JP2003192681A - Process for producing (S) -3-chloro-1- (2-thienyl) -1-propanol and (S) -3-N-methylamino-1- (2-thienyl) -1-propanol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce 1- (2-thienyl) -3-chloropropan-1-one and (S) -3-N-methylamino-1- (2-thienyl) -1-propanol industrially A simple manufacturing method. SOLUTION: 1- (2-thienyl) -3-chloropropan-1-one is reacted with hydrogen in the presence of a transition metal-containing asymmetric hydrogenation catalyst, a base and an optically active nitrogen-containing compound to produce asymmetric hydrogen. (S) -3-chloro-1- (2-thienyl)-
A method for producing 1-propanol. 1- (2-thienyl) -3-chloropropane-1- obtained by reacting thiophene and 3-chloropropionic acid chloride in the presence of Friedel-Crafts catalyst
Is reacted with hydrogen in the presence of an asymmetric hydrogenation catalyst containing a transition metal, a base, and an optically active nitrogen-containing compound to give (S) -3-chloro-1- (2-thienyl)- A method for producing (S) -3-N-methylamino-1- (2-thienyl) -1-propanol, comprising the steps of obtaining 1-propanol and reacting it with methylamine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to (S) -3-chloro-1- (2-thienyl) -1-propanol, which is useful as a raw material or a synthetic intermediate for medicines, agricultural chemicals and various chemicals, and
(S) -3-N-methylamino-1- (2-thienyl) -1
-Relating to a new process for producing propanol.

[0002]

BACKGROUND OF THE INVENTION (S) -3-Chloro-1- (2-thienyl) -1-propanol and S (-) 3-N-methylamino-1- (2-thienyl) -1-propanol. As WJ Wheeler, F. Kuo, Journal of Labeled Comp
Sounds and Radiopharmaceuticals, Vol.XXXVI, No.3 (199
5) is known. The manufacturing method can be represented by the following scheme 1.

[0003]

[Chemical 1]

[0004]

However, in the above report, (S) -3-chloro-1- (2-thienyl)-
1-propanol and (S) -3-N-methylamino-
The method for producing 1- (2-thienyl) -1-propanol has 1) long synthetic steps and high production cost, 2) high price of starting materials, 3) low total yield, and 4) extremely expensive reducing agent. 5) It has a step of using column chromatography for purification of the product, and has a drawback that it is not an industrial production method.

[0005]

On the other hand, the present inventors have found that (S) -3-chloro-1- (2-thienyl) -1-propanol and (S) -3-N-methylamino-1. −
As a result of diligent efforts to provide an industrial method for producing (2-thienyl) -1-propanol, as a result of the steps shown in Scheme 2 below, thiophene was produced from inexpensive thiophene in a short step (E, F, G). The inventors have found a method for easily and quickly producing a target substance and completed the present invention.

[0006]

[Chemical 2] That is, the first invention of the present invention is that 1- (2-thienyl) -3-chloropropan-1-one is treated with hydrogen in the presence of an asymmetric hydrogenation catalyst containing a transition metal, a base and an optically active nitrogen-containing compound. (S) -3-characterized by reacting
It is a method for producing chloro-1- (2-thienyl) -1-propanol.

A second invention of the present invention is the following 1).
To (3) are included, (S) -3-N
-Methylamino-1- (2-thienyl) -1-propanol.

1) First step of obtaining 1- (2-thienyl) -3-chloropropan-1-one by reacting thiophene with 3-chloropropionic acid chloride in the presence of Friedel-Crafts catalyst, 2) 1- By reacting (2-thienyl) -3-chloropropan-1-one with hydrogen in the presence of a transition metal asymmetric hydrogenation catalyst, a base and an optically active nitrogen-containing compound, (S) -3-chloro-1-
A second step to obtain (2-thienyl) -1-propanol,
3) (S) -3-chloro-1- (2-thienyl) -1-
By reacting propanol with methylamine (S) -3-N-methylamino-1- (2-thienyl)
Third step of obtaining -1-propanol Further, in the present invention, the above-mentioned asymmetric hydrogenation catalyst is a complex of Group VIII metal, for example, a metal complex having an optically active ligand, and the base is an alkali metal. One of its modes is that it is a hydroxide of an alkaline earth metal, a salt thereof, or a quaternary ammonium salt, and that the optically active compound as the nitrogen-containing asymmetric compound is an optically active amine compound.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The asymmetric hydrogenation catalyst containing a transition metal of the present invention has, for example, the general formula (a):

[Chemical 3] (M ¹ is a Group VIII transition metal such as ruthenium, rhodium, iridium, palladium and platinum, X is a hydrogen atom,
A halogen atom, a carboxyl group, a hydroxy group, an alkoxy group and the like are shown, and L is an optically active phosphine ligand, an optically active organic arsenic compound ligand and the like. m and n are integers).

In the asymmetric hydrogenation catalyst containing a transition metal represented by the above general formula (a), M ¹ is a Group VIII transition metal such as ruthenium, rhodium, iridium, palladium and platinum, and ruthenium is particularly preferable. . X is hydrogen, a halogen atom, a carboxyl group, a hydroxy group,
Indicates an alkoxy group. L is an optically active phosphine ligand or the like, and includes, for example, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), and an alkyl group or an aryl group substituent on the naphthyl ring of BINAP. A BINAP derivative having, for example, 2,2'-bis (diphenylphosphino) -6,6'-dimethyl-1,1 '
-Binaphthyl, a BINAP derivative in which the naphthyl ring of BINAP is partially hydrogenated, such as 2,2'-bis (diphenylphosphino) -5,6,7,8,5 ', 6',
7'8'-octahydro-1,1'-binaphthyl, BI
BINAP derivatives having 1 to 5 alkyl group substituents on the benzene ring on the phosphorus atom of NAP, such as 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl, 2,2'-bis (Dicyclohexylphosphino)-
6,6'-dimethyl-1,1'-biphenyl, 1-
[1′2-bis- (diphenylphosphino) ferrocenyl] ethyldiamine, 2,3-bis (diphenylphosphino) butane, 1-cyclohexyl-1,2-bis (diphenylphosphino) ethane, 1-substituted-3 , 4-bis (diphenylphosphino) pyrrolidine, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane, 1,2-bis [(o
-Methoxyphenyl) phenylphosphino] ethane,
(Substituted-1,2-bis (phosphorano) benzene), 5,
6-bis (diphenylphosphino) -2-norbornene, N, N'-bis- (diphenylphosphino) -N,
N'-bis (1-phenylethyl) ethylenediamine,
1,2-bis (diphenylphosphino) propane, 2,
4-bis (diphenylphosphino) pentane and the like can be mentioned. Furthermore, an optically active phosphine ligand represented by a monodentate general formula PR ¹ R ² R ³ (optically active phosphine ligand in which R ¹ R ² R ³ is a substituent different from all three types, or at least one group is optically active) An optically active phosphine ligand which is a group) may be used. In the case of a bidentate phosphine ligand, n is 1-2, and in the case of a monodentate phosphine ligand, it is 3-4. Of course, the optically active phosphine ligand that can be used in the present invention is not limited to these, and the metal is not limited to ruthenium.

The amount of the above-mentioned transition metal-containing asymmetric hydrogenation catalyst used in the present invention varies depending on the reaction vessel, the type of reaction, or the economy, but it is at least 1 / 100,000 with respect to the carbonyl compound as the reaction substrate, preferably. Is 1
A molar ratio of / 10,000 can be used, and the upper limit is preferably 1/500, preferably 1/100. If it is less than this range, the reaction time is long, and if it is more than this range, the cost of the catalyst becomes excessive.

The base is, for example, a compound represented by the general formula (b)

[Chemical 4] (M ² represents an alkali metal or an alkaline earth metal, Y represents a hydroxy group, an alkoxy group, a mercapto group,
A naphthyl group is shown. ) Or a quaternary ammonium hydroxide is used.

Specifically, KOH, KOCH ₃ , KOCH
(CH ₃ ) ₂ , KC ₁₀ H ₇ , LiOH, LiOCH ₃ ,
_{LiOCH (CH 3) 2, (} CH 3) 4 N + OH -,
_{C 6 H 5 CH 2 N (} CH 3) 3 + OH - , and the like.

The amount of the above base used is 0.5 equivalent or more, preferably 2 equivalent or more with respect to the asymmetric hydrogenation catalyst containing a transition metal, and the upper limit is 100 equivalents, preferably 40 equivalents.
It is below the equivalent. If it is less than this lower limit, it takes a long reaction time, and if it is more than this upper limit, the catalyst is easily deactivated.

In the present invention, a nitrogen-containing compound such as an optically active amine compound is used. This compound has, for example, the general formula NR.
An amine compound represented by ⁴ R ⁵ R ⁶ which is an optically active monoamine in which at least one of the substituents is an optically active group, and the remainder is hydrogen or a saturated or unsaturated hydrocarbon group or an aryl group, or Formula (c)

[Chemical 5] (R ⁷ , R ⁸ , R ¹³ , and R ¹⁴ are hydrogen or a saturated or unsaturated hydrocarbon group, an aryl group, a urethane group, a sulfonyl group, etc., and R ⁹ , R ¹⁰ , R ¹¹ , and R ¹² are these substituents. Are the same or different groups such that the carbons bonded to each other are asymmetric centers, and are hydrogen or alkyl groups, aromatic monocyclic and polycyclic groups, saturated or unsaturated hydrocarbon groups, and cyclic hydrocarbons. Group, etc.) is an optically active diamine compound. For example optically active 1,2
-Diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3
-Dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine, 1-isobutyl-2,2-diphenylethylenediamine, 1-isopropyl-2,2
-Diphenylethylenediamine, 1-methyl-2,2-
Di (p-methoxyphenyl) ethylenediamine, 1-isobutyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-2,2-di (p-methoxyphenyl) ethylenediamine, 1-benzyl-2,
2-di (p-methoxyphenyl) ethylenediamine, 1
-Methyl-2,2-dinaphthylethylenediamine, 1-
Isobutyl-2,2-dinaphthylethylenediamine, 1
An optically active diamine compound such as isopropyl-2,2-dinaphthylethylenediamine and R ⁷ to R ¹³
Examples of the optically active diamine compound in which one or two of the substituents are a sulfonyl group or a urethane group. Further, the optically active diamine that can be used is not limited to the exemplified optically active ethylenediamine derivative, and optically active propanediamine, butanediamine, and phenylenediamine derivatives can be used.
The amount of these optically active amine compounds used is 1 equivalent, preferably 2 in the case of a monoamine compound, with respect to the transition metal complex.
It is an equivalent or more, and the upper limit is preferably 4 equivalents or less.
If it is less than this, the reaction is slow, and if it is more than this, the catalyst is easily deactivated. In the case of a diamine compound, 0.5 equivalent,
It is preferably 1 equivalent or more, and the upper limit is 2.5 equivalents or less, preferably 2 equivalents or less. If it is less than this, the reaction is slow, and if it is more than this, the catalyst is easily deactivated.

In the present invention, the combination of the absolute structure of the optically active ligand and the absolute configuration of the optically active nitrogen-containing compound in the asymmetric hydrogenation catalyst as a catalyst component is important for obtaining a high asymmetric yield. And, for example, as shown in Comparative Examples below, a combination of an R-phosphine ligand and R, R-diamine gives the desired (S) -3-chloro-1- (2-thienyl) -1-propanol. . With the combination of the R-phosphine ligand and S, S-diamine, the reaction proceeds but the asymmetric yield is extremely reduced.

In the present invention, the three components of the asymmetric hydrogenation catalyst containing a transition metal, which is used as a catalyst, the base and the optically active nitrogen-containing compound, allow the asymmetric hydrogenation reaction to proceed smoothly and achieve a high asymmetric yield. Is an essential ingredient for
If even one component is insufficient, an alcohol compound with sufficient reaction activity and high optical purity cannot be obtained. In the present invention, any suitable liquid solvent can be used as long as it can solubilize the reaction raw material and the catalyst system. As examples, toluene, aromatic hydrocarbon solvents such as xylene, pentane, aliphatic hydrocarbon solvents such as hexane, halogen-containing hydrocarbon solvents such as methylene chloride, ethers, ether solvents such as tetrahydrofuran, methanol, ethanol,
2-propanol, butanol, alcohol solvents such as benzyl alcohol, acetonitrile, DMF and DM
An organic solvent containing a hetero atom such as SO can be used. Since the product is alcohol, an alcohol solvent is preferable. Even more preferably, it is 2-propanol.

The amount of organic solvent is determined by the solubility of the reaction substrate and economic efficiency. In the case of 2-propanol, the reaction can be carried out in a state in which the substrate concentration is as low as 1% or less to a solvent-free state, but preferably 20% by mass or more, and the upper limit is preferably 50% by mass or less. If it is less than this range, the productivity will be deteriorated, and if it is more than this range, there is a concern that the catalytic action may be reduced. The hydrogen pressure in the present invention is at least 1 atm or more, preferably 3 atm or more, and the upper limit is 100 atm or less, preferably 30 atm or less. If it is lower than this, the reaction becomes slow, and if it is higher than this, the economic efficiency becomes low. It is possible to maintain high activity even at 10 atm or less.

The reaction temperature may be -30 ° C to 100 ° C in consideration of economy, but the reaction can be carried out at room temperature of 10 to 40 ° C. The reaction time varies depending on the reaction conditions such as the reaction substrate concentration, temperature and pressure, but the reaction is completed in several minutes to 10 hours.

The reaction in the present invention can be carried out in either a batch system or a continuous system.

The E step shown in Scheme 2 is Ahmed M. E
l-Khawaga, Maher E. El-Zohry and Mohamed T. Ismail,
According to the method described in Phosphorus and Sulfur, 33, 25 (1987), thiophene and 3-chloropropionic acid chloride are subjected to an acylation reaction in the presence of Friedel-Crafts catalyst to give a good yield.

Step G shown in Scheme 2 is (S) -3.
It can be produced in good yield by aminating -chloro-1- (2-thienyl) -1-propanol in the presence of excess methylamine. The amount of methylamine used in this reaction may be 1 to 200 equivalents, but is preferably 5 equivalents or more from the viewpoint of suppressing the production of tertiary amines, and 30 equivalents or less from the economical viewpoint. Also, the reaction can be carried out under high pressure. The reaction temperature may be in the range of −78 ° C. to 100 ° C., but the reaction can be carried out in the vicinity of room temperature of 10 to 40 ° C. The reaction time varies depending on the reaction conditions, but the reaction is completed within a few minutes to a few hours. Any appropriate solvent can be used in this reaction as long as it can solubilize the reaction substrate without solvent or as a liquid solvent. Examples include alcohol solvents such as methanol, ethanol, 2-propanol, butanol, and benzyl alcohol, ether solvents such as dioxane and tetrahydrofuran, aromatic hydrocarbon solvents such as toluene and xylene, halogen-containing hydrocarbon solvents such as methylene chloride, and acetonitrile. ,
It can also be carried out in an organic solvent containing a hetero atom such as DMF or DMSO, or a mixed solvent thereof with an aqueous solvent.

[0023]

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

Example 1 Synthesis of 1- (2-thienyl) -3-chloropropan-1-one Aluminum chloride (40 g, 0.3 g) was placed in a three-neck round bottom flask.
(0 mol) and 125 ml of carbon disulfide were added and the mixture was cooled to 5 ° C. Nitromethane (18.3g, 0.30m)
ol) was slowly added and stirred for 30 minutes. Further, 3-chloropropionic acid chloride (31.7 g, 0.25 mo)
l) was added, followed by thiophene (21.0 g, 0.25 m
ol) was added slowly. After reacting at 5 ° C for 1 hour,
The reaction solution was added to 300 ml of ice-cold water, and the mixture was further stirred for 1 hour. Toluene was added to this and the organic layer was separated. The organic layer was washed with aqueous sodium hydrogen carbonate and then concentrated under reduced pressure to give a pale brown liquid 3.
9.5 g was obtained (yield 90.5%).

Example 2 (S) -3-chloro-1- (2
Synthesis of -thienyl) -1-propanol In a Schlenk reaction tube, a 0.5 M solution of KOH in 2-propanol (40 µL), (R, R) -diphenylethylenediamine (2.1 mg, 0.01 mmol) and 1- (2
-Thienyl) -3-chloropropan-1-one (873
mg, 5.0 mmol) and 3 ml of 2-propanol were introduced under an argon stream, degassing-argon substitution was performed, and then this solution was further added with RuCl ₂ ((R) -BINA.
P) (dmf) _n (9.6 mg, 0.01 mmol) is added to adjust the reaction solution. This solution was repeatedly degassed and replaced with argon to completely dissolve it, and then 100 m
The reaction was started by transferring to a glass autoclave of 1 and pressurizing hydrogen to a predetermined pressure. After stirring at 28 ° C. for 6 hours, the temperature was returned to room temperature, and the reaction compound was subjected to gas chromatography and H ¹ NMR analysis to identify the product and determine the reaction yield (99% or more). Further obtained (S) -3-
The optical purity of chloro-1- (2-thienyl) -1-propanol was determined by HPLC using an optically active column and a result of 97% ee was obtained.

Example 3 (S) -3-N-methylamino-
Synthesis of 1- (2-thienyl) -1-propanol A 40% methylamine / methanol solution (15.5 g, 200 mmol) was placed in a 3-neck round bottom flask. At room temperature, (S) -3-chloro-1- (2-thienyl) -1
-Propanol (3.53 g, 20 mmol) was added dropwise and reacted for 30 minutes. After distilling off methanol and methylamine under reduced pressure, water was added and the mixture was extracted with methyl t-butyl ether. After washing the organic layer with brine, the organic layer was concentrated, n-heptane was added, and the precipitated solid was suction filtered,
2.87 g of a slightly yellow solid was obtained (yield 83.8%).

[0027]

EFFECTS OF THE INVENTION According to the present invention, (S) -3-chloro-1- (2-thienyl) -1- is obtained with high purity, high yield and low cost by a simple operation without complicated purification by a column or the like. It becomes possible to obtain propanol. In addition, (S) -3-N-methylamino-1- (2-thienyl) -1-propanol can be easily produced in a short time.

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Claims (7)

[Claims] 1. Asymmetric reaction of 1- (2-thienyl) -3-chloropropan-1-one with hydrogen in the presence of an asymmetric hydrogenation catalyst containing a transition metal, a base and an optically active nitrogen-containing compound. A method for producing (S) -3-chloro-1- (2-thienyl) -1-propanol, which comprises hydrogenating. 2. A method for producing (S) -3-N-methylamino-1- (2-thienyl) -1-propanol, which comprises the following steps 1) to 3). 1) The first step for obtaining 1- (2-thienyl) -3-chloropropan-1-one by reacting thiophene with 3-chloropropionic acid chloride in the presence of Friedel-Crafts catalyst. 2) 1- (2-thienyl) -3-chloropropane-1-
(S) -3-chloro-1- (2-thienyl) -1- by reacting one with hydrogen in the presence of an asymmetric hydrogenation catalyst containing a transition metal, a base and an optically active nitrogen-containing compound.
Second step to obtain propanol. 3) (S) -3-chloro-1- (2-thienyl) -1-
By reacting propanol with methylamine
(S) -3-N-Methylamino-1- (2-thienyl)-
Third step to obtain 1-propanol. 3. An asymmetric hydrogenation catalyst containing a transition metal is VIII.
The production method according to claim 1, which is a complex of a group transition metal. 4. The production method according to claim 1, wherein the asymmetric hydrogenation catalyst containing a transition metal has an optically active ligand. 5. The method according to claim 4, wherein the optically active ligand is a phosphine ligand. 6. The method according to claim 1, wherein the base is a hydroxide, an alkoxy compound, a mercapto compound or a naphthyl compound of an alkali metal or an alkaline earth metal, or a quaternary ammonium hydroxide. 7. The production method according to claim 1, wherein the optically active nitrogen-containing compound is an optically active amine compound.