JP2001294583A - Method for producing optically active 1-(benzofuran-2- yl)-2-propylaminopentane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method excellent in practicality for producing an optically active 1-(benzofuran-2-yl)-2-propylaminopentane derivative useful as a medicine, especially an antipsychotic agent, an antidepressant agent, an antiparkinson agent and an antialzheimer agent. SOLUTION: This method for producing the optically active 1-(benzofuran-2- yl)-2-propylaminopentane derivative with high purity, in high selectivity and high yield by an extremely simple operation without using a special catalyst, or the like, comprises using an optically active aziridine compound or an optically active amide compound, capable of being chiral-pool synthesized from a commercial amino acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to optically active 1- (benzofuran-2), which is useful as a drug, especially a psychotropic drug, an antidepressant drug, an anti-Parkinson's disease drug and an anti-Alzheimer's disease drug.
-Yl) -2-propylaminopentane derivative with a high practicality.

[0002]

2. Description of the Related Art Novel phenylethylamine derivatives containing 1- (benzofuran-2-yl) -2-propylaminopentane disclosed in Japanese Patent Application No. 9-247445 differ from catecholamine-substituted release-promoting action. Enhancement effect of catecholaminergic system by enhancing membrane potential-dependent exocytosis (Catecholaminergic Act
(Efficacy Enhance effect: CAE effect), the release of excess catecholamine and catecholamine found in conventional catecholamine-substituted release promoting agents such as monoamine oxidase inhibitors, catecholamine uptake inhibitors, and stimulants such as amphetamine. It does not induce amine depletion at nerve endings. Therefore, the compound has few problems such as an abnormal increase in locomotor activity (excitatory action), neurotoxicity to the central nervous system, and decreased response to patients, and is a safe and useful antidepressant, psychotropic, antiparkinson. It has been clarified that the compound exhibits excellent action effects as a disease drug, an anti-Alzheimer's disease drug and the like.

The present compound has an asymmetric carbon in its molecular structure. Among the compounds disclosed in Japanese Patent Application No. 9-247445, 1- (benzofuran-2-yl)
In -2-propylaminopentane, the (-) form is
It has been disclosed in International Application PCT / JP99 / 05729 that it has superior pharmacological activity as compared to the (+) form or the racemic form.

Heretofore, optically active 1- (benzofuran-
As a method for obtaining an optically active amine such as 2-yl) -2-propylaminopentane, a method of once synthesizing a racemic body and optically resolving it, a method using an enzyme,
And asymmetric synthesis methods are known. Of these, the optical resolution method requires not only an optically active acid or the like in an equivalent amount or more with respect to the amine, but also requires complicated operations such as crystallization, separation, and purification. Further, in the method using an enzyme or the asymmetric synthesis method, the reaction substrate is limited, and at the present time, its practicality is poor due to selectivity and complicated operation.

On the other hand, the international application PCT / JP99 / 0572
Optically active 1- (benzofuran-2-yl) disclosed in No. 9
-2-Propylaminopentane is obtained by optically resolving a compound synthesized as a racemate, but this optical resolution cannot be achieved by a resolution method using a racemate in the form of a diastereomer salt or derivative. Was only performed by high performance liquid chromatography preparative separation using For this reason, a large amount of solvent and a long time are required for the separation, and the productivity is extremely low.

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to an optically active 1- (benzofuran-2-yl)-which is useful as a drug, especially a psychotropic drug, an antidepressant drug, an anti-Parkinson's disease drug and an anti-Alzheimer's disease drug. An object of the present invention is to provide a method for producing one optical isomer of 2-propylaminopentane with high selectivity and high yield.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to establish an industrial method for synthesizing an optically active 1- (benzofuran-2-yl) -2-propylaminopentane derivative. By a simple operation, an optically active aziridine compound or an optically active amide compound that can be synthesized from a commercially available optically active amino acid like a chiral pool is used, and via a corresponding optically active amine, a highly selective and high-yield optical system is obtained. A method for synthesizing active 1- (benzofuran-2-yl) -2-propylaminopentane derivatives has been established.

The process for producing an optically active 1- (benzofuran-2-yl) -2-propylaminopentane derivative according to the present invention starts from optically active norvaline, which is one of the optically active amino acids that can be easily obtained industrially. It is a raw material and is roughly classified into two independent routes, a first synthetic route using an optically active aziridine compound as a synthetic intermediate and a second synthetic route also using an optically active amide compound.

In the first synthetic route, an optically active aziridine compound is reacted with 2-benzofuran lithium, and the aziridine ring is coupled with ring opening while maintaining the absolute configuration of the asymmetric center (so-called chiral pool-like). 2) The desired optically active 1- (benzofuran-2-yl) -2-
It is intended to construct a basic skeleton of a propylaminopentane derivative. In addition, in the present synthesis route, in addition to the method of once isolating the above-mentioned coupling product as a free amine compound, there is a method of treating the coupling product as a lithium salt as a modification.

On the other hand, the second synthetic route is based on optically active N-
The methoxy-N-methylamide compound is reacted with 2-benzofuran lithium to obtain a corresponding ketone by a condensation reaction at a carbonyl group, and by reducing this,
An object of the present invention is to construct a basic skeleton of a desired optically active 1- (benzofuran-2-yl) -2-propylaminopentane derivative while maintaining the absolute configuration of asymmetric carbon. Hereinafter, embodiments of the present invention will be described for each synthesis route.

[0011]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Optically active 1- (benzofuran-2-) using an optically active aziridine compound as a synthetic intermediate
1) Method for producing 2-propylaminopentane
Is composed of the following steps a to f.

That is, the step (a) is performed by the following formula (I):

Embedded image By reacting a reducing agent with the optically active norvaline represented by the formula:
Carboxyl group is reduced, formula (II),

Embedded image [Wherein, * represents the same meaning as described above]. In this process,
An organic solvent such as tetrahydrofuran or diethyl ether is used as a reaction solvent, and lithium aluminum hydride, diborane, a borane complex or the like is used as a reducing agent.

In the step (b), an amino group and a hydroxyl group are sulfonylated by reacting an optically active norvalinol of the formula (II) with a sulfonyl halide such as methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base. Formula (III),

Embedded image [Wherein, R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group,
Or a substituted phenyl group, and * has the same meaning as described above]. In this step, pyridine or the like is used as a base, which can also serve as a reaction solvent. When another reaction solvent is used in combination, methylene chloride,
Use chloroform or the like.

In the step (c), the compound of the general formula (III) is added to an organic solvent such as tetrahydrofuran, diethyl ether, N, N-dimethylformamide or water or a mixture thereof to form a strong compound such as sodium hydroxide or potassium hydroxide. Ring closure by reacting a base, general formula (IV),

Embedded image [Wherein, R and * have the same meanings as described above].

In the step d, the compound of the general formula (IV) is added to an organic solvent such as tetrahydrofuran, diethyl ether or the like by n
Reaction with 2-benzofuran lithium prepared using -butyllithium or the like to perform coupling with benzofuran accompanied by ring-opening of an aziridine ring;
(V),

Embedded image [Wherein, R and * have the same meanings as described above], in which optically active benzofurylsulfonylaminopentane compound is obtained.

In the step (e), the compound of the general formula (V) is reacted with a propyl halide such as propyl bromide in the presence of a strong base to perform N-propylation, and the compound of the general formula (VI)

Embedded image [Wherein, R and * have the same meanings as described above], in which optically active benzofurylsulfonylpropylaminopentane compound is obtained. In this step, an organic solvent such as N, N-dimethylformamide is used as a reaction solvent, and sodium hydride, sodium amide, alkyl lithium or the like is used as a strong base.

In the step (f), the compound of the general formula (VI) is reacted with an alkali metal and a polycyclic aromatic hydrocarbon to desulfonylate the compound of the formula (VII),

Embedded image [Wherein * has the same meaning as described above], a step of obtaining optically active 1- (benzofuran-2-yl) -2-propylaminopentane. In this step, an organic solvent such as ethylene glycol dimethyl ether is used as a reaction solvent, sodium or the like is used as an alkali metal, and naphthalene or anthracene is used as a polycyclic aromatic hydrocarbon.

The above reactions a to c give an optically active aziridine compound while maintaining the absolute configuration of the chiral center of optically active norvaline. Further, the reaction of d, after deprotonating the α-position proton of the hetero atom on the benzofuran ring with alkyllithium, reacting an optically active aziridine compound as an electrophile, and coupling with ring opening of the aziridine ring, This is to construct the basic skeleton of the desired optically active 1- (benzofuran-2-yl) -2-propylaminopentane derivative as a chiral pool. Subsequent reactions e to f lead to optically active 1- (benzofuran-2-yl) -2-propylaminopentane which is the final product by deprotection of the amino group and alkylation of the amino group.

In place of the steps d to e in the above step, after the coupling reaction of the aziridine compound of the formula (IV) with lithium 2-benzofuran, the compound of the general formula (VIII)

Embedded image [Wherein R and * have the same meanings as described above], the optical activity 1 can be obtained by isolating a lithium salt represented by the following formula and reacting the lithium salt with propyl halide without using a strong base.
The synthesis of-(benzofuran-2-yl) -2-propylaminopentane can be achieved. In this case, the reaction solvent and the like may be the same as those in the above steps d and e. This route is positioned as a modification of the first synthesis route, and has the advantage that the operation of obtaining the compound of formula (V) and the addition of a base can be omitted.

Next, an optically active 1- (benzofuran-2-yl)-using an optically active amide compound as a synthetic intermediate.
The method for producing 2-propylaminopentane (second synthesis route) includes the following steps a to f.

That is, the step (a) is performed by the following formula (I):

Embedded image In the formula, * indicates the position of an asymmetric carbon atom, and benzyl chloroformate (Z
-Chloride) to protect the amino group, and formula (IX),

Embedded image [Wherein, Z represents a benzyloxycarbonyl group, and * represents the same meaning as described above]. The reaction in this step is carried out according to a general method for introducing a protecting group into an amino group.For example, as a reaction solvent, an organic solvent such as water or methanol, or a mixture thereof, Sodium, sodium carbonate, sodium hydrogen carbonate and the like are used.

In the step (b), the optically active Z-norvaline of the formula (IX) is reacted with N-methyl-O-methylhydroxylamine hydrochloride in the presence of a base and a condensing agent to obtain a compound of the formula (X)

Embedded image [Wherein, Z and * have the same meanings as described above]. In this step, an organic solvent such as methylene chloride is used as a reaction solvent, a weak base such as N-methylmorpholine is used as a base, and 1-ethyl-3- [3- (diethylamino) propyl] carbodiimide hydrochloride is used as a condensing agent. (WSCDI) or the like. At this time, 1-hydroxybenzotriazole or the like can be used as an additive in order to prevent side reactions and improve the yield.

In the step (c), the compound of the formula (X) is reacted with 2-benzofuran lithium prepared using n-butyllithium or the like in an organic solvent such as tetrahydrofuran or diethyl ether to form a carbonyl with benzofuran. Perform a condensation reaction on the group, formula (XI),

Embedded image [Wherein Z and * have the same meanings as described above], a process for obtaining an optically active benzofurylaminopentanone compound represented by the following formula:

In the step (d), the compound of the formula (XI) is reacted with hydrosilane in a strong acid to reduce the carbonyl group and deprotect the amino group.

Embedded image [Wherein * represents the same meaning as described above], a process for obtaining an optically active benzofurylaminopentane compound represented by the following formula:
In this step, trifluoroacetic acid or the like is used as a strong acid and solvent, and triethylsilane or the like is used as a hydrosilane.

In the step e, the amino group is propionylated by reacting the compound of the formula (XII) with propionyl chloride, propionic anhydride or the like in the presence of a base to convert the compound to a compound of the formula (XIII),

Embedded image [Wherein, R and * have the same meanings as described above], in which the optically active benzofurylpropionylaminopentane compound is obtained. In this step, tetrahydrofuran, chloroform, carbon tetrachloride or the like is used as a reaction solvent, and triethylamine, pyridine or the like is used as a base.

In the step (f), the compound of the formula (XIII) is reacted with a reducing agent to reduce the amide group, and the compound of the formula (VII)

Embedded image [Wherein * has the same meaning as described above], a step of obtaining optically active 1- (benzofuran-2-yl) -2-propylaminopentane. In this step, an organic solvent such as tetrahydrofuran or diethyl ether is used as a reaction solvent, and lithium aluminum hydride or lithium aluminum hydride-aluminum chloride is used as a reducing agent.

The above reaction a or b gives an optically active N-methoxy-N-methylamide compound while maintaining the absolute configuration of the chiral center of optically active norvaline. The reactions c to d are carried out by deprotonating the α-position proton of the hetero atom on the benzofuran ring with alkyllithium, and then reacting the compound with an optically active N-methoxy-N-methylamide compound as an electrophile to condense the carbonyl group. The reaction is carried out, and the subsequent reduction of the carbonyl group accompanied by deprotection of the amino group allows the basic skeleton of the desired optically active 1- (benzofuran-2-yl) -2-propylaminopentane derivative to be obtained as a chiral pool. To build. The subsequent reactions e to f lead to the optically active 1- (benzofuran-2-yl) -2-propylaminopentane, which is the final target, by introducing an alkyl group into the amino group.

There is no particular limitation on the reaction temperature and reaction time in each of the above steps, but it is desirable to follow general reaction conditions in view of the characteristics of the reaction reagent. For example, the reaction temperature is preferably from −40 ° C. to the reflux temperature of the reaction solvent, and the reaction time is preferably from tens of minutes to 24 hours.

Thus, by carrying out these steps, the optically active norvaline can be converted to the corresponding optically active 1- with a high purity of 99% or more and an optical purity of 98% ee or more.
The synthesis of both isomers of (benzofuran-2-yl) -2-propylaminopentane can be achieved stereoselectively. Further, the yield was also dramatically improved as compared with the conventional optical resolution method using HPLC fractionation.

The specific rotation and HPLC analysis of both isomers of optically active 1- (benzofuran-2-yl) -2-propylaminopentane obtained by the practice of the present invention showed that (R)- (R) -1- (benzofuran-2-yl) -2-propylaminopentane synthesized using norvaline as a starting material is a (-)-isomer, and synthesized using (S) -norvaline as a starting material (S). -1- (benzofuran-2-yl) -2-propylaminopentane is (+)-
It turned out to be an isomer.

[0031]

As described above, an optically active aziridine compound or an optically active amide compound which can be synthesized from a commercially available optically active amino acid in a chiral pool manner is used to obtain a highly selective compound via the corresponding optically active amine. A method for synthesizing both isomers of optically active 1- (benzofuran-2-yl) -2-propylaminopentane with high yield has been established. In addition, it has become possible to determine the absolute configuration of the asymmetric center, which cannot be achieved by the prior art. This method can be applied to the synthesis of other optically active ethylamine derivatives by selecting an appropriate optically active amino acid.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

[0033]

Example 1 1) Synthesis of (R) -norvalinol (II) A solution of lithium aluminum hydride (14.8 g, 389 mmol) in tetrahydrofuran (450 ml) was stirred under ice-cooling with (R) -norvaline (I) (30.4 g). g, 260 mmol) for 30 minutes and refluxed for 2 hours. Water was slowly added to this gray suspension under ice-cooling and stirring until the generation of hydrogen was completed, and insolubles were removed by filtration. This insoluble was washed six times with ethyl acetate (150 ml). The filtrate and the washing solution are combined, dried over anhydrous sodium sulfate, and then concentrated.
(R) -Norvalinol (II) (26.8 g, quantitative) was obtained. Colorless oil.

¹ H-NMR (CDCl ₃ ): δ 0.93 (t, J = 7.1 Hz, 3
H), 1.11-1.57 (m, 4H), 2.56-3.10 (br, 4H), 3.27 (dd, J
= 10.8, 7.7Hz, 1H), 3.56 (dd, J = 10.8, 3.7Hz, 1H)

[0035] 2) (R) -N, O- Visto sill nor burrs Nord (III: RSO ₂ synthesis of tosyl group) (R) - pyridine Norubarinoru (II) (26.8g, 260mmol)
(160 ml), p-toluenesulfonyl chloride (124 g, 649 mmol) was added to the solution under ice-cooling with stirring for 30 minutes, and the mixture was stirred under ice-cooling for 2 hours. To this brown solution was added diethyl ether (8
00ml) and water (200ml). The organic layer was washed four times with a 1M aqueous hydrochloric acid solution (250 ml). This organic layer was used for the next reaction.

¹ H-NMR (CDCl ₃ ): δ 0.72 (t, J = 7.1 Hz, 3
H), 0.90-1.50 (m, 4H), 2.42 (s, 3H), 2.46 (s, 3H), 3.3
0-3.40 (m, 1H), 3.82 (dd, J = 10.1, 4.4Hz, 1H), 3.95 (d
d, J = 10.1, 3.3Hz, 1H), 4.79 (d, J = 8.4Hz, 1H), 7.25-
7.37 (m, 4H), 7.71 (t, J = 8.1Hz, 4H)

3) (R) -N-tosylaziridine (IV: RSO
Synthesis of III (tosyl group ₂ ) III (RSO ₂ is tosyl group) in diethyl ether (800 ml) solution, under ice cooling and stirring, 2.5 M sodium hydroxide aqueous solution (800 ml)
Was added over 15 minutes, and the mixture was stirred under ice cooling until an excessive amount of p-toluenesulfonyl chloride was decomposed (17 hours). After the reaction,
The reaction solution was allowed to stand, and the organic layer was separated. The organic layer was washed twice with water (200 ml) and then with a saturated saline solution (200 ml), dried over anhydrous sodium sulfate and concentrated. The brown oily residue was purified by column chromatography (ethyl acetate: n-
Hexane = 1: 4) and IV (RSO ₂ is a tosyl group) (42.3 g,
68%). Pale yellow oil.

¹ H-NMR (CDCl ₃ ): δ 0.86 (t, J = 7.1 Hz, 3
H), 1.23-1.61 (m, 4H), 2.06 (d, J = 4.4Hz, 1H), 2.44
(s, 3H), 2.62 (d, J = 7.1Hz, 1H), 2.74 (m, 1H), 7.34
(d, J = 9.4Hz, 2H), 7.82 (dd, J = 1.7Hz, 2H)

4) (R) -1- (benzofuran-2-yl)
2- (tosylamino) pentane (V: RSO ₂ is tosyl group) under argon atmosphere, benzofuran (2.5 ml, 22.8 mmol) with stirring under ice cooling in diethyl ether (20ml) solution of, n- butyl lithium (14.8 ml , 1.54M in hexane, 22.8mmol) and stirred under reflux for 30 minutes. With stirring under ice cooling to the orange solution, (R)-N-tosyl aziridine (IV: RSO ₂ is tosyl group)
(1.82 g, 7.6 mmol) in diethyl ether (15 ml) was added, and the mixture was stirred at room temperature for 2 hours. Water (30 ml) was added to this brown suspension under ice-cooling and stirring, and the mixture was separated. Water the organic layer (30 ml)
, And dried over anhydrous sodium sulfate and concentrated. The residual orange oil was purified by column chromatography (ethyl acetate: n-hexane = 1: 5) to obtain V (RSO ₂ is a tosyl group) (2.01 g, 74%). Orange crystals.

¹ H-NMR (CDCl ₃ ): δ 0.82 (t, J = 7.1 Hz, 3
H), 1.25-1.82 (m, 4H), 2.31 (s, 3H), 2.76 (dd, J = 14.8,
6.4Hz, 1H), 2.84 (dd, J = 14.8, 6.4Hz, 1H), 3.61 (m,
1H), 4.82 (d, J = 7.1Hz, 1H), 6.33 (s, 1H), 7.07 (d, J =
7.7Hz, 2H), 7.19-7.30 (m, 2H), 7.33 (d, J = 7.4Hz, 1
H), 7.43 (d, J = 7.2Hz, 1H), 7.64 (d, J = 7.4Hz, 2H)

5) (R) -1- (benzofuran-2-yl)
-2- (N-propyl-N-tosylamino) pentane (V
I: RSO ₂ Synthetic V (RSO ₂ is tosyl group) (9.60 g of tosyl group), in dimethylformamide (100ml) solution of 26.9 mmol) with stirring under ice cooling, 60% sodium hydride (1.61 g, 40.3 mmol ) Was added and the mixture was stirred under ice cooling for 10 minutes.
Bromopropane (3.7 ml, 4 ml
0.3 mmol) and stirred at 70 ° C. for 1 hour. The brown solution was poured into ice water (200 ml) and stirred at room temperature for 15 minutes. The precipitated crystals were collected by filtration and washed three times with water (50 ml). In addition, diethyl ether (150 ml) was added to the filtrate, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue orange oily substance was purified by column chromatography (ethyl acetate: n-hexane = 1: 9), and this was combined with the previously collected one, and then VI (RSO ₂ was a tosyl group) (8.97 g, 84%) I got Yellow crystals.

¹ H-NMR (CDCl ₃ ): δ 0.83 (t, J = 7.3 Hz, 3
H), 0.89 (t, J = 7.1Hz, 3H), 1.20-1.84 (m, 6H), 2.31
(s, 3H), 2.78 (m, 1H), 3.06 (m, 1H), 4.19 (dt, J = 7.1H
z, 7.1Z, 1H), 6.35 (s, 1H), 7.07 (d, J = 8.4Hz, 2H), 7.
13-7.33 (m, 2H), 7.42-7.50 (m, 2H), 7.63 (d, J = 8.4Hz,
2H) IR (KBr): 2970, 2940, 2880, 1610, 1460, 1340, 132
5, 1265, 1165, 1152, 1100, 1030, 1018, 965, 950, 9
40, 860, 820, 760, 718, 658, 580, 560 cm ^-1

6) (R) -1- (benzofuran-2-yl)
Synthesis of -2-propylaminopentane (VII) hydrochloride Under an argon atmosphere, a sodium (3.26 g, 139 mmol) was added to a solution of naphthalene (17.8 g, 139 mmol) in ethylene glycol dimethyl ether (90 ml) under acetone-dry ice cooling, Ultrasound was applied. After stirring this black solution at room temperature for 30 minutes, VI (13.9 g, 34.8 mmol) in ethylene glycol dimethyl ether (70 ml) was added dropwise over 30 minutes under cooling and stirring with acetone-dry ice. The brown solution was stirred for 30 minutes under cooling with acetone-dry ice. Water was added to the brown solution with stirring under cooling with acetone-dry ice until the color of the solution turned orange. Also, add diethyl ether (3
00ml), and the mixture was separated. The organic layer was washed with water (100 ml) and extracted five times with a 2M aqueous hydrochloric acid solution (120 ml). The aqueous layer was washed with diethyl ether (100 ml), made basic with 28% aqueous ammonia, and extracted with diethyl ether (400 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain VII (5.84 g, 68%) as a pale yellow oil. This was treated with hydrogen chloride-diethyl ether to obtain the hydrochloride salt of VII (5.97 g, 89%). Colorless needle crystals.

Melting point: 167.0-168.0 ° C. (ethanol-ether) ¹ H-NMR (CDCl ₃ ): δ 0.91 (t, J = 7.4 Hz, 3H), 0.94 (t, J
= 7.4Hz, 3H), 1.35-1.72 (m, 2H), 1.72-2.15 (m, 4H),
2.88 (m, 2H), 3.27 (m, 1H), 3.57 (m, 2H), 6.65 (s, 1
H), 7.10-7.38 (m, 2H), 7.38-7.65 (m, 2H), 9.62 (br, 2
H) IR (KBr): 3430, 2960, 2870, 2790, 2750, 2700, 251
0, 2430, 1608, 1595, 1476, 1457, 1255, 1179, 952,
808, 777, 762 cm ^-1 Elemental analysis: C ₁₆ H ₂₃ NO ・ HCl Theoretical value: C 68.19%, H 8.58%, N 4.97% Actual value: C 68.36%, H 8.42%, N 5.06% Specific rotation : [Α] _D = -4.23 (c = 4.40, MeOH, 20 ° C) Optical purity: 98% ee or more (HPL using chiral column
HPLC: Column: Chiralpak AD-RH (4.6 mm x 150 mm) Eluent: 20 mM phosphate buffer: acetonitrile = 3: 2 Column temperature: room temperature Detection: UV 279 nm Injection amount: 1 mg of VII hydrochloride Dissolve in 20 ml of eluate and inject 5 μl.

[0045]

Example 2 1) (R) -1- (benzofuran-2-yl)
-2- (Tosylamino) pentane lithium salt (VIII: RSO ₂
Under an argon atmosphere, a solution of benzofuran (6.4 ml, 59.4 mmol) in tetrahydrofuran (20 ml) was added with stirring under ice-cooling, and n-butyllithium (39.6 ml, 1.50 M in hexane, 59.4 mmol) was added. The mixture was stirred under reflux for minutes. With stirring under ice cooling to the reaction solution, (R)-N-tosyl aziridine (IV: RSO ₂ is tosyl group)
(11.8 g, 49.5 mmol) in tetrahydrofuran (17 ml) was added to 2
The mixture was added dropwise over 0 minutes, and the mixture was stirred under ice cooling for 30 minutes. Diethyl ether (20 ml) was added to the reaction solution under ice-cooling and stirring, and the mixture was cooled under ice-cooling.
After stirring for minutes, the crystals were filtered. The crystals were washed four times with diethyl ether (50 ml), and VIII (RSO ₂ was a tosyl group) (12.
5g, 70%). Yellow crystals.

Melting point: 237.0 ° C .- (decomposition) IR (KBr): 3300, 2970, 2940, 2875, 1600, 1460, 132
5, 1260, 1163, 1100, 950, 822, 760, 665, 590, 560,
485, 420 cm ^{-1 1} H-NMR (CDCl ₃ ): δ 0.83 (t, J = 7.1 Hz, 3H), 1.20-1.55
(m, 4H), 2.32 (s, 3H), 2.75 (dd, J = 6.4, 15.1Hz, 1H),
2.85 (dd, 1H, J = 5.7, 15.1Hz, 1H), 3.61 (m, 1H), 6.33
(s, 1H), 7.08 (d, J = 8.1Hz, 2H), 7.14-7.49 (m, 4H),
7.64 (d, 2H)

2) (R) -1- (benzofuran-2-yl)
-2- (N-propyl-N-tosylamino) pentane (VI: RS
O ₂ synthesis VIII (RSO ₂ is tosyl group) (37.0 g, stirring under ice cooling in dimethylformamide (100ml) solution of 101 mmol) of tosyl group), bromopropane (1
1.1 ml, 122 mmol) and stirred at 70 ° C. for 3 hours. Water (100 ml) and diethyl ether were added to the reaction solution while stirring on ice.
(300 ml) was added and the mixture was separated. The organic layer was washed three times with water (100 ml) and then with a saturated saline solution (50 ml), dried over anhydrous sodium sulfate and concentrated. The brown amorphous residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain brown crystals (31.86 g). Recrystallization from n-hexane gave VI (RSO ₂ is a tosyl group) (20.64 g, 51%). Yellow crystals.

[0048]

Example 3 1) Synthesis of (R) -N- (benzyloxycarbonyl) norvaline (IX) (R) -norvaline (I) (7.00 g, 59.8 mmol) was dissolved in a 2M aqueous sodium hydroxide solution (35 ml). And cooled in an ice bath. Benzyl chloroformate (Z-chloride) (8.45 ml, 59.8 mmol) and 2
M sodium carbonate aqueous solution (53 ml) was added alternately in tenths. After the addition was completed, stirring was continued for 30 minutes in an ice bath, and further stirred at room temperature for one day. Add this alkaline solution with ether 2
Washed twice. Concentrated hydrochloric acid was added dropwise while stirring the washed aqueous solution in an ice bath while stirring, and the separated oily substance was extracted with ethyl acetate. The aqueous layer was saturated with brine and extracted once more with ethyl acetate. The organic layer was collected, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and IX (11.1 g, 74
%). White crystals.

¹ H-NMR (CDCl ₃ ): δ 0.94 (t, J = 7.1 Hz, 3
H), 1.60-2.00 (m, 4H), 4.30-4.50 (m, 1H), 5.12 (s, 1
H), 5.20-5.30 (m, 1H), 7.35 (s, 1H)

2) Synthesis of (R) -N- (benzyloxycarbonyl) -N-methoxy-N-methylnorvalinamide (X) 1-hydroxybenzotriazole (1.88 g, 13.9 mmol)
And N-methylmorpholine (1.62 ml, 17.4 mmol) at -10 ° C
Was added to a solution of 1-ethyl-3- [3- (diethylamino) propyl] carbodiimide hydrochloride (WSCDI) (2.66 g, 13.9 mmol) in methylene chloride (70 ml). The mixture was warmed to room temperature, a methylene chloride solution (28 ml) of (R) -N- (benzyloxycarbonyl) norvaline (IX) (3.50 g, 13.9 mmol) was added dropwise to the mixture, and the mixture was stirred for 30 minutes. Cooled to -10 ° C. N-methyl-O-methylhydroxylamine hydrochloride
(1.37 g, 14.1 mmol) and N-methylmorpholine (1.6 ml, 17 m
mol) in methylene chloride (21 ml) was added dropwise and the resulting mixture was warmed to room temperature and stirred. Concentrate the reaction mixture,
The mixture was separated with water and ethyl acetate, and the organic layer was washed successively with 10% hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purified by chromatography (methylene chloride: methanol = 40: 1), X (3.9 g, 94%)
I got Colorless oil.

¹ H-NMR (CDCl ₃ ): δ 0.92 (t, J = 7.1 Hz, 3
H), 1.35-1.75 (m, 4H), 3.21 (s, 1H), 3.78 (s, 3H), 4.7
0-4.80 (m, 1H), 5.00-5.15 (m, 2H), 5.40-5.50 (m, 1H),
7.25-7.34 (m, 5H)

4) (R) -1- (benzofuran-2-yl)
Synthesis of -2-{(benzyloxycarbonyl) amino} -1-pentanone (XI) A solution of benzofuran (2.46 g, 25.4 mmol) in tetrahydrofuran (90 ml) at −35 ° C. was n-butyllithium (33 ml, 1.54 M).
(hexane, 51 mmol) was added dropwise over 3 minutes or more, and the mixture was further stirred at -30 to -25 ° C for 10 minutes. X (3.00g, 1
0.2 mmol) in tetrahydrofuran (36 ml) is quickly added dropwise within 1 minute and stirred at -30 ° C. After the reaction, the reaction mixture was poured into saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were added, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
(n-hexane: methylene chloride = 1: 1), XI
(1.63 g, 46%). Colorless oil.

¹ H-NMR (CDCl ₃ ): δ 0.94 (t, J = 7.1 Hz, 3
H), 1.40-2.10 (m, 4H), 5.12 (s, 2H), 5.26-5.30 (m, 1
H), 7.25-7.36 (m, 5H), 7.48-7.75 (m, 5H)

4) (R) -1- (benzofuran-2-yl)
Synthesis of -2-aminopentane (XII) XI (1.50 g, 4.26 mmol) was dissolved in trifluoroacetic acid (6.6 ml), and triethylsilane (3.0 ml) was added, followed by heating at 55-60 ° C for 2 hours. did. Water (1 ml) and methanol (1 ml) were added to the reaction solution.
Was added and stirred overnight. The solvent was added to a saturated aqueous solution of hydrogencarbonate for neutralization, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (methylene chloride: methanol = 20: 1).
XII (0.47 g, 54%) was obtained. Colorless oil.

¹ H-NMR (CDCl ₃ ): δ 0.91 (t, J = 7.0 Hz, 3
H), 1.35-1.80 (m, 4H), 3.10-3.40 (m, 2H), 3.68 (m, 1
H), 6.56 (s, 1H), 7.10-7.50 (m, 2H), 7.40-7.52 (m, 2
H), 7.64 (s, 2H)

5) (R) -1- (benzofuran-2-yl)
Synthesis of -2-propionylaminopentane (XIII) XII (0.47 g, 2.31 mmol) and triethylamine (0.40 ml)
Was dissolved in methylene chloride, and propionyl chloride was added under ice cooling.
(0.48 ml) was added dropwise. The mixture was heated to room temperature and further stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (methylene chloride:
Purified with methanol = 40: 1), XIII (0.49 g, 82%)
I got Colorless oil.

¹ H-NMR (CDCl ₃ ): δ 0.91 (t, J = 6.7 Hz, 3
H), 1.15 (t, J = 7.7Hz, 3H), 1.40-1.55 (m, 4H), 2.19
(q, J = 7.7Hz, 2H), 2.80-3.10 (m, 2H), 4.32 (m, 1H),
5.43 (m, 1H), 6.47 (s, 1H), 7.10-7.40 (m, 2H), 7.40-
7.52 (m, 2H)

6) (R) -1- (benzofuran-2-yl)
Synthesis of -2-propylaminopentane (VII) hydrochloride XIII (1.76 g, 6.6) was added to a suspension of lithium aluminum hydride (1.03 g, 27.1 mmol) in diethyl ether (20 ml) under ice cooling.
A solution of 79 mmol) in diethyl ether (20 ml) was added dropwise. 30
After stirring for minutes, the mixture was further refluxed. After the reaction, sodium fluoride was added to the reaction solution under ice cooling and the mixture was stirred, water was added, and the mixture was further stirred at room temperature. The organic layer was washed successively with dichloromethane containing 5% ethanol and ethyl acetate containing 5% ethanol, and the organic layer was distilled off under reduced pressure. The resulting crude product was purified by column chromatography to give VII (1.40 g, 84%). I got Treatment with hydrochloric acid-diethyl ether yields the hydrochloride salt of VII (1.
24g, 64%). Colorless needles.

Melting point: 165.5-167.0 ° C. (ethanol-ether) Elemental analysis: as C ₁₆ H ₂₃ NO.HCl Theoretical value: C 68.19%, H 8.58%, N 4.97% Observed value: C 68.02%, H 8.38%, N 4.88% Optical purity: 98% ee or more (HPLC using chiral column
(Determined by analysis)

[Brief description of the drawings]

FIG. 1 is a process chart showing a synthesis route of an optically active 1- (benzofuran-2-propylaminopentane derivative according to the present invention.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Takuya Asa 1-34 Nishiotsuka, Matsubara-shi, Osaka Fujimoto Pharmaceutical Co., Ltd. F-term (reference) 4C037 PA09 4H039 CA19 CD10

Claims (5)

[Claims] 1. Each of the following steps a to c: a. General formula (IV), [Wherein, R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group,
Or a substituted phenyl group, and * indicates the position of an asymmetric carbon atom].
(V), A step of obtaining an optically active benzofurylsulfonylaminopentane compound represented by the formula: wherein R and * have the same meanings as described above, b. The compound of the general formula (V) is reacted with propyl halide in the presence of a strong base to obtain a compound of the general formula (VI): A step of obtaining an optically active benzofurylsulfonylpropylaminopentane compound represented by the formula: wherein R and * have the same meanings as described above, c. The compound of the general formula (VI) is reacted with an alkali metal and a polycyclic aromatic hydrocarbon to obtain a compound of the formula (VII): [Wherein * represents the same meaning as described above], the step of obtaining an optically active 1- (benzofuran-2-yl) -2-propylaminopentane represented by the formula:
A method for producing (benzofuran-2-yl) -2-propylaminopentane. 2. The following steps a to f: a. Formula (I), embedded image In the formula, * represents the position of an asymmetric carbon atom, and a reducing agent is reacted with optically active norvaline represented by the formula (II): Obtaining an optically active norvalinol represented by the formula: wherein * represents the same meaning as described above, b. A compound of the formula (II) is reacted with a sulfonyl halide in the presence of a base to give a compound of the formula (III): [Wherein, R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group,
Or a substituted phenyl group, and * has the same meaning as described above.) C. The compound of the general formula (III) is reacted with a strong base to give a compound of the general formula (IV): A process for obtaining an optically active aziridine compound represented by the formula: wherein R and * are as defined above, d. The compound of general formula (IV) is reacted with lithium 2-benzofuran to obtain a compound of general formula (V): A step of obtaining an optically active benzofurylsulfonylaminopentane compound represented by the formula: wherein R and * are as defined above, e. The compound of the general formula (V) is reacted with propyl halide in the presence of a strong base to obtain a compound of the general formula (VI): A step of obtaining an optically active benzofurylsulfonylpropylaminopentane compound represented by the formula: wherein R and * have the same meanings as described above; f. The compound of the general formula (VI) is reacted with an alkali metal and a polycyclic aromatic hydrocarbon to obtain a compound of the formula (VII): [Wherein * represents the same meaning as described above], the step of obtaining an optically active 1- (benzofuran-2-yl) -2-propylaminopentane represented by the formula:
A method for producing (benzofuran-2-yl) -2-propylaminopentane. 3. The following steps a to e: a. Formula (I), embedded image In the formula, * represents the position of an asymmetric carbon atom, and a reducing agent is reacted with optically active norvaline represented by the formula (II): Obtaining an optically active norvalinol represented by the formula: wherein * represents the same meaning as described above, b. A compound of the formula (II) is reacted with a sulfonyl halide in the presence of a base to give a compound of the formula (III): [Wherein, R represents an alkyl group having 1 to 4 carbon atoms, a phenyl group,
Or a substituted phenyl group, and * has the same meaning as described above], a step of obtaining an optically active bissulfonyl compound represented by the formula: c. The compound of the general formula (III) is reacted with a strong base to give a compound of the general formula (IV): A process for obtaining an optically active aziridine compound represented by the formula: wherein R and * are as defined above, d. The compound of the general formula (IV) is reacted with lithium 2-benzofuran to form the compound of the general formula (VIII): [Wherein R and * have the same meanings as described above], are isolated and reacted with propyl halide without using a strong base to obtain a compound represented by the general formula (VI): A process of obtaining an optically active benzofurylsulfonylpropylaminopentane compound represented by the formula: wherein R and * have the same meanings as described above, e. The compound of the general formula (VI) is reacted with an alkali metal and a polycyclic aromatic hydrocarbon to obtain a compound of the formula (VII): [Wherein * represents the same meaning as described above], the step of obtaining an optically active 1- (benzofuran-2-yl) -2-propylaminopentane represented by the formula:
A method for producing (benzofuran-2-yl) -2-propylaminopentane. 4. Each of the following steps a to d: a. Formula (X), [Wherein Z represents a benzyloxycarbonyl group and * represents the position of an asymmetric carbon atom].
(XI), embedded image A step of obtaining an optically active benzofurylaminopentanone compound represented by the formula: wherein Z and * are as defined above, b. The compound of formula (XI) is reacted with hydrosilane in the presence of a strong acid to give a compound of formula (XII) Obtaining an optically active benzofurylaminopentane compound represented by the formula: wherein * represents the same meaning as described above; c. The compound of formula (XII) is reacted with propionyl halide or the like in the presence of a base to give a compound of formula (XIII) A process of obtaining an optically active benzofurylpropionylaminopentane compound represented by the formula: wherein R and * have the same meanings as described above, d. The compound of formula (XIII) is reacted with a reducing agent to give a compound of formula (VI
I) 、 embedded image [Wherein * represents the same meaning as described above], the step of obtaining an optically active 1- (benzofuran-2-yl) -2-propylaminopentane represented by the formula:
A method for producing (benzofuran-2-yl) -2-propylaminopentane. 5. The following steps a to f: a. Formula (I), embedded image In the formula, * indicates the position of an asymmetric carbon atom, and benzyl chloroformate (Z
-Chloride) to give a compound of formula (IX) Wherein Z represents a benzyloxycarbonyl group and * has the same meaning as described above; b. Obtaining an optically active Z-norvaline; The optically active Z-norvaline of the formula (IX) is reacted with N-methyl-O-methylhydroxylamine hydrochloride in the presence of a base and a condensing agent to obtain a compound of the formula (X): A step of obtaining an optically active amide compound represented by the formula: wherein Z and * are as defined above, c. The compound of formula (X) is reacted with lithium 2-benzofuran to form a compound of formula (XI) Obtaining an optically active benzofurylaminopentanone compound represented by the formula: wherein Z and * are as defined above, d. The compound of formula (XI) is reacted with hydrosilane in the presence of a strong acid to give a compound of formula (XII) Obtaining an optically active benzofurylaminopentane compound represented by the formula: [wherein * represents the same meaning as described above], e. The compound of formula (XII) is reacted with propionyl halide or the like in the presence of a base to give a compound of formula (XIII) A step of obtaining an optically active benzofurylpropionylaminopentane compound represented by the formula: wherein R and * have the same meanings as above, f. The compound of formula (XIII) is reacted with a reducing agent to give a compound of formula (VI
I) 、 embedded image [Wherein * represents the same meaning as described above], the step of obtaining an optically active 1- (benzofuran-2-yl) -2-propylaminopentane represented by the formula:
A method for producing (benzofuran-2-yl) -2-propylaminopentane.