IE83355B1 - Optically pure (R)-1-(3-amino-4-benzyloxyphenyl)-2-[N-benzyl-N-[(R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethanol, production method thereof and its use in the synthesis of formoterol - Google Patents

Description

DESCRIPTION Optically pure (R)(3-aminobenzyl0xypheny1)—2—[N-benzyl-N-[(R)-2—(4- methoxypheny1)—1—methylethy1]amino]ethano1, production method thereof and its use in the synthesis of formoterol TECHNICAL FIELD This invention relates to a novel crystal of optically pure (R)—l—(3—amino—4—benzyloxyphenyl) [NLbenzyl—AF[(R)—2—(4—methoxyphenyl)—l- methylethyl]aminolethanol and a production method thereof and to a method for the production of N-[2—hydroxy—5- [(R)—l—hydroxy—2—[(R)—2—(4—methoxyphenyl)—l— methylethylamino]ethyl]phenyl]formamide or an acid addition salt thereof, which is useful as a bronchodilator, by using said crystal.

BACKGROUND ART Formoterol, N—[2—hydroxy‘5~[(RS)—l—hydroxy— ~[(RS)—2~(4»methoxyphenyl)—l— methylethylamino]ethyllphenyl]formamide, has been put on the market mainly in Japan and Europe and used as an agent for the treatment of symptoms of obstructive pulmonary diseases such as asthma. Formoterol has two asymmetric carbon atoms in the molecule and is a racemic body composed of (R,R)— and (S,S)—isomer among four stereoisomers.

In this connection, when described simply as “formoterol” in this specification, it means a racemic body composed of (R,R)— and (S,S)—isomer. Also, when stereoisomers of formoterol and its related compounds are described regarding the two asymmetric carbon atoms, the carbon atom to which hydroxyl group is linked is defined as a, and the other one to which methyl group is linked is defined as B, and they are expressed in the order of (a,B). In addition, the symbol Bn in the structural formula represents a benzyl group.

OH H ‘N Two reports have been published so far regarding the bronchodilation action of four stereoisomers of N>[2— hydroxy—5—[l—hydroxy—2—[2—(4-methoxyphenyl) methylethylamino]ethyl]phenyl]formamide represented by the above formula. Murase et al. have reported that its action decreases in the order of (R,R) > (R,S) > (S,S) > (S,R), and the (R,R)—isomer shows 3 to l4 times higher effect than that of the other isomers (Chem. Pharm. Bull., 26, , 1978), and Trofast et al. have reported that its action decreases in the order of (R,R) >> (R,S) = (S,R) > (S,S), and the (R,R)-isomer shows 100 to 1,000 times higher effect than that of the other isomers (Chirality, , 443, 1991). These results suggest that the (R,R)—isomer of formoterol (to be referred to as “compound (I)” hereinafter) is useful as a bronchodilator for the treatment of symptoms of obstructive pulmonary diseases such as asthma in comparison with the other isomers.

H OHCHN N l I (1) HO OCH Four methods have been reported so far regarding the synthesis of four stereoisomers of AF[2—hydroxy— —[1~hydroxy—2-[2-(4~methoxyphenyl)—1— methylethylamino]ethyl]phenyl]formamide, particularly the compound (I). (1) A method in which a racemic body of (R,R)—isomer and (S,S)-isomer, or a diastereomeric mixture of (R,R)-isomer and (S,R)—isomer, of N>[2—hydroxy[1—hydroxy—2—[2—(4— methoxyphenyl)—l—methylethylamino]ethyl]pheny1]formamide is subjected to optical resolution using optically active tartaric acid (Murase et al., mentioned in the foregoing). (2) A method in which the diastereomeric mixture is separated by HPLC when an intermediate formed as a diastereomeric mixture by the reaction of an optically pure N—[(R)—l-phenylethyl]—2—(4-methoxyphenyl)—(R)~l— methylethylamine with a racemic 4—benzyloxy—3—nitrostyrene oxide is converted into the (R,R)—isomer of formoterol (Trofast et al., mentioned in the foregoing). (3) A method in which formoterol as a racemic body of (R,R)—isomer and (S,S)—isomer is separated by HPLC using a chiral column (International Patent Publication WO 95/18094). (4) A method in which the compound of interest is synthesized via the reaction of an optically pure (R)-N4 benzyl—2—(4—methoxyphenyl)methylethylamine with an optically pure (R)-4—benzyloxy—3—nitrostyrene oxide or (R)-4—benzyloxy—3—formamidostyrene oxide (International Patent Publication WO 98/21175; Hett et al., Tetrahedron Lett., 38, ll25, l997, and Org. Process Res. DeV., 2, 96, 1998).

The methods of from (1) to (3) are low in yield and require a step for the purification by silica gel column chromatography and/or a step for the separation of stereoisomers by HPLC. Also, the method of (4) requires relatively severe reaction conditions (24 hours at a temperature of from 110 to 130°C in the absence of solvent) for the reaction of the optically pure amine with the optically pure epoxide and it further requires a purification step using optically active tartaric acid because of the diastereomer contained in the (R,R)-isomer of formoterol in 2 to 3%.

The literature mentioned in the foregoing (Tetrahedron Lett., 38, 1125, 1997) describes that the compound (I) was produced via four steps from (R)—4— benzyloxy-3—nitrostyrene oxide and (R)—NLbenzyl—2—(4— methoxyphenyl)—l—methylethylamine (compound (V)). The reaction steps include cleavage of epoxide, catalytic reduction of nitro group, formylation of primary amino group and elimination of benzyl group, and these steps do not accompany steric inversion of the asymmetric carbon atoms, so that the intermediate of the second step is presumed to be (R)(3—amino~4-benzyloxyphenyl)—2—[N> benzyl—N—[(R)—2—(4—methoxyphenyl)—l- methylethyl]amino]ethanol (to be referred to as “compound (III)” hereinafter). However, said literature does not describe about isolation of the aforementioned compound (III) in its experiments, while describing that the compound (I) produced by this method contains 2 to 3% of diastereomer. Accordingly, it is considered that the compound (III) considered to be an intermediate of said production method also contained 2 to 3% of diastereomer.

Thus, not only crystallization of the compound (III) but also separation of optically pure compound by utilizing crystallization are not taught or suggested.

In consequence, the known synthesis methods of the (R,R)—isomer of formoterol (compound (I)) were not satisfactory as an industrial production method of the yield, quality, operation, etc., so that great concern has been directed toward the improvement of these factors.

DISCLOSURE OF THE INVENTION Under such state of art, the inventors of the present invention have conducted extensive studies on the production method of compound (I) and unexpectedly found that the compound (III), which is an optically pure intermediate having (R,R)-configuration, can be crystallized. Thereafter, the present invention has been accomplished by further finding that, when (RS)—l—(3— amino—4—benzyloxyphenyl)—2—[N=benzyl—N-[(R)—2—(4— methoxyphenyl)-l—methylethyl]amino]ethanol (to be referred to as “compound (II)“ hereinafter), which is a diastereomeric mixture of (R,R)— and (S,R)—isomer, is used as a starting material, the fractional crystallization is unexpectedly possible and the compound (III) having excellent optical purity can be isolated as crystals, and that the compound (I) having an optical purity of 99% or more can be produced by the use of said crystals as an intermediate for the production.

The following describes the present invention in detail.

Crystals of the compound of the present invention, (R)—l—(3—amino—4—benzyloxyphenyl)—2~[N—benzyl—N=[(R)—2—(4— methoxyphenyl)—1—methylethyl]amino]ethanol, having (R,R) configuration as represented by the following formula (III) OH Bn HZN fV\I//\\E::;1\ (Hp OCH BHO 3 are crystals which contain the compound (III) as the main component and from which the compound (I) having excellent optical purity can be produced, preferably crystals characterized by a heat absorption peak of from 92 to 98°C by the DSC analysis and lattice spacing peaks of 14.34, 9.93, 9.30, 9.00, 4.89, 4.69, 4.51, 4.35, 4.13, 3.89 and 3.52 A by the powder X—ray diffraction measurement.

Particularly, the crystals of compound (III) to be provided by the present invention are crystals which are characterized in that they show a melting point of 94.2°C (the melting point may vary slightly depending on the apparatus and measuring conditions) and a specific rotation of [oc],,2° = -89.4° (c = 1, methanol). In view of the characteristics of the powder X—ray diffraction data, crystal lattice spacing and general pattern are important in confirming identity of crystals, and the relative strength slightly changes depending on the direction of crystal growth, size of particles and measuring conditions, so that it should not be taken strictly.

The crystals of the compound (III) of the present invention having (R,R) configuration are produced by diastereomeric resolution effected by fractional crystallization of a compound represented by the following formula (II).

OH on HZN N I fig (H) Bno \ OCH This step is carried out by dissolving the diastereomeric mixture compound (II) in a single solvent or a mixture of two or more solvents selected from water, alcohols (e.g., methanol, ethanol and 2—propanol), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane), ethyl acetate, etc., preferably in methanol, and precipitating the compound (III) by cooling the thus prepared solution. It is preferable to dissolve the compound (II) with heating, cool down the solution to 0°C to effect the precipitation under stirring. In certain cases, it may be preferable to effect the precipitation by adding separately prepared crystals of the compound (III) as a seed. By subjecting the thus obtained crystals to usual recrystallization treatment as occasion demands, crystals of the compound (III) can be obtained as the (R,R)—isomer having an optical purity of 99% or more. It is preferable to carry out the recrystallization under the same conditions of the case of the aforementioned precipitation treatment.

Also, according to the present invention, (R,R)- isomer of formoterol, namely N>[2—hydroxy—5—[(R)—l— hydroxy—2—[(R)—2—(4—methoxyphenyl)—1— methylethylamino]ethyl]phenyl]formamide (compound (I)), can be obtained with a high optical purity.

(Step 1) A compound (IV) having (R,R) configuration is obtained by formylation of the primary amino group of compound (III).

OH B OHCHN N / l. fig (Iv) BnO/V OCH (Step 2) The compound (I) is obtained by eliminating the benzyl groups of the compound (IV) through hydrogenolysis.

H HCHN OCH HO 3 This compound (I) may optionally be led to acid addition salt by the conventional way.

The step 1 is formylation reaction of the primary amino group of compound (III).

The reaction is carried out using a mixed acid anhydride of formic acid and various acids, preferably a mixed acid anhydride obtained from formic acid and acetic anhydride, in equivalent to excess amount, preferably 3 to equivalents, based on the compound (III), in a solvent inert to the reaction selected from halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, ethers, ethyl acetate, etc. or in the absence of solvent, preferably in chloroform or toluene or in the absence of solvent. The reaction is carried out at a temperature of from cooling to heating, preferably at O to °C. As occasion demands, the reaction product is subsequently reacted under room temperature or a heating temperature, preferably at 20 to 40°C, in alcohols, preferably methanol, if necessary in the presence of a base such as potassium carbonate.

The step 2 is elimination of benzyl groups.

Examples of the solvent to be used include organic solvents inert to the reaction such as aromatic hydrocarbons, ethers, alcohols, ethyl acetate and acetic acid, preferably methanol and ethanol. These solvents may be used alone or as a mixture of two or more. The reaction is carried out in the presence of a catalyst (desirably palladium—carbon) at a temperature of from cooling to heating, preferably at O to 30°C, under ordinary or compressed hydrogen pressure, preferably at not more than atm.

In addition, the compound (I) thus obtained can be made into acid addition salts by subjecting it to the conventional salt formation treatment. Such salts are pharmaceutically acceptable salts, and illustrative examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid. Fumaric acid is preferable. Also, the compound (I) or its acid addition salts may form hydrates or solvates.

The starting material compound (II) of the present invention is produced by the following steps.

Bn \ NHBn 0; O N [ll : OZN Br 2 / J // + | \\ -—-—> I CFIO \\ 3 BnO / B“O OCH3 (VD (Vm OH Bn OH Bn BnO \ \ OCH3 BnO \ OCH3 OTB (m The first step is a condensation reaction of an amino compound (V) having (R) configuration with an a—haloketone compound (VI). The compound (V) can be synthesized by the method of Murase et al. (described in the foregoing) or of Hett et al. (described in the foregoing), and the compound (VI) can be synthesized by the method of Murase et al.

(Chem. Pharm. Bull., 25, 1368, 1977).

An organic solvent inert to the reaction is used as the solvent, and its examples include halogenated hydrocarbons, aromatic hydrocarbons, ethers, ketones such as acetone and 2-butanone, alcohols, N,N~dimethylformamide and ethyl acetate, of which 2—butanone is preferred. The reaction is carried at a temperature of from cooling to refluxing temperature, preferably under reflux. In carrying out the reaction, the compound (V) is used in equivalent or excess amount, preferably 2 equivalents, based on the compound (VI). As occasion demands, the reaction may be carried out in the presence of an organic base (preferably triethylamine or pyridine) or an inorganic base (preferably sodium hydroxide or potassium carbonate).

The second step is a reduction reaction of the ketone group of compound (VII).

Examples of the solvent to be used include halogenated hydrocarbons, aromatic hydrocarbons, ethers and alcohols, which may be used alone or as a mixture of two or more. Preferred is a mixed solvent of toluene and methanol. The reaction is carried out using various reducing agents in equivalent to excess amount, preferably in an amount which can complete the reaction, and at a temperature of from cooling to heating, preferably from O to 30°C. Preferable reducing agents includes sodium borohydride. Preferably, the reducing agent is used in almost the same molar amount with the compound (VII).

The third step is a reduction reaction of the nitro group of compound (VIII).

An organic solvent inert to the reaction is used as the solvent, and its examples include aromatic hydrocarbons, ethers, alcohols, ethyl acetate and acetic acid, of which toluene is preferred. These solvents may be used alone or as a mixture of two or more. The reaction is carried out in the presence of a catalyst (preferably Raney nickel, platinum oxide or platinum—carbon) at room temperature or with heating, preferably at 50 to 100°C, under ordinary or compressed hydrogen pressure, preferably at not more than 40 atm. In an alternative method, the reduction reaction is carried out in water or alcohols alone or a mixed solvent thereof at a temperature of from ice—cooling to heating, preferably under reflux, in the presence of a metal such as iron powder, zinc or tin in equivalent or excess amount, if necessary in the present of an acid such as hydrochloric acid.

INDUSTRIAL APPLICABILITY The (R,R)—isomer of formoterol (compound (I)) having an optical purity of 99% or more can be produced using the crystals of compound (III) of the present invention and employing the aforementioned steps 1 and 2, and it is not necessary to purify the thus obtained compound (I), for example, using optically active tartaric acid. In addition, since it does not require purification by chromatography in each step, the production method of compound (I) which uses the crystals of the present invention is industrially advantageous. In consequence, the crystals of compound (III) of the present invention are useful in producing the compound (I) which is drawing attention as a bronchodilator for the treatment of symptoms of obstructive pulmonary diseases such as asthma.

BEST MODE OF CARRYING OUT THE INVENTION The following illustratively describes the present invention with reference to the Production Examples of the (R,R)—isomer of formoterol (compound (I)). In this connection the present invention is not restricted by these Examples. Also, synthesis of the starting material is shown in Reference Examples.

The following HPLC conditions were used for the determination of chemical purity (%) and optical purity (%ee, %de) of each compound. In the data, RT means retention time by HPLC, and MS means mass spectrometry value (FAB [M+H]U. Also, copper (Cu) was used as the radiation source for the measurement of powder X-ray diffraction.

(HPLC conditions) Condition 1 (column: Nucleosil 5C18 manufactured by GL Science, 4.0 mm I.D. x l50 mm; detector: 254 nm; column temperature: 40°C; mobile phase: 1 liter aqueous solution containing 1.5 g of dipotassium hydrogenphosphate/acetonitrile (40/60); flow rate: 1.3 ml/min).

Condition 2 (column: ODS—A A—302 manufactured by YMC, 4.6 mm I.D. x 150 mm; detector: 280 nm; column temperature: 40°C; mobile phase: 0.01 M ammonium acetate aqueous solution/acetonitrile/acetic acid (85/12/5); flow rate: 1.0 ml/min).

Condition 3 (column: Chiralcel OJ manufactured by Daicel, 4.6 mm I.D. x 250 mm; detector: 254 nm; column temperature: 40°C; mobile phase: n—hexane/ethanol (50/50); flow rate: 1.5 ml/min).

Condition 4 (column: Chiralcel OJ manufactured by Daicel, 4.6 mm I.D. X 250 mm; detector: 220 nm; column temperature: 40°C; mobile phase: n—hexane/ethanol (70/30); flow rate: 1.0 ml/min).

Condition 5 (mobile phase: 1 liter aqueous solution containing 1.5 g of dipotassium hydrogenphosphate/methanol (60/40) adjusted to pH 8.8 with acetic acid; other factors are the same as those of the condition 2).

Condition 6 (column: CHIRAL—AGP manufactured by Chrom. Tech , 4.0 mm I.D. x 100 mm; detector: 220 nm; column temperature: 45°C; mobile phase: a solution prepared by adjusting 0.2M potassium dihydrogenphosphate aqueous solution to pH 7.2 with 0.2 M disodium hydrogenphosphate aqueous solution/methanol (985/15); flow rate: 1.0 ml/min).

The following formulae were used for the calculation of optical purity (%ee, %de) by HPLC.

Compound (I), compound (III) and compound (IV): %ee = [((R,R)—isomer) — ((S,S)-isomer)]/[((R,R)—isomer) + ((S,S)—isomer)) X 100 %de = [((R,R)—isomer) — ((S,R)—isomer)]/[((R,R)—isomer) + ((S,R)-isomer)] X 100 Compound (V) and compound (VII): %ee = [((R)—isomer) — ((S)—isomer)]/[((R)—isomer) + ((S)—isomer)] X 100 REFERENCE EXAMAPLE l A 33.44 g portion of 4’~benzyloxy—2—bromo~3’— nitroacetophenone (compound (VI)) was added to 500 ml of 2-butanone solution containing 50.00 g of (R)~NLbenzyl—2— (4—methoxyphenyl)—l—methylethylamine (compound (V), optical purity 99.8% ee), and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled with ice and then filtered, and the resulting filtrate was concentrated under a reduced pressure to obtain 2—(N> benzyl—N—[(R)—2—(4—methoxyphenyl)methylethyl]amino]—4’— benzyloxy—3’—nitroacetophenone (compound (VII)) (yellow oil). This compound was used in the subsequent step without purification. A portion of the compound was purified by a silica gel column chromatography (n- hexane/ethyl acetate = 3/1) to obtain the following physical property data. Purity: 99.4%ee (condition 3, RT = 12 minutes); MS: 525; specific rotation: [a]f° = + 12.4° (c = 1, benzene).

REFERENCE EXAMPLE 2 Under ice—cooling, 4.335 g of sodium borohydride was added to a mixture of the compound (VII) obtained in the above example, 300 ml of toluene and 100 ml of methanol.

The reaction mixture was stirred at room temperature for 1.4 hours and then cooled with ice, and 105 g of 5% (w/w) acetic acid aqueous solution was added dropwise thereto.

The resulting reaction mixture was stirred for 1 hour and then allowed to stand to effect separation of layers. The organic layer was washed twice with 300 ml of water and then dried with anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was evaporated under a reduced pressure, thereby obtaining 49.5 g of (RS)—2—[N>benzyl—N¥[(R)(4—methoxyphenyl)—l— methylethyl]amino]-l-(4—benzyloxy—3~nitrophenyl)ethanol (compound (VIII)) (orange oil). (R,R)-isomer/(S,R)—isomer = about 6/4; MS: 527.

REFERENCE EXAMPLE 3 A 4.87 g portion of Raney nickel was added to 280 ml of toluene solution containing 48.6 g of the compound (VIII), and the mixture was stirred in a compressed hydrogen atmosphere (initial pressure: 10 atm.) at an inner temperature of 100°C or less for 5.3 hours until absorption of hydrogen was almost completed. After removal of the catalyst by filtration, the resulting filtrate was concentrated under a reduced pressure to obtain 47.65 g of (RS)—l-(3—amino—4—benzyloxyphenyl)[N>benzyl—N—[(R)—2— (4—methoxyphenyl)—l—methylethyl]amino]ethanol (compound (II)) (yellow oil). (R,R)—isomer/(S,R)—isomer = about 6/4; MS: 497.

EXAMPLE 1 A 13.77 g portion of the compound (II) was dissolved with heating in 96 ml of methanol, and the solution was cooled down to room temperature with stirring and then inoculated with (R)(3-aminobenzyloxyphenyl)[AF benzyl—N—[(R)—2—(4—methoxyphenyl) methylethyl]amino]ethanol (compound (III)). After commencement of crystallization, the mixture was stirred for 0.5 hour and then cooled to an inner temperature of 0°C and stirred overnight. The thus precipitated crystals were collected by filtration and again recrystallized twice from methanol to obtain 4.l42 g of the compound (III) (slightly yellowish white crystalline powder). Purity: 99.6%de (condition 1, RT = 16.7 minutes), 100%ee (condition 4, RT = 29 minutes), (R,S)—isomer was not detected; MS: 497; melting point: 94.2°C; specific rotation: [a]Dm = —89.4° (c = 1, methanol); elemental analysis: (C, 77.39, H, 7.31, N, 5.64 for CuH3@bO3) C, 77.72, H, 7.40, N, 5.61; powder X—ray diffraction [lattice spacing (A) (relative strength)] 14.34 (82), 9.93 (24), 9.30 (24), 9.00 (46), 4.89 (41), 4.69 (98), 4.51 (22), 4.35 (20), 4.13 (27), 3.89 (38), 3.52 (100); DSC: 95.1°C.

Powder X—ray diffraction spectrum of the crystal is shown in Fig. 1, and its DSC analysis spectrum is shown in Fig. 2.

EXAMPLE 2 A 3.1096 g of acetic anhydride was mixed with .1206 g of formic acid to carry out the reaction for 15 hours or more, and then 4.142 g of the compound (III) and 16 ml of chloroform were added to the resulting mixture under ice—cooling. The reaction mixture was stirred at room temperature for 4.7 hours, 28 ml of water was added dropwise thereto, and the mixture was stirred for 10 minutes and then allowed to stand to effect separation of layers. The organic layer was washed with 28 ml of water, ml of 2.0% sodium bicarbonate aqueous solution, 28 ml X of water in that order and then dried with anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, the solvent was evaporated under a reduced pressure and then the thus obtained residue was dissolved in 19 ml of methanol and stirred at an outer temperature of 40°C for 3.8 hours. By concentrating the reaction mixture under a reduced pressure, 4.045 g of AF[5~[(R)—2— [AFbenzyl—AF[(R)—2—(4—methoxyphenyl)—l—methylethyl]amino]— l—hydroxyethylJ—2—benzyloxyphenyl]formamide (compound (IV)) (light yellow oil) was obtained. MS: 525.

EXAMPLE 3 A 524.0 mg portion of 10% palladium—carbon was added to 37 ml of methanol solution containing 3.743 g of the compound (IV), and the mixture was stirred at room temperature in an atmosphere of hydrogen under ordinary pressure for 3.9 hours until absorption of hydrogen was almost stopped. After removal of the catalyst by filtration, the resulting filtrate was concentrated under a reduced pressure to obtain 2.421 g of N—[2~hydroxy—5— [(R)-l—hydroxy—2-[(R)—2—(4—methoxyphenyl)—l— methylethylamino]ethyl]phenyl]formamide (compound (I)) (yellow oil). MS: 345.

EXAMPLE 4 A 390.6 mg portion of fumaric acid was added to .2 ml of methanol solution containing 2.318 g of the compound (I). The reaction mixture was heated to an inner temperature of 50°C and mixed with 31.2 ml of ethyl acetate. With stirring, this was cooled to about room temperature and inoculated with N>[2—hydroxy—5—[(R)—1— hydroxy—2—[(R)—2—(4—methoxyphenyl)—1— methylethylamino]ethyl]phenyl]formamide hemifumarate (0.5 fumarate of compound (I)). After commencement of crystallization, this was stirred for 1 hour and then cooled to an inner temperature of 0°C and stirred overnight. The thus precipitated crystals were collected by filtration and dried to obtain 2.509 g of 0.5 fumarate of the compound (I) (slightly yellowish white crystals).

Purity: 100%de (condition 5, RT = 14.7 minutes), l00%ee (condition 6, RT = 6.2 minutes), (R,S)—isomer was not detected; MS: 345; melting point: 143.8°C (decomposition); specific rotation: [a]Dm = —47.0° (c = 1, H20); elemental analysis: (C, 62.12, H, 6.55, N, 6.90 for C19H24N2O4'0.5C4H4O4'O.2H2O) C, 62.19, H, 6.53, N, 6.94,‘ powder X—ray diffraction [lattice spacing (A) (relative strength)] 6.01 (36), 5.55 (52), 5.49 (46), 5.13 (23), .00 (29), 4.96 (37), 4.78 (55), 4.53 (100), 4.40 (41), 3.99 (75), 3.92 (20).

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a powder X—ray diffraction pattern of a crystal of (R)(3—amino—4—benzyloxyphenyl)—2—[N—benzyl— N—[(R)—2—(4~methoxyphenyl)—1—methylethyl]amino]ethanol.

Fig. 2 shows a DSC analysis pattern of a crystal of (R)—l—(3—aminobenzyloxyphenyl)[NLbenzyl-N>[(R)-2—(4— methoxyphenyl)-l—methylethyl]amino]ethanol.

Claims (4)

1. A crystal of a compound (R)—1—(3—amino benzyloxyphenyl)—2—[N>benzyl—N>[(R)—2—(4—methoxyphenyl)—l— methylethyl]amino]ethanol having an (aR,BR) configuration represented by the following formula (III) OH Qn N B H2” on 1/\@\ (111) OCH BN0 3 (wherein Bn represents a benzyl group), which shows a heat absorption peak of from 92 to 98°C by the DSC analysis and lattice spacing peaks of l4.34, 9.93, 9.30, 9.00, 4.89, 10 4.69, 4.51, 4.35, 4.l3, 3.89 and 3.52 § by the powder X—ray diffraction measurement.

2. A method for producing crystals of a compound (R)—1—(3—amino—4—benzyloxyphenyl)—2—[N>benzyl—NL[(R)—2—(4— methoxyphenyl)methylethyl]amino]ethanol having an 15 (aR,BR) configuration represented by the following formula (III) OH E}n H N N B 2 a 7/\E:L (EH) BnO OCH

3 24 (wherein Bn represents a benzyl group, the same shall apply hereinafter), which comprises carrying out fractional crystallization of (RS)—1—(3—amino—4— benzyloxyphenyl)—2—[N>benzyl—N—[(R)—2—(4-methoxyphenyl)—l— methylethyl]amino]ethanol represented by the following formula (II) as a diastereomeric mixture having (aR,BR) and (aS,BR) configurations. 10 3. A method for producing a compound N>[2—hydroxy— 5—[(R)—l-hydroxy—2—[(R)-2—(4—methoxyphenyl)—l— methylethylamino]ethyl]phenyl]formamide represented by the following formula (I) OH H OHCHN N t/I WAC) m Ho \ OCH3 15 or an acid addition salt thereof, which comprises 25 formylating the primary amino group of a compound having an (aR,BR) configuration represented by the following formula (III) OH Bn H?“ // i a N4?/\1&::l\ UH) \\ BHO OCH3 5 (wherein Bn represents a benzyl group, the same shall apply hereinafter) in crystalline form, thereby obtaining a compound having an (dR,fiR) configuration represented by the following formula (IV) OH fin \\ BnO OCH3 10 eliminating the benzyl groups (Bn) of the compound (IV) by hydrogenolysis, and optionally subjecting the resulting compound to salt formation treatment. 26

4. A crystal according to claim 1, substantially as described herein with reference to the Examples and/or as illustrated in the accompanying