL) were added to a 50 mL two-necked flask sufficiently purged with nitrogen. The temperature of the solution was raised to 45 ° C., and then 14.82 g (100.0 mmol) of allyl benzyl ether was added dropwise. After completion of dropping, the reaction was continued for 48 hours at 45 ° C. After completion of the reaction, the solvent was distilled off after cooling to room temperature. The obtained concentrated residue was purified using silica gel column chromatography (silica gel, ethyl acetate / hexane = 2/1) to obtain 9.64 g of 2- (3-benzyloxypropylsulfanyl) -ethanol, yield 42. Obtained as a slightly yellow transparent liquid at 6%.
¹ H-NMR (CDCl ₃ ): δ = 7.38-7.13 (m, 5H), 4.49 (s, 2H), 3.71 (t, J = 6.0 Hz, 2H), 3. 55 (t, J = 6.0 Hz, 2H), 2.71 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.88 (tt, J = 7.2, 6.0Hz, 2H)

In any of the examples, a large amount of by-products did not occur, there was no danger of explosion, and there was no problem in terms of safety.

Claims (3)

In the nitrogen-substituted reactor, the following general formula (1):

(X in the formula represents a halogen, a hydroxyl group, an alkyl ether group, an aromatic ether group, a benzyl ether group, a trialkylsilyl ether group, an alkyl ester group or an alkylamide group.)
In the presence of an azo compound, an allyl compound represented by the following general formula (2):

(A in the formula represents an alkylene group.)
The following general formula (3) characterized by reacting at 20 to 75 ° C. with a hydroxymercapto compound represented by:

(X and A in the formula are as defined above.)
The manufacturing method of (substituted propylsulfanyl) -alkyl alcohol represented by these. Hydroxy mercapto compound The method of claim 1, wherein the 2-mercaptoethanol.   The method according to claim 1 or 2, wherein the azo compound is 2,2'-azobisisobutyronitrile or dimethyl-2,2'-azobis (2-methylpropionate).