JP2003335732A - METHOD FOR PRODUCING OPTICALLY ACTIVE gamma- HYDROXYALKYLAMINES - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for simply producing optically active γ- hydroxyalkylamines useful as an intermediate for medicines and agrochemicals without causing racemization of an asymmetric carbon atom. <P>SOLUTION: The method for producing the optically active γ- hydroxyalkylamines is carried out as follows. A carbonyl group of optically active β-hydroxyamides is reduced to produce the optically active γ- hydroxyalkylamines. In the process, an acid treatment is carried out within the range of pH ≥4 after completing the reducing reaction. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active γ-hydroxyalkylamines. Optically active γ-hydroxyalkylamines are useful compounds as intermediates for medicines and agricultural chemicals. Especially optically active 3-methylamino-
It is known that the 1- (2'-thienyl) propan-1-ol derivative is a substance useful as a physiologically active or pharmacologically active ingredient (medicine, agricultural chemical, etc.).

[0002]

Optically active 3-methylamino-1- (2 '
As a method for producing a (thienyl) propan-1-ol derivative, 1) Tetrahedoron Letters, p. 7101 (1990) or N, N-dimethylamino as shown in the following reaction formula (A) described in JP-A-4-226948. A method of asymmetrically reducing a ketone derivative and then protecting the hydroxy group and then demethylating the same.

[0003]

[Chemical 3] 2) The following reaction formula described in Patent Registration No. 2549681.
As in (B), a method is known in which a N, N-dimethylamino alcohol derivative is optically resolved and then the hydroxy group is protected to demethylate.

[0004]

[Chemical 4]

However, in the method 1), the optically active ligand is expensive and the optical yield is as low as about 85%.
In method 2), half of the substrate is wasted because it is optically resolved. Furthermore, in both 1) and 2), active zinc is used in the demethylation step, so the reagent preparation is complicated, and it is necessary to remove the metal residue after the reaction, and the free hydroxy group at the α-position of the thiophene ring is racemized. There are drawbacks such as the complexity of the process such as easy protection of the hydroxy group, and the appearance of a cheaper and simpler production method has been desired.

[0006]

Therefore, the optically active 3-
It is an object of the present invention to provide a novel method for producing a methylamino-1- (2′-thienyl) propan-1-ol derivative.

[0007]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that (3S) -3-hydroxy-N-methyl-3- (2'-thienyl) propionamides. In the production of γ-hydroxyalkylamines by reducing the carbonyl group of β-hydroxyamides such as the above, acid treatment is carried out in a specific range such as pH 4 or more to prevent racemization even if hydroxy groups are not protected. The present inventors have completed the present invention by discovering that they can be easily produced without using them.

That is, the gist of the present invention is to reduce the carbonyl group of optically active β-hydroxyamides to obtain optically active γ-hydroxyamides.
In producing hydroxyalkylamines, there is a method for producing optically active γ-hydroxyalkylamines, which is characterized by performing an acid treatment in the range of pH 4 or more after completion of the reduction reaction. The present invention will be described in detail below.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION
The present invention relates to a method for producing optically active γ-hydroxyalkylamines by reducing the carbonyl group of hydroxyamides. (Optically Active β-Hydroxyamides) The optically active β-hydroxyamides used in the present invention are compounds in which the β-position is an asymmetric carbon having a hydroxyl group bonded to the carbonyl group forming an amide group. Α of the carbonyl group of the compound
The position is a methylene group which may be substituted as long as it does not affect the reaction, and the nitrogen atom of the amide group may be substituted as long as it does not adversely affect the reaction. Further, a substituent is further bonded to the carbon to which the hydroxyl group is bonded so that the carbon becomes an asymmetric carbon. Representative examples of these substituents include a carbon chain which may be substituted with an arbitrary substituent such as an alkyl group and a haloalkyl group, a ring group such as an aryl group and a heteroaryl group. As the compound, one having a molecular weight of 750 or less, preferably 500 or less is usually used. Preferred specific examples of the above-mentioned optically active β-hydroxyamides include the following general formula (I)

[0010]

[Chemical 5]

(Wherein A represents an aromatic ring, R ¹ and R ² represent a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, and R ³ and R ⁴ represent a hydrogen atom or an alkyl group (here, , R ³ and R ⁴ may be combined to form a carbon ring).)). General formula (I)
Examples of A include aromatic rings such as a phenyl group, a naphthyl group, a thienyl group, a pyridyl group, a pyrrolyl group, and a furanyl group. Of these, a phenyl group or a thienyl group is preferable, and a thienyl group is particularly preferable. These may be optionally substituted as long as they do not adversely affect the reaction.

Typical examples of the substituent include a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an aralkyl group, an aryl group and a heteroaryl group. Among these, the preferable type of substituent, the number of substitutions, and the substitution position are preferably A having a high electron donating property, and are thus determined in consideration.
In the formula, examples of the alkyl group represented by R ^{1 to} R ⁴ include linear or branched alkyl groups such as a methyl group, an ethyl group, a propyl group, and an isopropyl group.
8 is an alkyl group. Examples of the aryl group of R ¹ and R ² include a phenyl group, a tolyl group, and a halophenyl group, and examples of the aralkyl group include a benzyl group.

R ¹ and R ² are preferably a methyl group or an ethyl group as the alkyl group, a phenyl group as the aryl group, and a benzyl group as the aralkyl group. Also, R ³ and a preferred R ^4, a hydrogen atom, an alkyl group, or R ³ and R ⁴ having 1 to 4 carbon atoms include cyclohexane ring formed together, more preferably R ³ and R ⁴ At least one of them is preferably a hydrogen atom, and particularly preferably both are hydrogen atoms. Among the compounds represented by the above general formula (I), more preferable specific examples include the following general formula (I ′)

[0014]

[Chemical 6]

(In the formula, R ^{1 to} R ⁴ have the same meanings as defined above, and R ⁵
Represents a halogen atom or an alkyl group, and n represents an integer of 0 to 3. ) Is a compound represented by. In the above formula, R ⁵
Is a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom; or a linear or branched alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or an isobutyl group, preferably having 1 to 10 carbon atoms. 6 is an alkyl group.

Further, n is an integer of 0 to 3, of which n is preferably 0 or 1, and the substitution position thereof is preferably the α-position of the sulfur atom of the thiophene ring, particularly preferably n. It is 0. The above-mentioned optically active β-hydroxyamides can be optionally produced according to known methods or by a combination thereof, but regarding the compound represented by the above general formula (I ′),
Production route (wherein as follows, R ⁶ is methyl, ethyl, propyl, an alkyl group, such as n- butyl R ³ ~
It is more efficient and preferable to produce it with R ⁵ and n having the same meanings as described above.

[0017]

[Chemical 7]

That is, acetylthiophene and carbonic acid esters such as diethyl carbonate, or thiophenecarboxylic acid esters and acetic acid esters such as ethyl acetate,
After condensation in the presence of a base such as potassium t-butoxide to produce a thienyl keto ester derivative, asymmetric reduction reaction of carbonyl group is performed using a microorganism or an asymmetric hydrogen transfer catalyst. Further, optically active 3-hydroxy-3- (2'-thienyl) propionamides can be obtained by performing an amidation reaction of the ester.

(Reduction Reaction of Amide Derivative) As a method for reducing the above-mentioned optically active β-hydroxyamides, a known reduction method for an amide group can be mentioned, and specifically, a borane-based reducing agent and an aluminum-based reduction method. The reduction reaction is carried out using the agent. The borane-based reducing agent is preferably BH ₃
Tetrahydrofuran complex, diethyl ether complex, dimethylamine complex, pyridine complex, methyl sulfide complex, trimethylamine complex and the like, or by reacting NaBH ₄ and (MeO) ₂ SO ₂ in an equimolar amount to give a reaction system. Among them, a method for preparing BH ₃ can also be mentioned. Of these, a methyl sulfide complex of BH ₃ and a tetrahydrofuran complex are more preferable, and a tetrahydrofuran complex is particularly preferable.

Examples of the aluminum-based reducing agent include aluminum hydride, lithium aluminum hydride and Red-Al (sodium bis (methoxyethoxy) aluminum hydride). Of these, aluminum hydride or Re is preferable.
d-Al is mentioned, and Red-Al is particularly preferable.

The amount of the reducing agent to be used varies depending on the number of moles of hydride required depending on the kind of the amide group.
It may be used so that the required number of equivalents is more than that required depending on the substrate, but generally it is 7 equivalents or more as a hydride in the case of an amide group of a primary amine and 6 equivalents or more as a hydride in the case of an amide group of a secondary amine. In the case of an amide group of a tertiary amine, it is said that 5 equivalents or more of hydride should be used.

However, when the amount of the reducing agent used is too large, side reactions such as hydrogenolysis of the substrate occur undesirably. Therefore, the amount of hydride with respect to the substrate is usually 30 equivalents or less, preferably 15 equivalents or less, and particularly preferably. It is used in the range of 13.5 equivalents or less. Examples of the method of contacting the substrate with the reducing agent include a method of adding the reducing agent solution to the substrate solution, a method of adding the substrate solution to the reducing agent solution, and the like. good.

The solvent to be used is not particularly limited as long as it does not inactivate the reducing agent, and specifically, ether solvents such as diethyl ether and tetrahydrofuran, aromatic solvents such as toluene and xylene, methylene chloride, chloroform and the like. The halogen solvent described in (4) above is preferable, and of these, an ether solvent is preferable, and tetrahydrofuran is particularly preferable.

When a borane-based reducing agent is used, the reaction temperature is usually low because the reaction time is considerably long.
Range from room temperature or higher to the boiling point of the solvent used,
When an aluminum-based reducing agent is used, it is usually 0 to 1
It is in the range of 00 ° C, preferably 20 to 60 ° C.

(Method of acid treatment) After reacting for a predetermined time,
Water is added to the reaction solution to terminate the reaction while cooling with ice or the like if necessary, and then the reaction solution is subjected to acid treatment. The amount of water used may be 0.5 times by volume or more and 10 times by volume or less, preferably 1 time by volume or more and 5 times by volume or less with respect to the substrate. The acid used in the acid treatment is not particularly limited as long as the pH of the reaction solution can be controlled within an appropriate range, but specifically, a mineral acid such as dilute hydrochloric acid or dilute sulfuric acid; or a carboxylic acid such as formic acid or acetic acid or methane. Examples thereof include organic acids such as sulfonic acids and sulfonic acids such as p-toluenesulfonic acid, preferably dilute hydrochloric acid or C _{1 to} C _4.
Of carboxylic acids, particularly preferably acetic acid.

In the production method of the present invention, the above acid treatment is carried out at pH 4
Or higher, preferably pH 4.5 or higher, particularly preferably pH
It is characterized in that it is controlled within a range of 4.6 or more. If it is lower than this pH, racemization of the asymmetric carbon having a hydroxyl group bonded thereto occurs, which is not preferable. On the other hand, in terms of removal efficiency of the inactivated reducing agent, it is preferable to carry out the acid treatment usually at a pH of less than 7, more preferably at a pH of 6 or less, further preferably at a pH of 5.5 or less, and particularly preferably at a pH of 5 or less.

Regarding the acid treatment time, if the treatment time is short under ice cooling, the efficiency of removing the reducing agent may be poor. On the other hand, if the treatment time is too long at a high temperature such as the boiling point of the solvent, racemization may occur. Although there is a possibility that the reducing agent can be removed, it is not particularly limited as long as the reducing agent can be removed, but it is usually 15 minutes or more. However, if the treatment time is too long, the possibility of racemization increases, so that the treatment is usually performed within 48 hours, preferably within 24 hours.

If the treatment temperature is higher than necessary, racemization may occur.
It is carried out at 0 ° C or lower, preferably 40 ° C or lower. However, if the treatment temperature is too low, the efficiency of removing the reducing agent may be deteriorated. Therefore, the treatment is usually performed at -5 ° C or higher, preferably 0 ° C or higher. After the above-mentioned acid treatment, in isolating the desired amines, a general isolation and purification method may be carried out. Specifically, after the treatment liquid is made basic, the desired amines are treated with an organic solvent. Isolate by combining with general purification methods such as concentration, chromatographic purification, and crystallization.

The optical purity of the desired amines obtained above depends on the optical purity of the optically active amide as a raw material, but is usually 80% ee or more, preferably 90% ee or more, and particularly preferably 95% ee. As described above, the target product can be efficiently obtained without impairing the optical purity of the raw material.

(Optically Active γ-Hydroxyalkylamine Derivative) The optically active γ-hydroxyalkylamines obtained above are further protected by protecting the hydroxyl groups thereof, and are useful as intermediates for pharmaceuticals and agricultural chemicals. Amine derivatives can be prepared.

As the method for protecting the hydroxyl group, any general protecting method for hydroxyl group such as etherification, silylation, carbonate formation, sulfonate formation, etc. can be used, and preferably, the protection method under basic conditions is used. It is better to use. For example, specifically, as described in Japanese Patent Registration No. 2549681, a halide such as 1-fluoronaphthalene in a polar solvent such as dimethylacetamide in the presence of a base such as 60% sodium hydride, A method of heating to protect the hydroxyl group, if necessary, may be mentioned.

Especially (1S) -3-methylamino-1-
Naphthylated products of (2′-thienyl) propan-1-ol are disclosed in JP-A-4-226948 and JP-2549681.
As described in the publication, it is known to be useful as an antidepressant drug. Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0033]

EXAMPLES Production Example 1 Production of 3-oxo-3- (2'-thienyl) propionic acid ethyl ester

[0034]

[Chemical 8]

After 89.1 g of 60% NaH was added to 2 L Kolben and NaH was washed 3 times with 300 mL of hexane,
1 L of dimethylformamide was added, and the internal temperature was raised to 40 ° C. A solution prepared by dissolving 116 g of thiophene-2-carboxylic acid ethyl ester in 160 mL of dimethylformamide was added thereto, and immediately 217 mL of ethyl acetate was added dropwise over 3 hours. After the completion of the reaction, the reaction vessel was cooled with ice and slowly added dropwise to 0.75 L of cold water prepared in advance so that the internal temperature was 10 ° C or lower. Next 4N
Hydrochloric acid water (880 mL) was added dropwise at this temperature, the layers were separated, and the aqueous layer was extracted twice with 1.38 L of ethyl acetate. After extraction, the extract was dried over anhydrous sodium sulfate and concentrated to obtain 123.6 g (yield 83.4%) of 3-oxo-3- (2'-thienyl) propionic acid ethyl ester. ¹ H-NMR (CDCl ₃ , 400 MHz): δ1.27
(T, J = 8 Hz, 3H), 3.92 (s, 2H),
4.21 (q, J = 8 Hz, 2H), 7.15 (dd,
J = 5Hz, 1Hz, 1H), 7.70 (d, J = 5H
z, 1H), 7.74 (d, J = 1 Hz, 1H) Production Example 2 Production of 3-oxo-3- (2′-thienyl) propionic acid ethyl ester

[0036]

[Chemical 9]

36 mL of diethyl carbonate was charged, the temperature was raised to 62 ° C., 12.8 g of potassium t-butoxide was added, and the mixture was stirred for a while. When the reaction solution became brown, 6.0 g of 2-acetylthiophene was added to 43 mL of toluene.
The solution previously dissolved in was slowly added dropwise. The temperature was further raised to 82 ° C. and aging was carried out for 7 hours. After completion of the reaction, add 150 mL of water and stir, then 120 mL of ethyl acetate
After the addition of liquid and liquid separation, the organic layer is saturated brine 120 mL, saturated ammonium chloride 120 mL, saturated brine 120 mL.
Washed in that order, dried over sodium sulfate, and concentrated to give crude 3-
Oxo-3- (2'-thienyl) propionic acid ethyl ester was obtained. This is purified by distillation (130 ° C to 137 ° C,
5 mmHg) to obtain 3.4 g (purity 94%).

Production Example 3 (3S) -3-Hydroxy-3
Preparation of-(2'-thienyl) propionic acid ethyl ester

[0039]

[Chemical 10]

A medium consisting of 2% glucose, 1% yeast extract, 1% polypeptone, and 0.6% malt extract was added to a medium containing Filobasidium uniguttalatum.
uniguttulatum) IFO0699 strain was inoculated and cultured aerobically at 28 ° C. for 24 hours. After culturing, culture solution (1m
L) was collected and centrifuged to isolate bacterial cells. Glucose 100 mM, 3-oxo-3- (2'-thienyl)
Propionic acid ethyl ester 0.24%, NADH
Reaction solution 20 consisting of 0.01%, NADPH 0.01%, Tris-HCl buffer 100 mM (pH 7.5)
The suspension was suspended in 0 μL, and reacted by shaking at 30 ° C. Reaction start 1
After 8 hours, 800 μL of 2-propanol was added, and the cells were sterilized by centrifugation, and the supernatant sample was analyzed by HPLC.
Chiralpak AD-RH (manufactured by Daicel) was used for the analysis.

The produced (3S) -3-hydroxy-3-
The concentration of (2'-thienyl) propionic acid ethyl ester is
729 mg / L, and its optical purity is 99.5% ee.
It was ¹ H-NMR (CDCl₃, 400 MHz): δ1.27
(T, J = 8 Hz, 3H), 2.85 (m, 2H),
3.46 (d, J = 4 Hz, 1 H), 4.19 (q, J
= 8Hz, 2H), 5.37 (td, J = 3Hz, 5H
z, 1H), 6.98 (m, 2H), 7.26 (m, 1)
H) Production Example 4 (3S) -3-hydroxy-N-methyl-3
Preparation of-(2'-thienyl) propionamide

[0042]

[Chemical 11]

(3S) -3-Hydroxy-3- (2'-thienyl) propionic acid ethyl ester (99.5% e)
e) 81.4 g was dissolved in 440 mL of a 40% monomethylamine-methanol solution at room temperature, and the mixture was stirred at that temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to give crude (3S) -3.
73.2 g of -hydroxy-N-methyl-3- (2'-thienyl) propionamide was obtained.

10.0 g of this is added to 50 mL of toluene
In addition to the temperature of 80 ℃, methanol 2.5mL
Was added to complete dissolution. Then, the mixture was allowed to cool to room temperature (25 ° C.) and (3S) -3-hydroxy-N-methyl-3- (2 ′).
-Thienyl) propionamide crystals were precipitated and then filtered, toluene / methanol = 20/1 (V / V) 50 ml
After washing with, dried (3S) -3-hydroxy-N-
6.7 g (purity 99%,> 99.9% ee) of white solid of methyl-3- (2'-thienyl) propionamide was obtained. ¹ H-NMR (CDCl ₃ , 400 MHz): δ2.67
(D, J = 6 Hz, 2H), 2.82 (s), 2.83
(S, 3H including the former), 4.40 (bs, 1
H), 5.35 (m, 1H), 5.81 (bs, 1
H), 6.96 (m, 2H), 7.24 (m, 1H) Example 1 (1S) -3-methylamino-1- (2'-
Production of thienyl) propan-1-ol

[0045]

[Chemical 12]

316.2 mL (2 times the molar amount of the substrate) of 1.03 M BH ₃ tetrahydrofuran solution was added to 2 L Kolben and ice-cooled. Then, 31.44 g of (3S) -3-hydroxy-N-methyl-3- (2'-thienyl) propionamide (purity 95.9%,> 99.9% ee).
Was dissolved in 235.8 mL of tetrahydrofuran, and the mixture was slowly added dropwise so that the internal temperature was 2 to 5 ° C. Next, the temperature was raised and heating under reflux was performed for 3 hours. The reaction is monitored by liquid chromatography, and after completion of the reaction, the mixture is cooled with ice to give water 628.8.
mL was slowly added dropwise so that the internal temperature was 15 ° C or lower. The pH of the reaction solution at this time was 9. Subsequently, 9.81 g of acetic acid was added under ice cooling. The pH after completion of the addition was 5.

After stirring for about 15 minutes, the pH was adjusted to around 8 with 25% NaOH water to remove by-products, the solvent was replaced with 551 mL of toluene, and the aqueous layer was extracted twice with 551 mL of toluene. Did. In addition, p at this time
If H is too high, a large amount of the target product is extracted together with by-products, so that the pH is usually 6.5 to 9, preferably p.
It is advisable to perform extraction after adjusting to the range of H7 to 8.5.

Further, 28% ammonia water is added to the aqueous layer after extraction to adjust the pH to about 11, and then the desired product is extracted with ethyl acetate, dried and concentrated to (1S) -3-.
Methylamino-1- (2′-thienyl) propane-1-
17.4 g of all (> 99.9% ee) was obtained. After removing the by-products in this way, it is better to raise the pH of the liquid in order to efficiently extract the target product.
It is better to do it at about 1 or more. ¹ H-NMR (CDCl ₃ , 400 MHz): δ1.93
(M, 2H), 2.44 (s, 3H), 2.80 (m,
2H), 5.15 (td, J = 3Hz, 8Hz, 1
H), 6.95 (m, 2H), 7.21 (d, J = 6.
2 Hz, 1H) Comparative Example 1 (1S) -3-Methylamino-1- (2′-thienyl) propan-1-ol (97% ee) 0.05 g at 20 ° C.
Was dissolved in 1 ml of tetrahydrofuran to which 35% hydrochloric acid had been added (pH in system = about 1) and stirred for 30 minutes, the optical yield was 75% ee.

Comparative Example 2 0.05 g of (1S) -3-methylamino-1- (2′-thienyl) propan-1-ol (97% ee) was added at 20 ° C.
It was dissolved in 1 ml of tetrahydrofuran to which acetic acid was added (pH in system = about 3) and stirred for 48 hours to give an optical yield of 95% ee.

Reference Example 1 (1S) -3-Methylamino-1- (2'-thienyl) propan-1-ol (96.6% ee) 0.05 g
When dissolved in 1 ml of tetrahydrofuran added with a buffer solution of pH = 4.0 at 0 ° C. and stirred for 48 hours, the optical yield was 96.6% ee.

[0051]

INDUSTRIAL APPLICABILITY According to the present invention, when the carbonyl group of optically active β-hydroxyamides is reduced to produce optically active γ-hydroxyalkylamines, the racemic reaction is not necessary even if the conventional protection of hydroxyl groups is not carried out. It is possible to provide a method for producing optically active γ-hydroxyalkylamines without conversion.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) // C07M 7:00 C07M 7:00 (72) Inventor Yoichi Matsumoto 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Mitsubishi Chemical Corporation F term (reference) 4C023 CA04 4H006 AA02 AC52 AC81 BA52 BA66 BC53 BE22 BE23

Claims (6)

[Claims] 1. When the carbonyl group of an optically active β-hydroxyamide is reduced to produce an optically active γ-hydroxyalkylamine, an acid treatment is carried out at a pH of 4 or higher after the reduction reaction is completed. Process for producing optically active γ-hydroxyalkylamines. 2. An optically active β-hydroxyamide is represented by the following general formula (I): (In the formula, A represents an aromatic ring, R ¹ and R ² represent a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, and R ³
And R ⁴ represents a hydrogen atom or an alkyl group (wherein
R ³ and R ⁴ may together form a carbocycle). ) It is a compound represented by these, The manufacturing method of Claim 1 characterized by the above-mentioned. 3. An optically active β-hydroxyamide is represented by the following general formula (I ′): (In the formula, R ^{1 to} R ⁴ have the same meanings as described above, R ⁵ represents a halogen atom or an alkyl group, and n represents an integer of 0 to 3.) The manufacturing method according to claim 1. 4. The production method according to claim 1, wherein the acid treatment is performed with an organic acid. 5. The production method according to claim 1, wherein the acid treatment is carried out in a pH range of 6 or lower. 6. An optically active γ-characterized in that the optically active γ-hydroxyalkylamines obtained by the method according to any one of claims 1 to 5 are further subjected to a hydroxyl group protection reaction.
-A method for producing a hydroxyalkylamine derivative.