JP2011074016A - Method of manufacturing 3-mercapto-1-propanol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To manufacture 3-mercapto-1-propanol (3MPO) in a high yield without using an ignitable aluminum lithium hydride. <P>SOLUTION: A compound represented by formula (1) is added to allyl alcohol to synthesize a compound represented by formula (2), and then the compound represented by formula (2) is hydrolyzed to give 3MPO in a high yield. In the formula, R<SP>1</SP>is an alkyl group. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel method for producing 3-mercapto-1-propanol (also referred to as “3-sulfanyl-1-propanol”) useful as an intermediate for production of pharmaceuticals, agricultural chemicals, electronic materials and the like.

  3-mercapto-1-propanol (hereinafter sometimes abbreviated as “3MPO”) is an intermediate for producing electronic materials (Patent Document 1), an intermediate for producing herbicide components (Patent Document 2), and pharmaceutical products. It is useful as an intermediate for production (Non-Patent Document 1). As a method for producing 3MPO, the following methods (a) and (b) have been known so far.

(A) A method of reducing 3-mercaptopropionic acid with lithium aluminum hydride (LiAlH ₄ ) as represented by the following formula (Non-patent Document 2).

  (B) A method of reacting 3-chloro-1-propanol with thiourea and then hydrolyzing the intermediate product with sodium hydroxide as represented by the following formula (Non-patent Document 3).

JP 2002-255968 A JP 2000-109477 A

Journal of the American Chemical Society, 2006, Vol. 128, pp. 6526-6527 Tetrahedron Letters, 1989, Vol. 30, No. 21, pp. 2763-2766 Journal of the American Chemical Society, 1945, Vol. 67, pp. 594-597

  Since the said manufacturing method (a) uses pyrophoric lithium aluminum hydride, it is not suitable for industrial production. In addition, the production method (b) has a low yield of 3MPO of about 40%. Therefore, an object of the present invention is to provide a method for producing 3MPO in a high yield without using ignitable lithium aluminum hydride.

The method for producing 3-mercapto-1-propanol according to the present invention, which has achieved the above object,
A compound represented by formula (1) is added to allyl alcohol to synthesize a compound represented by formula (2), and then the compound represented by formula (2) is hydrolyzed to give 3-mercapto-1- Propanol is synthesized (in the following formula, R ¹ represents an alkyl group).

  Hereinafter, the “compound represented by the formula (1)” and the “compound represented by the formula (2)” are abbreviated as “compound (1)” and “compound (2)”, respectively.

  Compound (1) is preferably thio-S-acetic acid. The hydrolysis of the compound (2) is preferably performed in the presence of at least one selected from the group consisting of hydrochloric acid and sulfuric acid, or at least one selected from the group consisting of ammonia and hydrazine.

  According to the production method of the present invention, 3-mercapto-1-propanol (3MPO) can be obtained in high yield without using ignitable lithium aluminum hydride.

  The production method of the present invention is obtained at low cost by the addition reaction (first reaction) of compound (1) to allyl alcohol and the hydrolysis reaction (second reaction) of compound (2) obtained in the first reaction. It is characterized in that 3MPO can be produced in high yield from allyl alcohol which is easy to do. Hereinafter, the first reaction and the second reaction will be described in order.

<First reaction>
The compound (1) used in the first reaction is a thio-S-carboxylic acid and can be easily obtained in the same manner as allyl alcohol. A compound (1) may be used individually by 1 type, and may use 2 or more types together. Compound (1) the number of carbon atoms in the alkyl group R ¹ in is preferably 1 to 10, more preferably 1-4. Examples of R ¹ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a butan-2-yl group, a 2-methylpropyl group, and a 2-methylpropan-2-yl group. Among them, a methyl group {that is, when the compound (1) is thio-S-acetic acid}, an ethyl group {that is, when the compound (1) is thio-S-propionic acid} is preferable, and a methyl group is more preferable. The amount of compound (1) to be used is preferably 1.0 to 2.0 mol, more preferably 1.0 to 1.5 mol, per 1 mol of allyl alcohol.

  The addition reaction (first reaction) of compound (1) to allyl alcohol is preferably carried out in the presence of a radical generator. As the radical generator, a known polymerization initiator (for example, 2,2′-azobisisobutyronitrile) used for radical polymerization or oxygen can be used, and among these, oxygen is preferable. When oxygen is used as the radical generator, the first reaction may be performed in an oxygen-containing gas atmosphere. The oxygen concentration in the gas atmosphere is preferably about 1 to 20% by volume. The gas atmosphere other than oxygen is preferably an inert gas (for example, nitrogen). As a method for supplying oxygen as a radical initiator, for example, (i) a method in which a gas atmosphere containing a predetermined concentration of oxygen is set before starting the reaction, the system is sealed, and the first reaction is performed; Various methods such as a method of continuously supplying a gas containing oxygen at a predetermined concentration during one reaction can be employed.

  The first reaction may be performed without a solvent or in a solvent that does not inhibit the reaction. A solvent may be used individually by 1 type and may use 2 or more types together. Examples of the solvent for the first reaction include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane and octane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and dichloropropane; acetic acid and propionic acid Carboxylic acids such as; and the like. When using a solvent, the amount thereof is preferably 50 mL or less, more preferably 15 mL or less, with respect to 1 g of allyl alcohol. When oxygen is used as the radical initiator, the first reaction is preferably carried out without solvent or in halogenated hydrocarbons; more preferably without solvent or in dichloromethane, chloroform or a mixed solvent thereof.

  The reaction temperature of the first reaction is preferably about 10 to 100 ° C., more preferably about 20 to 80 ° C., and the reaction time is preferably about 0.1 to 24 hours, more preferably 0.5 to 10 ° C. It is about time.

  The reaction mixture obtained after completion of the first reaction may be used for the second reaction as it is, or unreacted allyl alcohol and compound (1) and optionally used solvent are distilled off to remove compound (2). May be isolated and used in the second reaction.

<Second reaction>
The hydrolysis reaction (second reaction) of compound (2) which is thiocarboxylic acid S- (3-hydroxypropyl) is preferably performed in the presence of an acid or a base. An acid may be used individually by 1 type and may use 2 or more types together. Similarly, the base may be used alone or in combination of two or more.

  As the acid, either an inorganic acid or an organic acid can be used. Examples of the inorganic acid include hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, boric acid, hydrogen azide, chloric acid, bromic acid, carbonic acid, hydrogen sulfide and the like. Examples of the organic acid include trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like. Preferred acids are hydrochloric acid, sulfuric acid, trifluoroacetic acid, and methanesulfonic acid, and more preferred acids are hydrochloric acid and sulfuric acid. When an acid is used, the amount thereof is preferably 0.001 to 1.0 mol, more preferably 0.05 to 0.5 mol, per 1 mol of compound (2).

  Examples of the base include sodium hydroxide, potassium hydroxide, hydrazine, and ammonia. Among these, hydrazine and ammonia are preferable. When a base is used, the amount thereof is preferably 1.0 to 5.0 mol, more preferably 1.0 to 3.0 mol, per 1 mol of compound (2).

  The hydrolysis reaction (second reaction) is preferably performed in a solvent. A solvent may be used individually by 1 type and may use 2 or more types together. Examples of the solvent for the second reaction include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, cyclopentyl methyl ether, tert-butyl methyl ether, anisole, and the like. Ethers; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dichloropropane; methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert Alcohols such as butanol; acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl -2 aprotic polar solvents such as imidazolidinone; and water. Among these, methanol, water, and a mixed solvent of methanol and water preferred. The amount of the solvent in the second reaction is preferably 0.5 to 50 mL, more preferably 1 to 15 mL with respect to 1 g of compound (2).

  The reaction temperature of the second reaction is preferably about 10 to 120 ° C., more preferably about 20 to 100 ° C., depending on the solvent used, and the reaction time is preferably about 0.1 to 24 hours. Preferably it is about 0.5 to 10 hours.

  After completion of the second reaction, it is preferable to purify the crude product after obtaining a crude product of 3MPO by a conventional method such as quenching, extraction, washing, dehumidification, and solvent evaporation. Examples of the purification means include distillation, column chromatography, crystallization and the like.

  EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited by the following examples, and appropriate modifications are made within a range that can meet the above and the following purposes. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

Example 1
After adding allyl alcohol (5.8 g, 100 mmol) and chloroform (60 mL) to a 100 mL flask and sealing the gas atmosphere in the flask with a nitrogen concentration of about 85 vol% and an oxygen concentration of about 15 vol%, the flask contents were The temperature was raised to 50-60 ° C., and thio-S-acetic acid (8.0 g, 105 mmol) was added dropwise. After completion of dropping, the reaction was carried out at 50 to 60 ° C. for 2 hours. After completion of the reaction, chloroform was distilled off under reduced pressure at 50 ° C. to obtain 12.5 g (93 mmol, 93% yield with respect to allyl alcohol) of thioacetic acid S- (3-hydroxypropyl) as a slightly yellow liquid. .

  To the 200 mL flask, add the total amount of thioacetic acid S- (3-hydroxypropyl) (12.5 g, 93 mmol), hydrazine monohydrate (5.1 g, 102 mmol) and methanol (100 mL) obtained as described above. It was made to react at 20-30 degreeC for 1 hour. After completion of the reaction, methanol was distilled off, water (30 mL) was added, and the mixture was extracted with chloroform (50 mL × 3 times). The extracted chloroform layer was dehumidified with anhydrous magnesium sulfate (10 g), the anhydrous magnesium sulfate was filtered, and the crude product obtained by distilling off the chloroform was subjected to simple distillation (15 Torr, 90 ° C.). The yellow liquid 3MPO was obtained in 7.2 g (78 mmol). The yield of 3MPO was 84% based on the intermediate product S- (3-hydroxypropyl) thioacetate and 78% based on the starting material, allyl alcohol.

¹ H-NMR (CDCl ₃ ) of 3MPO obtained in Example 1
δ = 3.75 (t, 2H), 2.63 (m, 2H), 1.87 (m, 2H), 1.48 (m, 1H), 1.38 (t, 1H)

Example 2
After adding allyl alcohol (5.8 g, 100 mmol) and chloroform (30 mL) to a 100 mL flask and sealing the gas atmosphere in the flask with a nitrogen concentration of about 85 vol% and an oxygen concentration of about 15 vol%, the flask contents were The temperature was raised to 50-60 ° C., and thio-S-acetic acid (8.0 g, 105 mmol) was added dropwise. After completion of dropping, the reaction was carried out at 50 to 60 ° C. for 2 hours. After completion of the reaction, chloroform was distilled off under reduced pressure at 50 ° C. to obtain 12.1 g (90 mmol, yield 90% with respect to allyl alcohol) of thioacetic acid S- (3-hydroxypropyl) as a slightly yellow liquid. .

  To a 100 mL flask was added the total amount of thioacetic acid S- (3-hydroxypropyl) (12.1 g, 90 mmol) obtained above, 28% aqueous ammonia (13.7 g, 225 mmol) and water (30 mL), It was made to react at 20-30 degreeC for 5 hours. After completion of the reaction, the mixture was extracted with chloroform (50 mL × 3 times). The extracted chloroform layer was dehumidified with anhydrous magnesium sulfate (10 g), the anhydrous magnesium sulfate was filtered, and the crude product obtained by distilling off the chloroform was subjected to simple distillation (15 Torr, 90 ° C.). The yellow liquid 3MPO was obtained in 6.5 g (70 mmol). The yield of 3MPO was 78% with respect to the intermediate product S- (3-hydroxypropyl) thioacetate and 70% with respect to the starting material allyl alcohol.

¹ H-NMR (CDCl ₃ ) of 3MPO obtained in Example 2
δ = 3.75 (t, 2H), 2.63 (m, 2H), 1.87 (m, 2H), 1.48 (m, 1H), 1.38 (t, 1H)

Example 3
After adding allyl alcohol (5.8 g, 100 mmol) and dichloromethane (60 mL) to a 100 mL flask and sealing the gas atmosphere in the flask with a nitrogen concentration of about 85% by volume and an oxygen concentration of about 15% by volume, the flask contents were The temperature was raised to 50-60 ° C., and thio-S-acetic acid (8.0 g, 105 mmol) was added dropwise. After completion of dropping, the reaction was carried out at 50 to 60 ° C. for 2 hours. After completion of the reaction, dichloromethane was distilled off under reduced pressure at 50 ° C. to obtain 12.9 g (96 mmol, yield 96% with respect to allyl alcohol) of thioacetic acid S- (3-hydroxypropyl) as a slightly yellow liquid. .

  To a 200 mL flask, add the total amount of thioacetic acid S- (3-hydroxypropyl) (12.9 g, 96 mmol), 98% sulfuric acid (0.96 g, 9.6 mmol) and methanol (100 mL) obtained as described above. , Reacted at 50 to 60 ° C. for 3 hours. After completion of the reaction, methanol was distilled off, water (30 mL) was added, and the mixture was extracted with chloroform (50 mL × 3 times). The extracted chloroform layer was dehumidified with anhydrous magnesium sulfate (10 g), the anhydrous magnesium sulfate was filtered, and the crude product obtained by distilling off the chloroform was subjected to simple distillation (15 Torr, 90 ° C.). 7.8 g (84 mmol) of 3MPO as a yellow liquid was obtained. The yield of 3MPO was 88% with respect to the intermediate product S- (3-hydroxypropyl) thioacetate, and 84% with respect to the starting material, allyl alcohol.

¹ H-NMR (CDCl ₃ ) of 3MPO obtained in Example 3
δ = 3.75 (t, 2H), 2.63 (m, 2H), 1.87 (m, 2H), 1.48 (m, 1H), 1.38 (t, 1H)

Example 4
After adding allyl alcohol (5.8 g, 100 mmol) and chloroform (60 mL) to a 100 mL flask and sealing the gas atmosphere in the flask with a nitrogen concentration of about 96 vol% and an oxygen concentration of about 4 vol%, the flask contents were The temperature was raised to 50-60 ° C., and thio-S-acetic acid (8.0 g, 105 mmol) was added dropwise. After completion of dropping, the reaction was carried out at 50 to 60 ° C. for 2 hours. After completion of the reaction, chloroform was distilled off under reduced pressure at 50 ° C. to obtain 12.6 g (94 mmol, 94% yield based on allyl alcohol) of thioacetic acid S- (3-hydroxypropyl) as a slightly yellow liquid. .

  A 200 mL flask was charged with the total amount of S- (3-hydroxypropyl) thioacetate (12.6 g, 94 mmol), 35% aqueous hydrochloric acid (0.98 g, 9.4 mmol) and methanol (120 mL) obtained as described above. In addition, the mixture was reacted at 50 to 60 ° C. for 2 hours. After completion of the reaction, methanol and hydrochloric acid were distilled off, and simple distillation (15 Torr, 90 ° C.) was performed to obtain 7.2 g (78 mmol) of 3MPO as a slightly yellow liquid. The yield of 3MPO was 83% based on the intermediate product S- (3-hydroxypropyl) thioacetate and 78% based on the starting material, allyl alcohol.

¹ H-NMR (CDCl ₃ ) of 3MPO obtained in Example 4
δ = 3.75 (t, 2H), 2.63 (m, 2H), 1.87 (m, 2H), 1.48 (m, 1H), 1.38 (t, 1H)

Example 5
After adding allyl alcohol (5.8 g, 100 mmol) to a 100 mL flask and sealing the gas atmosphere in the flask with a nitrogen concentration of about 96% by volume and an oxygen concentration of about 4% by volume, the flask contents were brought to 50-60 ° C. The temperature was raised, and thio-S-acetic acid (8.0 g, 105 mmol) was added dropwise. After completion of dropping, the reaction was carried out at 50 to 60 ° C. for 2 hours. After completion of the reaction, the remaining allyl alcohol and thio-S-acetic acid were distilled off to obtain 11.4 g (85 mmol, 85% yield of allyl alcohol) of thioacetic acid S- (3-hydroxypropyl) as a slightly yellow liquid. %).

  A 200 mL flask was charged with the entire amount of thioacetic acid S- (3-hydroxypropyl) (11.4 g, 85 mmol), 35% aqueous hydrochloric acid (0.88 g, 8.5 mmol) and methanol (120 mL) obtained as described above. In addition, the mixture was reacted at 50 to 60 ° C. for 2 hours. After completion of the reaction, methanol and hydrochloric acid were distilled off, and simple distillation (15 Torr, 90 ° C.) was performed to obtain 6.7 g (72 mmol) of 3MPO as a slightly yellow liquid. The yield of 3MPO was 85% with respect to S- (3-hydroxypropyl) thioacetate as an intermediate product, and 72% with respect to allyl alcohol as a starting material.

¹ H-NMR (CDCl ₃ ) of 3MPO obtained in Example 5
δ = 3.75 (t, 2H), 2.63 (m, 2H), 1.87 (m, 2H), 1.48 (m, 1H), 1.38 (t, 1H)

Example 6
After adding allyl alcohol (5.8 g, 100 mmol) and chloroform (60 mL) to a 100 mL flask and sealing the gas atmosphere in the flask with a nitrogen concentration of about 85 vol% and an oxygen concentration of about 15 vol%, the flask contents were The temperature was raised to 50-60 ° C., and thio-S-propionic acid (9.9 g, 110 mmol) was added dropwise. After completion of dropping, the reaction was carried out at 50 to 60 ° C. for 3 hours. After completion of the reaction, chloroform was distilled off under reduced pressure at 50 ° C. to obtain 13.5 g (91 mmol, 91% yield with respect to allyl alcohol) of thiopropionic acid S- (3-hydroxypropyl) as a slightly yellow liquid. It was.

  A 200 mL flask was charged with the total amount of thiopropionic acid S- (3-hydroxypropyl) (13.5 g, 91 mmol), hydrazine monohydrate (5.0 g, 100 mmol) and methanol (100 mL) obtained as described above. In addition, the mixture was reacted at 20 to 30 ° C. for 1 hour. After completion of the reaction, methanol was distilled off, water (30 mL) was added, and the mixture was extracted with chloroform (50 mL × 3 times). The extracted chloroform layer was dehumidified with anhydrous magnesium sulfate (10 g), the anhydrous magnesium sulfate was filtered, and the crude product obtained by distilling off the chloroform was subjected to simple distillation (15 Torr, 90 ° C.). 6.7 g (72 mmol) of 3MPO as a yellow liquid was obtained. The yield of 3MPO was 80% with respect to the intermediate product S- (3-hydroxypropyl) thiopropionate, and 72% with respect to the starting material, allyl alcohol.

¹ H-NMR (CDCl ₃ ) of 3MPO obtained in Example 6
δ = 3.75 (t, 2H), 2.63 (m, 2H), 1.87 (m, 2H), 1.48 (m, 1H), 1.38 (t, 1H)

  The conditions of Examples 1 to 6 and the yield of 3MPO are shown in Table 1 below. Unlike the conventional production method (a), the production method of the present invention can produce 3MPO without using ignitable lithium aluminum hydride. Further, the yield of 3MPO (based on allyl alcohol as a starting material) in the production method of the present invention is 70 to 84%, which is a significant improvement over the conventional production method (b).

  According to the production method of the present invention, 3-mercapto-1-propanol (3MPO) can be obtained in high yield without using ignitable lithium aluminum hydride. 3MPO is useful as an intermediate for production of pharmaceuticals, agricultural chemicals, electronic materials and the like.

Claims (3)

A method for producing 3-mercapto-1-propanol, comprising:
A compound represented by formula (1) is added to allyl alcohol to synthesize a compound represented by formula (2), and then the compound represented by formula (2) is hydrolyzed to give 3-mercapto-1- A production method comprising synthesizing propanol.
[Wherein R ¹ represents an alkyl group. ]   The production method according to claim 1, wherein the compound represented by the formula (1) is thio-S-acetic acid.   The compound represented by formula (2) is hydrolyzed in the presence of at least one selected from the group consisting of hydrochloric acid and sulfuric acid, or at least one selected from the group consisting of ammonia and hydrazine. The manufacturing method as described.