JP2003113154A - Method for producing (r)-(-)-3'-(2-amino-1-hydroxyethyl)-4'- fluoromethane sulfoneanilide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for enantio-selectively producing (R)-(-)-3'-(2- amino-1-hydroxyethyl)-4'-fluoromethane sulfoneanilide hydrochloride from 3- dibenzylaminoacetyl-4-fluoromethane sulfoneanilide. SOLUTION: This method for producing (R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'- fluoromethane sulfoneanilide hydrochloride comprises an asymmetric reduction step for reacting 3-dibenzylaminoacetyl-4-fluoromethane sulfoneanilide with a hydrido reagent in the presence of an optically active cobalt complex and a step for carrying out a debenzylation reaction of the resultant compound by using a reduction catalyst under hydrogen atmosphere after carrying out the previous step.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention is useful as a synthetic intermediate or a drug substance of a physiologically active compound such as a drug (R).
The present invention relates to a method for enantioselectively producing-(-)-3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide.

[0002]

(R)-(-)-3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride is
This compound is expected to be effective as a therapeutic agent for urinary incontinence and is under development.

This (R)-(-)-3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride can be produced according to the process shown in the following reaction formula (I). It has been reported (WO91 / 12236). Reaction formula (I):

[0004]

[Chemical 6]

According to this method, an asymmetric catalyst such as a rhodium complex having an optically active phosphorus compound as a ligand is used in a solvent under a hydrogen atmosphere of 1.5 to 3.5 MPa to generate a corresponding ketone. Can be synthesized by asymmetric hydrogenation. However, this method is problematic in that it requires high-pressure reaction equipment, that the handling of the asymmetric complex catalyst is complicated, and that purification by crystallization as a tartrate salt must be repeated even after the asymmetric hydrogenation reaction. However, it is not always sufficient.

[0006]

The object of the present invention is to solve the problems in the prior art, to use a simple method, with a high yield and high optical purity, and to be represented by the above formula (c) (R). -(-)-
It is to provide a method for producing 3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide or an acid addition salt thereof.

[0007]

Under the circumstances, as a result of intensive investigations by the present inventors, it has been found that an asymmetric reduction reaction is carried out using an optically active cobalt complex catalyst, followed by a debenzylation reaction. According to the above, it was found that the target product can be obtained by a simple method with excellent yield and optical purity, and the above-mentioned object was achieved.

That is, the present invention provides the following reaction formula (II):

[0009]

[Chemical 7]

As shown in (3), as shown in equation (1),
Steps (Step 1) and (2) of performing asymmetric reduction reaction of dibenzylaminoacetyl-4-fluoromethanesulfonanilide using a hydride reagent in the presence of an optically active cobalt complex catalyst
The resulting (R)-(-)-3 '-(2-dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide represented by the formula (b) is converted into an acid addition salt and then hydrogen. (R)-(-)-3 '-(2-amino-1 represented by the formula (c), which comprises a step (step 2) of performing a debenzylation reaction using a catalytic reduction catalyst in an atmosphere
A method for producing -hydroxyethyl) -4'-fluoromethanesulfonanilide or an acid addition salt thereof.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a process for producing (R)-(-)-3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide or an acid addition salt thereof according to the present invention ( Hereinafter, "the method of the present invention" will be described in detail. [Step 1: Asymmetric hydride reduction reaction] According to the method of the present invention, the formula (a):

[0012]

[Chemical 8]

3-dibenzylaminoacetyl-4 represented by
-Fluoromethanesulfonanilide is reacted with a hydride reagent in a solvent in the presence of an optically active cobalt complex catalyst to give a compound of formula (b):

[0014]

[Chemical 9]

It is possible to obtain (R)-(-)-3 '-(2-dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide represented by:

In this reaction, coexistence of an alcohol compound and a halogen compound is preferable in terms of improving the chemical yield and the optical yield. The compound of formula (a) is a known substance, and can be synthesized according to the method of WO91 / 12236.

The optically active cobalt complex used as a catalyst in the method of the present invention is described in JP-A-9-151.
The following general formula (f) disclosed in Japanese Patent No. 143:

[0018]

[Chemical 10]

(Where R is²And R³Is a different group and it
A hydrogen atom, a linear or branched alkyl group, or
Is an aryl group, which may have a substituent, 2
R²Two or two R³The two are connected to each other to form a ring.
R may be formed^Four, R ^FiveAnd R⁶Are the same but different
May be a hydrogen atom, a straight-chain or branched
Kill group or aryl group, acyl group or alkoxy
A carbonyl group, which may have a substituent)
And an optically active cobalt (II) complex.

Among these, especially the following general formula (d):

[0021]

[Chemical 11]

An optically active cobalt complex represented by the formula (wherein R ¹ is a methyl group or a mesityl group) is used.

Specific examples of the optically active cobalt complex represented by the general formula (d) include the following formulas (d-1) and (d-2).
Is mentioned.

[0024]

[Chemical 12]

[0025]

[Chemical 13]

In the method of the present invention, the above-mentioned general formula
General formula (e) obtained by deriving from the optically active cobalt (II) complex represented by (d):

[0027]

[Chemical 14]

The optically active cobalt (III) complex represented by the formula (R ¹ is as defined for the general formula (d) above, and X ⁻ represents an anion capable of forming a salt), is also a method of the present invention. It is effective as a catalyst used in.

In this general formula (e), X^-With a concrete example of
Then F^-, Cl^-, Br^-, I^-, OH^-, BF _Four ^-Etc.
It Component of optically active cobalt complex represented by the above formula (e)
As a body example, mention the following formula (e-1) or (e-2)
You can

[0030]

[Chemical 15]

[0031]

[Chemical 16]

The amount of the optically active cobalt complex represented by the general formula (d) or (e) used as a catalyst in the method of the present invention is 0.01 to 2 with respect to the compound of the formula (a).
It is 0 mol%, and more preferably 0.5 to 10 mol%.

In the method of the present invention, as the hydride reagent, lithium aluminum hydride, lithium tri (t-butoxy) lithium hydride, lithium borohydride, sodium borohydride disclosed in JP-A-9-151143 is used. Any of metal hydrides such as potassium borohydride, calcium borohydride, ammonium borohydride, and sodium cyanoborohydride can be used, but sodium borohydride is preferable from the viewpoint of operability.

The amount of the hydride reagent used may be 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound of the formula (a).

In the method of the present invention, the halogen compound used as an additive is trifluoromethylbenzene, dichloromethane, chloroform, carbon tetrachloride, chloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, methyl dichloroacetate, Examples thereof include benzyl chloride, benzal chloride, dibromomethane, bromoform, carbon tetrabromide, bromoethane, 1,2-dibromoethane, methyl iodide, diiodomethane, iodoform and carbon tetraiodide. Among these, dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, bromoform and iodoform are preferable in that the compound represented by the formula (b) can be obtained with high optical yield and high chemical yield. preferable.

When the halogen compound is used in the method of the present invention, it is used in a proportion of 0.001 to 20 mol, particularly 0.01 to 10 mol, per 1 mol of the compound of formula (a). Is preferred.

Alcohol compounds are disclosed in JP-A-9-15114.
Methanol, ethanol, 1 disclosed in Japanese Patent No. 3
-Propanol, 2-propanol, butanol, se
Aliphatic or alicyclic alcohols such as c-butanol, tert-butanol, cyclopentanol, cyclohexanol, and cycloheptanol, aromatic alcohols such as phenol and resorcin, polyalcohols such as ethylene glycol and propylene glycol, and ethylene glycol monomethyl. Ether, ethylene glycol monoethyl ether, propylene glycol monomethyl ether,
Tetrahydrofurfuryl alcohol, tetrahydropyran-2-methanol, furfuryl alcohol, tetrahydro-3-furan-methanol and the like can be used any of the chain or cyclic ether alcohol and other alcohol compounds, in the present invention, methanol,
Ethanol and tetrahydrofurfuryl alcohol are preferred.

The alcohol compound is used in an amount of 0.01 to 100 mol, and particularly 0.1 mol, per mol of the compound of the formula (a).
It is preferably used in a proportion of 1 to 50 mol.

In the method of the present invention, the reaction is preferably carried out in the liquid phase. At this time, a solvent may be used if necessary. Examples of the solvent to be used include aliphatic hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, alicyclic hydrocarbon solvents, ester solvents, and halogen solvents disclosed in JP-A-9-151143. Although any solvent such as a solvent can be used, an ether solvent such as tetrahydrofuran, an aromatic hydrocarbon solvent such as toluene, or an ester solvent such as ethyl acetate is preferable.

The reaction temperature is usually preferably -80 to 30 ° C, more preferably -40 to 10 ° C. The reaction pressure can be usually atmospheric pressure, but the reaction may be performed under increased pressure or reduced pressure.

The reaction time is usually about 10 minutes to 2 hours. Furthermore, the progress of the reaction can be confirmed by sequentially collecting samples of the reaction mixture and analyzing them by thin layer chromatography (TLC) or the like.

The compound of formula (b) obtained by the above reaction can be purified by a combination of known methods such as column chromatography, extraction and recrystallization.

Further, the compound of the formula (b) is converted into an acid addition salt by a conventional method, recrystallized and then re-released to give 9
It can be purified to a compound having a high optical purity of 9% ee or more. Examples of the acid addition salt used for purification include hydrochloride, tartrate and mandelate.

The purification for improving the optical purity can be carried out in each of the step 1 and the step 2 shown below, or the purification in the step 1 can be omitted or only the step 2 can be carried out. You may implement only in the process 1. [Step 2: Debenzylation reaction] The compound of formula (b) obtained by the asymmetric reduction reaction is converted into an acid addition salt, and the debenzylation reaction is carried out in a solvent under a hydrogen atmosphere in the presence of a catalytic reduction catalyst. Therefore, the general formula (c):

[0045]

[Chemical 17]

(R)-(-)-3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide represented by:
Alternatively, an acid addition salt thereof can be obtained.

In this reaction, the hydrogen pressure is 0.01 to 5 MPa.
It may be in the range of a, preferably in the range of 0.1 to 1 MPa. The solvent used is preferably an alcohol solvent, and particularly preferably a lower alcohol such as methanol, ethanol, 1-propanol or 2-propanol. The amount of solvent used is 2 with respect to the compound of formula (b).
~ 100 times by mass.

Examples of the catalytic reduction catalyst include metal catalysts such as palladium carbon, platinum oxide and Raney nickel. The amount of the catalyst used is 1 to the compound of the formula (b).
It is 70% by mass, preferably 10 to 30% by mass.

The reaction can be carried out usually in the temperature range of 0 ° C to 100 ° C, but the preferred temperature range is 10 ° C to 5 ° C.
It is 0 ° C. The reaction time is greatly affected by the hydrogen pressure and the amount of catalyst used, but the reaction is usually completed within 1 to 48 hours.

The compound of formula (c) obtained by the above reaction can be purified by a method such as filtration and crystallization.

Further, the compound of the above formula (c) can be purified to a compound having a high optical purity of 99% ee or more by converting it to an acid addition salt by a conventional method, recrystallizing it and then re-releasing it. . Examples of the acid addition salt used for purification include hydrochloride, tartrate and mandelate.

The optical purity of the compound of formula (c) or its acid addition salt can be determined by HPLC analysis or optical rotation analysis.

[0053]

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

In this example, the silica gel chromatography was performed by Merck No. 9385 silica gel was used.

For the measurement of optical purity, CHIRAL
PAK AD-H φ 4.6 mm X 250 mm (manufactured by Daicel Chemical Industries, Ltd.) was used to analyze under the following conditions using high performance liquid chromatography. Column temperature: 40 ° C. Mobile phase: Hexane / 2-propanol / diethylamine = 75/25 / 0.1 Flow rate: 1.0 mL / min Detection wavelength: 210 nm Optical rotation in pure water, DIP-360 (JASCO Corporation) Made)
Was measured using. Example 1 Sodium borohydride 5.6 mg in reactor
(0.15 mmol) was added, the atmosphere was replaced with nitrogen, 1 ml of tetrahydrofuran was added, and the mixture was cooled to 0 ° C. Optically active cobalt (I) having the configuration of (S, S) represented by formula (d-1) in a separate container
I) complex 1.2 mg (0.001 mmol), 3-dibenzylaminoacetyl-4-fluoromethanesulfonanilide 43 mg
(0.1 mmol), and nitrogen substitution, methanol 18 μl
(0.3 mmol), 8 μl of chloroform (0.1 mmol) and 1 ml of tetrahydrofuran were added to prepare a solution. The prepared solution was taken in a syringe, dropped into a suspension of sodium borohydride / tetrahydrofuran cooled to 0 ° C, and stirred at 0 ° C for 1 hour. Then, 1 ml of saline was added, and extraction was performed with 5 ml of ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to quantitatively (R)-(-)-3 '-(2-dibenzylamino-1-hydroxyethyl) -4. '-Fluoromethanesulfonanilide (optical purity
56% ee) was obtained. (Examples 2 to 3) In each example, the addition amount of the cobalt catalyst represented by the formula (d-1) was changed to the addition amount shown in Table 1 (expressed in mol% with respect to the compound represented by the formula (a)). Except
The reaction was carried out in the same manner as in Example 1. In each of the examples, (R)-(-)-3 '-(2-dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide was quantitatively obtained. The results of analyzing the optical purity of the obtained product are shown in Table 1.

[0056]

[Table 1]

(Example 4) (R)-(-)-with an optical yield of 82% ee
3 '-(2-Dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide 371 mg (0.8 mmol)
1 ml of a 1N hydrochloric acid ether solution was added to and stirred for 1 minute. The solution was concentrated under reduced pressure, and ether was added to solidify.
The precipitate was filtered and dried to obtain (R)-(-)-3 '-(2-dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride. (R)-(-)-3 'in the autoclave
-(2-Dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride, 5% palladium-carbon 92 mg (20 mass%) and methanol 3 ml were added, and hydrogen pressure was 0.3 MPa atmosphere. The mixture was stirred at room temperature for 19 hours. The solution is filtered through Celite and concentrated under reduced pressure to (R)-(-)-3 '-(2-amino
273 mg of 1-hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride were obtained.

Specific rotation [α] _D ³³ -17.7 ° (c =
0.200, H ₂ O) (Literature [α] _D −22.3 ° (c = 1.01, H ₂ O)

[0059]

According to the method of the present invention, 3-dibenzylaminoacetyl-4-fluoromethanesulfonanilide is used.
(R)-(-)-3 '-(2-amino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride can be prepared enantioselectively. This (R)-(-)-3 '-(2-amino-1-
Hydroxyethyl) -4'-fluoromethanesulfonanilide hydrochloride is a compound expected to be useful as a therapeutic agent for urinary incontinence.

Claims (4)

[Claims] 1. Formula (a): Asymmetric hydride reduction of 3-dibenzylaminoacetyl-4-fluoromethanesulfonanilide represented by the formula in the presence of an optically active cobalt complex catalyst and a hydride reagent,
(b): [Chemical formula 2] (R)-(-)-3 '-(2-dibenzylamino-1-hydroxyethyl) -4'-fluoromethanesulfonanilide represented by the formula (c) : [Chemical 3] (R)-(-)-3 '-(2-amino-1-hydroxyethyl) represented by
-4′-Fluoromethanesulfonanilide or a method for producing an acid addition salt thereof. 2. A step of (1) converting the compound represented by the formula (a) into a compound represented by the formula (b), and (2) converting the compound represented by the formula (b) into an acid addition salt, The method according to claim 1, comprising a step of converting the compound represented by the formula (c) by debenzylation reaction by hydrogen reduction. 3. The optically active cobalt complex catalyst is represented by the following general formula (d) or general formula (e): [Chemical 5] The method according to claim 1 or 2, wherein the compound is represented by (in the general formula (d) and the general formula (e), R ¹ represents a methyl group or a mesityl group). 4. The production method according to claim 1, wherein sodium borohydride is used as a hydride reagent in the asymmetric hydride reduction reaction.