JP2001089414A - Method for manufacturing tert-butoxycarbonyl chloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing tert-butoxycarbonyl chloride (BOC-chloride) useful for a protecting group of an intermediate to be used in organic synthesis of agricultural chemicals, medicament, etc., and to provide a method for conducting tert-butoxycarbonylation reaction (BOD-reaction) in which the formed BOC-chloride is reacted with amines or alcohols. SOLUTION: This method for manufacturing the BOC-chloride comprises reacting tert-butyl alcohol with phosgene in the presence of a pyridine compound of formula [I] (R1 is a halogen or a 2-4C alkyl; and R2 is H, methyl, or ethyl) at -40 to 0 deg.C in a benzene-based solvent, such as toluene. The resulting BOC- chloride is used for reacting with the amine or the alcohol to conduct the BOD- reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a te which is often used as a protecting group in the synthesis of organic compounds such as agricultural and pharmaceutical intermediates.
The present invention relates to a method for producing rt-butoxycarbonyl chloride (BOC-chloride) and a method for producing an organic intermediate using the same.

[0002]

2. Description of the Related Art Conventionally, as a method for producing BOC-chloride,
Using pyridine or 2- or 3-picoline as a base in tert-butyl alcohol and phosgene in an ether solvent, the reaction temperature is -25 to -15 ° C, and the ripening temperature is -15 to -5 ° C. A method for obtaining BOC-chloride with a yield of 85% (JP-A-10-114715) is known.

[0003]

When introducing BOC as a protecting group for agricultural pharmaceutical intermediates [0008] Although BOC ₂ O is used, BOC ₂
Since O is expensive, there has been a demand for a method that can be converted to BOC at a lower cost. A method for producing BOC-chloride in an ether-based solvent is known. However, since an ether-based solvent is industrially dangerous and difficult to recover, BOC-chloride is used in a more industrially advantageous solvent (eg, toluene). -Synthesis of chloride was desired. However, it has been found that when pyridine or 2- or 3-picoline described in JP-A-10-114715 is used as a base, the yield of BOC-chloride is significantly reduced in a toluene solvent.

[0004]

Means for Solving the Problems As a result of a detailed study of the above-mentioned problems, the present inventors have found that even if a benzene-based solvent which is industrially easy to use is used, the desired product can be easily obtained at a yield equal to or higher than the conventional one. The inventors have found the conditions that can be obtained, and have completed the present invention.

That is, the present invention relates to a method for preparing tert-butyl alcohol and phosgene in a benzene-based solvent by the formula [I]

Embedded image (Wherein R ¹ represents a halogen atom or C ₂ -C ₄ alkyl, and R ² represents a hydrogen atom, a methyl group or an ethyl group) at -40 to 0 ° C. in the presence of pyridines represented by A method for producing tert-butoxycarbonyl chloride, characterized by reacting. Further, the present invention provides a method for producing tert-butoxycarbonyl chloride, wherein the reaction solution is washed with water at 0 ° C. or lower. In addition, the tert-
This is a method for BOC conversion of amines, amino acids, and alcohols, using butoxycarbonyl chloride.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION As R ¹ , a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, ethyl, propyl,
Examples include an alkyl group such as isopropyl, butyl, isobutyl, and tert-butyl. As the pyridines used in the present invention, specifically, 2-ethylpyridine, 5-ethyl-
2-picoline. As benzene solvents,
Benzene which may be substituted, such as benzene, toluene and xylene, is preferred, with toluene being preferred.
The molar ratio of the reaction is from 0.7 to 1.5 mol, preferably from 0.9 to 1.1 mol, to 1 mol of tert-butanol. The base is 1.0-3.0 mol, preferably 1.1-1.3 mol. Regarding the reaction temperature, -40 to 0 ° C, preferably
When the temperature is -25 to -5 ° C and the reaction is aged at -20 to -5 ° C, the reaction can be performed in a relatively short time. On this occasion,
If the temperature is higher than 0 ° C., BOC-chloride is decomposed and the yield is lowered, which is not preferable.

The reaction is carried out by dissolving tert-butyl alcohol and phosgene in a benzene-based solvent, dropping pyridines dissolved in the benzene-based solvent, and aging.

The base hydrochloride generated during the reaction can be removed by filtration. However, water is added to the reaction solvent at a temperature of 0 ° C. or lower at 0.05 ° C. or lower for shortening the process and recovering the base.
It is advantageous to remove the aqueous layer from the reaction solvent by adding 0 times, preferably 0.1 to 1 times, and separating the aqueous layer. The base in the aqueous layer can be reused by removing water.

[0009] The BOC- in the benzene-based solvent thus obtained is obtained.
Chloride can be used together with a solvent as a protecting group for organic intermediates such as agricultural and pharmaceutical intermediates. Examples of the organic intermediate include amines, amino acids and alcohols.Examples of the amines include 3-hydroxypyrrolidine, piperazine derivatives, aminothiazolyl pentenoic acid, and the like; amino acids such as alanine, phenylalanine,
Examples of alcohols such as tryptophan, glutamic acid, valine, 4-hydroxyproline, 3-hydroxypyrrolidine, and aminophenylbutyric acid include phenolic alcohols such as phenol.

[0010]

The present invention will be described in detail below with reference to examples. The product was identified by MS, NMR and HPLC,
Quantification was performed.

Comparative Example 1 (Production of BOC-chloride) Phosgene (20 g, 0.2 mol) was mixed with tert-butyl alcohol (16.5 g, 0.1 g).
22mol) containing toluene solution 200ml, cooled and stirred at -20 ° C, 2-picoline 19.0g (0.24mol) containing toluene solution 6
0 g was gradually added dropwise over about 1 hour. Then reduce the temperature to -1
The temperature was raised to 0 ° C., and the mixture was aged and stirred for about 5 hours until phosgene disappeared. After completion of the reaction, the by-product pyridine hydrochloride was filtered off and washed with a small amount of toluene to obtain a toluene solution of BOC-chloride in a yield of 50% (vs. tert-butanol). Save -20
C. in a freezer.

Example 1 (Production of BOC-chloride) 16.6 g (0.168 mol) of phosgene was added to 11.9 g of tert-butyl alcohol.
The mixture was blown into 160 ml of a toluene solution containing g (0.16 mol), and 50 g of a toluene solution containing 23.3 g (0.192 mol) of 5-ethyl-2-picoline was gradually added dropwise over about 1 hour under cooling and stirring at -20 ° C.
Thereafter, the temperature was raised to -10 ° C, and the mixture was aged and stirred for about 2 hours until phosgene disappeared. After the completion of the reaction, the by-product pyridine hydrochloride was filtered off and washed with a small amount of toluene to obtain a toluene solution of BOC-chloride in a yield of 88% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.

Example 2 (Production of BOC-chloride) 16.6 g (0.168 mol) of phosgene was added to 11.9 g of tert-butyl alcohol.
g (0.16 mol) containing 160 ml of mesitylene solution, -20 ° C
Under cooling and stirring, 23.3 g (0.192 mol) of 5-ethyl-2-picoline
50 g of the contained mesitylene solution was gradually added dropwise over about 1 hour. Thereafter, the temperature was raised to -10 ° C, and the mixture was aged and stirred for about 2 hours until phosgene disappeared. After completion of the reaction, by-product pyridine hydrochloride was filtered off and washed with a small amount of mesitylene,
A mesitylene solution of C-chloride was obtained with a yield of 84% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.

Example 3 (Production of BOC-chloride) 31.2 g (0.315 mol) of phosgene was added to 22.2 g of tert-butyl alcohol.
The mixture was blown into 300 ml of a toluene solution containing g (0.30 mol), and 50 g of a toluene solution containing 43.6 g (0.360 mol) of 5-ethyl-2-picoline was gradually added dropwise over about 1 hour under cooling and stirring at -20 ° C.
Thereafter, aging was performed at -20 ° C, and aging and stirring were performed for about 4 hours until phosgene disappeared. After completion of the reaction, the by-product pyridine hydrochloride was filtered off and washed with a small amount of toluene to obtain a toluene solution of BOC-chloride in a yield of 90% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.

Example 4 (Production of BOC-chloride) 15.9 g (0.16 mol) of phosgene was added to 11.9 g of tert-butyl alcohol.
(0.16 mol) was added to 160 ml of a toluene solution, and 50 g of a toluene solution containing 20.6 g (0.192 mol) of 2-ethylpyridine was gradually added dropwise over about 1 hour while cooling and stirring at -20 ° C. Thereafter, the temperature was raised to -10 ° C, and the mixture was aged and stirred for about 3 hours until phosgene disappeared. After the reaction was completed, the by-product pyridine hydrochloride was separated by filtration and washed with a small amount of toluene. A toluene solution of BOC-chloride was obtained in 91% yield (vs. tert-butanol). Storage was performed in a freezer at -20 ° C.

Example 5 (Production of BOC-chloride (removal of base with water)) 31.2 g (0.315 mol) of phosgene was added to 22.2 g of tert-butyl alcohol.
g (0.30 mol) containing toluene solution 200ml, -5 ~ 0 ℃
5-ethyl-2-picoline 4 under cooling and stirring (mainly -3 ° C)
78 g of a toluene solution containing 3.6 g (0.36 mol) was gradually added dropwise over about 1 hour. Thereafter, aging was performed at -5 to 0 ° C (mainly -2 ° C), and the mixture was aged and stirred for about 3 hours until phosgene disappeared.
After completion of the reaction, 20 ml of cooled water was added under cooling to 0 ° C.
After stirring for 5 minutes, the by-product 5-ethyl-2-picoline hydrochloride is dissolved. After standing for 5 minutes, by separating into two layers and separating the aqueous layer, 240.1 g (21.0 wt%) of a toluene solution of Bock chloride
Was obtained in a yield of 80% (vs. tert-butanol). Storage is -20 ℃
Went in the freezer. When the aqueous layer is made alkaline (pH 13.7) by adding 55 g of a 28% aqueous solution of caustic soda, the aqueous layer is separated into two layers, and the aqueous layer is separated to recover 48.1 g of 5-ethyl-2-picoline (87.5 wt. %, Moisture 10.0wt%, toluene 2.5wt%)
Was obtained with a recovery of 96.5%. The obtained recovered 5-ethyl-2-picoline can be reused by removing water by azeotropic dehydration.

Example 6 (Production of BOC-chloride (removal of base with water)) 29.7 g (0.30 mol) of phosgene was added to 22.2 g of tert-butyl alcohol.
(0.30mol) containing toluene solution 200ml, -5 ~ 0 ℃
35.4 g of 2-ethylpyridine under cooling and stirring (mainly -2 ° C)
70 g of a toluene solution (0.33 mol) was gradually added dropwise over about 1 hour. Thereafter, aging was performed at -5 to 0 ° C (mainly -1 ° C), and the mixture was aged for about 3 hours until phosgene disappeared. After completion of the reaction, 20 ml of cooled water is added under cooling to 0 ° C., and the mixture is stirred for 5 minutes to dissolve 2-ethylpyridine hydrochloride by-produced. After standing for 5 minutes, the aqueous layer separated into two layers was separated to obtain 239.2 g (22.1 wt%) of a toluene solution of box chloride in a yield of 85% (vs. tert-butanol). Storage was performed in a freezer at -20 ° C. The aqueous layer was added with 51% of a 28% aqueous solution of caustic soda and made alkaline (pH 13.8), separated into two layers, and the aqueous layer was separated to recover 2-ethylpyridine 38.9%.
g (pure content: 84.9 wt%, water: 14.1 wt%, toluene: 0.9 wt%) was obtained at a recovery rate of 93.3%. The recovery rate was improved to 96.3% by re-extracting the aqueous layer with 20 ml of toluene. The obtained recovered 2-ethylpyridine can be reused by removing water by azeotropic dehydration.

Example 7 (N-tert-butoxycarbonyl-4-)
Production of hydroxyproline) Dissolve 3.9 g (30 mmol) of 4-hydroxyproline in 30 ml of water,
Under cooling and stirring at 0 ° C, 31.5 g (1
(5.6 wt%, 36 mmol). Next, at 0 ° C, 28% NaOH aqueous solution
9.4 g (66 mmol) was added dropwise over about 1 hour, and the mixture was aged and stirred at 0 ° C. for 3 hours. When HPLC analysis was performed on the reaction solution, N-tert
The production rate of -butoxycarbonyl-4-hydroxyproline is
86.2%. After the completion of the reaction, the reaction solution is separated, and the obtained aqueous layer (pH 8) is adjusted to pH 2.5 using 35 ml of 10% KHSO ₄ . This aqueous solution was extracted three times with ethyl acetate (400 ml in total), and the obtained ethyl acetate layer was dehydrated with magnesium sulfate.
Filtration and concentration. The concentrate was crystallized by adding 30 ml of hexane and stirring. The obtained crystals were filtered and pump-dried at 30 ° C. for 3 hours, N-tert-butoxycarbonyl-4-hydroxyproline 5.6 g (purity 99.6%, mp 124-125 ° C.), yield
81%.

Example 8 (N-tert-butoxycarbonyl-4-)
Production of hydroxyproline) Dissolve 3.9 g (30 mmol) of 4-hydroxyproline in 30 ml of water,
33.0 g (66 mmol) of an 8% aqueous NaOH solution are added. Next, while cooling and stirring at 0 ° C., 31.7 g of a Bock chloride toluene solution (15.5 wt%,
36 mmol) was added dropwise over 20 minutes, and the mixture was aged and stirred at 0 ° C. for 3 hours. When HPLC analysis is performed on the reaction solution, the yield of N-tert-butoxycarbonyl-4-hydroxyproline is 75.1%.
Met. After completion of the reaction, the reaction solution was separated, and the resulting aqueous layer was separated.
(PH8) is a PH2.5 with 10% KHSO ₄ 35ml. This aqueous solution was extracted three times with ethyl acetate (400 ml in total), and the obtained ethyl acetate layer was dried over magnesium sulfate, filtered,
Concentrated. The concentrate was crystallized by adding 30 ml of hexane and stirring. The obtained crystals were filtered and dried by pumping at 30 ° C. for 3 hours to obtain 4.9 g of N-tert-butoxycarbonyl-4-hydroxyproline (purity 99.7%, mp 124-125 ° C.) with a yield of 70%.

Example 9 (N-tert-butoxycarbonyl-3-
Production of hydroxypyrrolidine) 13.1 g (100 mmol) of 4-hydroxyproline and 0.49 g (5 mmol) of mesityl oxide are mixed with 50 ml of diglyme, and the mixture is heated and refluxed at 155 ° C. for 4 hours under a nitrogen stream. The obtained reaction solution is distilled and recovered using a Widmer type rectification tube (0.4 KPa / 30 to 35 ° C.). 14.3 g (100 mmol) of 28% NaOH aqueous solution was added to the residue containing 3-hydroxypyrrolidine as a main component.
Was added, and 93.4 g (19.0 wt%, 130 mmol) of Bock chloride toluene solution was added dropwise over 15 minutes while cooling and stirring at 4 to 6 ° C.
The mixture was aged and stirred at 66 ° C. for 3 hours. After completion of the reaction, the reaction solution was separated, and the obtained toluene layer was concentrated, and crystallized by adding 50 ml of Isopar G and stirring. The obtained crystals are filtered,
By drying under reduced pressure at room temperature for 3 hours, N-tert-butoxycarbonyl-3-hydroxypyrrolidine 16.1 g (purity 99.5%, mp62
-63 ° C) from 4-hydroxyproline in 86% yield.

Example 10 (N-tert-butoxycarbonyl-
Production of 3-hydroxypyrrolidine) 26.2 g (200 mmol) of 4-hydroxyproline and 0.98 g (10 mmol) of mesityl oxide are mixed with 90 ml of diglyme, and the mixture is heated and refluxed at 150 ° C for 4 hours under a nitrogen stream. The obtained reaction solution is
The mixture was cooled to 0 ° C., and 10 ml of an isopropanol solution saturated with hydrochloric acid gas was added dropwise to precipitate a salt, which was filtered and pump-dried to obtain 3-hydroxypyrrolidine hydrochloride (22.97 g, yield 93.8%). Half of 11.48 g (983 mmol) of this 3-hydroxypyrrolidine hydrochloride was added at 4 to 6 ° C with a 28% aqueous NaOH solution 28.0.
g (196 mmol) was added thereto, and while cooling and stirring at 4 to 6 ° C, 116.0 g (15.3 wt%, 130 mmol) of a Bock chloride toluene solution was added dropwise over 15 minutes, followed by aging and stirring at 4 to 6 ° C for 3 hours. After the reaction,
The reaction solution was separated, and the obtained toluene layer was concentrated. The concentrate was crystallized by adding 50 ml of Isopar G and stirring. The obtained crystals were filtered and dried under reduced pressure at room temperature for 3 hours to obtain 15.3 g of N-tert-butoxycarbonyl-3-hydroxypyrrolidine (purity 99.7%, mp61-62 ° C) at a yield of 81.9 from 4-hydroxyproline. %.

[0022]

According to the present invention, BOC-
Chloride can be produced, and it is suitable for a method for producing BOC-chloride on an industrial scale because a benzene-based solvent is used.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (reference) C07C 69/96 C07C 69/96 A // C07B 61/00 300 C07B 61/00 300 F term (reference) 4G069 AA02 BA21A BA21B BE38A BE38B CB68 4H006 AA02 AC40 AC47 AC48 AD16 BA51 BA92 BB11 BB31 BC10 BE52 BS90 4H039 CA66 CD10

Claims (6)

[Claims] (1) tert-butyl alcohol and phosgene,
In a benzene solvent, the formula [I] (Wherein, R ¹ represents a halogen atom or C ₂ -C ₄ alkyl, and R ² represents a hydrogen atom, a methyl group, or an ethyl group)
A method for producing tert-butoxycarbonyl chloride, wherein the reaction is carried out at -40 to 0 ° C. in the presence of a pyridine represented by the formula: 2. The method of claim 1, wherein tert-butyl alcohol and phosgene are
In a benzene solvent, the formula [I] (Wherein, R ¹ represents a halogen atom or C ₂ -C ₄ alkyl, and R ² represents a hydrogen atom, a methyl group, or an ethyl group)
In the presence of pyridines represented by -40 ~ 0 ° C.,
Further, the reaction solution is washed with water at 0 ° C or less.
A method for producing rt-butoxycarbonyl chloride. 3. The method according to claim 1, wherein the pyridine is 5-ethyl-2-picoline or 2-ethylpyridine.
A method for producing tert-butoxycarbonyl chloride. 4. A method for converting tert-butyl alcohol and phosgene into
In a benzene solvent, the formula [I] (Wherein, R ¹ represents a halogen atom or C ₂ -C ₄ alkyl, and R ₂ represents a hydrogen atom, a methyl group, or an ethyl group)
In the presence of pyridines represented by, characterized by using tert-butoxycarbonyl chloride obtained by reacting at -40 ~ 0 ℃, amines, alcohols, amino acids BO
C conversion method. 5. The amine is 3-hydroxypyrrolidine,
5. The BOC-forming method according to claim 4, wherein the piperazine derivative is aminothiazolylpentenoic acid. 6. The BOC-forming method according to claim 4, wherein the amino acids are alanine, phenylalanine, tryptophan, glutamic acid, valine, 2-naphthylalanine, 4-hydroxyproline, and aminophenylbutyric acid.