WO2000000459A1 - Process for the preparation of optically active trans-cyclohexylamine compounds - Google Patents

Abstract

A process for the preparation of optically active cyclohexylamine compounds useful as intermediates for the preparation of 1-phenyl-2-(3-phenylcyclohexyl-amino)ethanol compounds exhibiting a selective β3-adreneric receptor stimulating effect; N-substituted-3-phenylcyclohexylamine compounds as intermediates for the preparation; and 3-phenyl-2-cyclohexen-1-one compounds as raw materials therefor. The above process comprises conducting the reductive amination of a 3-phenyl-2-cyclohexen-1-one compound with an optically active amine compound through a Schiff base forming reaction and freeing the obtained product from the substituent on the nitrogen atom.

Description

 Specification Method for producing optically active trans-cyclohexylamine compound

The present invention is 1 to have a selective / 3 ₃ A de Lena Li down receptor stimulating effect - full et two Roux 2 - (3 - to full et two Rushiku port key Shirua Mi Roh) of ethanoate Lumpur compound A method for producing an optically active cyclyl hexylamine compound useful as a production intermediate, and an N-substituted-3-phenylphenylhexylamine compound as an intermediate for the production and a raw material for production 3 — Fluorine 2-cyclohexene — pertaining to one-ion compounds. Background art

1-Phenyl-2- (3-phenylphenylsilileiramino) ethanol compound having a selective i3 ₃ adrenergic receptor stimulating action and its production intermediate 3 — The process for producing xylamine compounds is described in the publication of WO97 / 155549.

(In the formula, R ₄ and R ₅ represent hydrogen, hydroxy and lower alkoxy, and R ₅ represents a lower alkyl group substituted by aryl. n means 1.)

 By reacting 3—phenylcyclohexane 111-one with optically active 1—phenylethylamine by the method described in WO 97/155549, N — [3 — (3-methoxyphenyl) cyclohexyl] A trans form of 1-1-phenylethylamine is obtained.

However, if the optically active 3—phenylcyclohexane is not used, the desired optically active 3—phenylene is not used. The lucyclohexylamine compound could not be obtained. Further, the optically active compound obtained here was a 1: 1 mixture of two types of diastereomers, and the selectivity of the diastereomers was not good. Disclosure of the invention

 Highly yielded optically active 3-phenylcyclohexylamine compound from inexpensive raw materials without using an ionic compound. To provide a new production method and raw materials for the production at a high rate.

 The present inventors use the 31-phenyl-2-onecyclohexene-11-one compound (I) instead of the 3-phenylphenylhexan-1-one compound. As a result, they have found that the desired optically active 3-hydroxyphenylhexylamine compound (IV) can be obtained, and the present invention has been completed.

 Specifically, a 3-phenyl-2-cyclohexane-one-one compound (I) and an optically active amide compound having a substituent capable of being removed on a nitrogen atom (ΠIII) ) To remove the substituent on the nitrogen atom of the N-substituted 1-3-phenylcyclohexylamine compound (m) obtained by the diastereoselective reductive amination reaction with This gives the optically active 3-phenylene hexylureaamine compound (IV).

(In the formula, R j represents hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl groups or carboxyl groups. ₂ represents a removable optically active substituent, and * represents an asymmetric carbon.

That is, the Schiff base of the 3-phenyl-2-cyclohexene-one compound (I) and the optically active amine compound (（) The substituent R ₂ is removed by a reductive amination reaction via a formation reaction, followed by, for example, a hydrogenolysis reaction or the like, and the optically active 3 -phenylcyclohexylamine compound (IV) is converted. Can be manufactured. It can also be reduced after isolation of the Schiff base.

 If necessary, the compound (IV) is purified by an optical resolution method using an optically active organic acid or the like to obtain a pure optically active 3-hexylamine hexylamine compound.

 When the substituent on the nitrogen atom is removed by hydrogenolysis, reductive amination and hydrogenolysis via Schiff base formation should be performed in one step in the same reaction vessel. You can do it. That is, it is an intermediate by the catalytic reduction reaction of 3 -phenyl 1 -cyclohexene 1 -one compound (I) and an optically active amine compound (Π). An optically active 3-phenylcyclohexylamine compound (IV) can be obtained without isolating the N-substituted-3-phenylcyclohexylamine compound (ΠΙ).

 In the present invention, R may be hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl groups or carboxy groups. A hydroxyl group, a lower alkoxy group or a lower alkoxy group substituted with one lower alkoxycarbonyl group is more preferred.

 The lower alkoxy group is an alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, / -pentyloxy, etc. Xyloxy groups and the like are preferred, with methoxy groups, ethoxy groups, proboxyl groups and isopropoxy groups being preferred, and methoxy groups being more preferred.

A lower alkoxycarbonyl group is an alkoxycarbonyl group having 2 to 7 carbon atoms, and specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isocarbonyl group. Propoxycarbonyl, butoxycarbonyl, isobutanol X-carbonyl group, 5-butoxycarbonyl group, / -butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, / -benzoyloxycarbonyl group And a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isocarbonyl group. A butoxycarbonyl group, a 5-butoxycarbonyl group and a / -butoxycarbonyl group are preferred, and an ethoxycarbonyl group is more preferred.

 The lower alkoxy group substituted with one or two lower alkoxycarbonyl groups is a group arbitrarily selected from the lower alkoxy groups described above, and is a group selected from the lower alkoxycarbonyl groups described above. Selected groups substituted by 1 to 2, specifically, methoxycarbonyl methoxy group, ethoxy carbonyl methoxy group, and 11- (methoxy carbonyl) eth Ethoxy group, 2 — (methoxycarbonyl) ethoxy group, 1 — (ethoxycarbonyl) ethoxy group, and 2 — (ethoxycarbonyl) ethoxy group. Xicarbonyl methoxy groups are preferred.

 The lower alkoxy group substituted by a carboxy group is a group selected from the lower alkoxy groups described above and substituted by a carboxy group, for example, a carboxy methoxy group, And a carboxyethoxy group.

 Examples of the method for removing the substituent on the nitrogen atom include a hydrogenolysis reaction, a hydrolysis reaction, an oxidation reaction by light irradiation, and a perch reduction reaction, and a hydrogenolysis reaction is preferable.

R ₂ may be any substituent having an asymmetric carbon which can be removed by the above-mentioned method for removing a substituent on a nitrogen atom, and is preferably an aralkyl group having an asymmetric carbon or an asymmetric carbon. A 1-substituted aryl group having a carbon is mentioned, and an aralkyl group having an asymmetric carbon is more preferred.

Examples of the aralkyl group having an asymmetric carbon include a substituted benzyl group and a substituted naphthylmethyl group. A 1- (1-naphthyl) ethyl group is preferred.

 Examples of the mono-substituted aryl group having an asymmetric carbon include a 1-methylaryl group and a 1-ethylaryl group.

 Specific examples of the optically active amine compound (II) include 1-phenylethylamine, 1_ (1—naphthyl) ethylamine, 1- (2-naphthyl) ethylamine, 1 — Methylarylamine, 1—ethylarylamine, etc., 1—phenylethylamine, 1- (1-naphthyl) ethylamine are preferred.

 The Schiff base formation reaction is carried out while heating and refluxing until a water discharge is eliminated (30 minutes to 10 hours) with a discharge unit installed. Solvents used include benzene, trillen, butyl alcohol, cyclohexane and the like, and it is desirable to add an acid such as p-toluenesulfonic acid as a catalyst.

 The catalytic reduction reaction is carried out at room temperature to 70 ° C for 30 minutes to 24 hours. The solvent may be any one that does not participate in the reaction.Examples include alcohols such as methanol, ethanol, diisopropylpropyl alcohol, butanol, and acetates such as ethyl acetate. No. Examples of the catalyst to be used include Raney nickel and palladium monocarbon. BEST MODE FOR CARRYING OUT THE INVENTION

 According to the method described in WO 97/15 55 49, 3 — (3-methoxyphenyl) cyclohexane-1 1 -on and (S) — 1 — Low-polarity [(1R *, 3R *)-3 ((3-Methoxyphenyl) cyclohexyl]] [(1S) by reaction with enethylethylamine — Phenylethyl] amine (Compound 1) and highly polar [(1S *, 3S *)-3] ((3-methoxyethoxy) cyclohexyl] 1-[( 1 S)-phenylethyl] amine (compound 2) is obtained in a 1: 1 ratio.

On the other hand, in the production method of the present invention, 3 — (3 — methoxyphenyl) — 2 — cyclohexene 1 — on and (R) — 1 — phenylethylamine And the polarity of the high-polarity [1 R *, 3 R *)-3 — (3-methoxyphenyl) cyclohexyl]-[(1R) -phenylethyl] amine (compound 3) and a diastereomer of low polarity [(1S *, 3 S *)-3 _ (3-methoxyphenyl) cyclohexyl] 1 [(1 R)-phenylethyl] amine (compound 4) in the ratio of 3: 1 be able to.

 Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Comparative Examples, and Examples.

 (Comparative Example 1)

 [(1 R *, 3 R *)-3-(3-methoxyphenyl) cyclohexyl] — [(1 S)-phenylethyl] amine

3 — (3 — methoxyphenyl) cyclohexane-1-one 10.0 g, (S) -11 — phenylethylamine 6.6 g, p—toluenesulfonate monohydrate 3 O mg of the hydrate was dissolved in 40 ml of 1-butanol, and the mixture was heated and refluxed for 3 hours with a detachment device attached. During this time, about 7 ml of the solvent was removed. After cooling, 3.0 g of Raney nickel was added to the reaction mixture, and the mixture was stirred at 40 ° C under a pressure of 1 kgf / cm ² hydrogen for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 15.7 g of a brown oil. The oil was a mixture of two diastereomers and contained Compound 1 and Compound 2 in a 1: 1 ratio.

<HPLC analysis conditions>

Eluent: phosphate buffer / acetonitrile mixture (4: 5) (phosphate buffer: 7.5 g of sodium hydrogen phosphate decahydrate and phosphorus) Prepare by dissolving 3.7 g of potassium dihydrogen oxide in 1.8 L of distilled water.)

Flow velocity: 1.0 m1 / min

Detection wavelength: 220 nm

Column: Y M C — P a c O D S — A M 3 0 2 '

 4.6 mm x 150 mm

 O D S A M 1 2 0-S 5

Column temperature: 35 ° C

<Retention time> Compound 1: 18 minutes, Compound 2: 15 minutes

 (Example 1)

 [(1 R *, 3 R *)-3 (3-methoxyphenyl) cyclohexyl] [(1 R)-phenylethyl] amide

3 — (3 — methoxyphenyl) 1 2 — cyclohexene 1 1 — on 10.0 g, (R) — 1 — phenylethylamine 6.6 g, p — 3 O mg of toluenesulfonate monohydrate was dissolved in 20 ml of ethanol, and the mixture was heated to reflux for 3 hours with a dian-star device. During this time, about 7 ml of the solvent was removed. After allowing to cool, 3.0 g of Raney nickel was added to the reaction mixture, and the mixture was stirred at 40 ° C. under a pressure of 1 kgf / cm ^{2 of} hydrogen for 10 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 14.9 g (yield; 97.4%) of a brown oil. This oil was a mixture of two diastereomeres and contained compound 3 and compound 4 in a 3: 1 ratio.

H P L C Analysis conditions>

 Same as (Comparative Example 1).

<Retention time>

Compound 3: 15 minutes, Compound 4: 18 minutes.

 The oily mixture was purified by silica gel chromatography (3/3 hexane: ethyl acetate = 5: 1, then repurified at 10: 1) to give the title compound (Compound 3). ). This was converted into a hydrochloride salt using a 4N hydrochloric acid / ethyl acetate solution.

 (As H C 1 salt)

Melting point: 22.0-24.0. C

[],) ² 48 = +26.3 ° (c = 0.98, CHC 1

APCI - MS (m Z z) : 3 1 0 (C, H, 7 NO + H) 'H - NMR (CDC 1) δ:.. 1 4 0 - 1 5 5 (1 H, m) 1.6-1.75 (1H, m) 1.80-2.60 (9Hm), 3.00-3.20 (1H, m) 3.30-3 . 4 5 (1

H m) 3.77 (3 H, s) 4 3 0-4.50 (1 H m) 6.60-6.75 (3 H m) 7.0 0-7.15 ( 1 H m) 7.30 — 7.45 (3 H m) 7.65-7.80 (2 H m) 9.86 (2 H brs)

 (Example 2)

— (1 R * 3 R *)-3: (3 — methoxysilane) cyclohexylamine (S) mandelate

 13.5 g of the oily mixture obtained in Example 1 was suspended in a mixture of 40 ml of ethanol and 28 ml of purified water. To this suspension was added 1.45 g of palladium-carbon containing 10% by weight, and the mixture was stirred at 60 ° C. for 4 hours in a hydrogen atmosphere. After filtering the reaction solution, the obtained filtrate was concentrated under reduced pressure to obtain 9.1 g of a brown oil.

 Dissolve 9.0 g of this oil in 17 ml of ethanol and stir

20 ml of an ethanol solution of 6.62 g of (S) mandelic acid was added, and the mixture was stirred for 1 hour while cooling. The crystallized crystals were collected by filtration and air-dried at 50 ° C until a constant weight was reached. 7.0 g of the obtained crystals were recrystallized from ethanol to give 6.4 g (yield; 41.8%) of the title compound as white crystals.

Melting point: 181.0-182.0 ° C

[HI] ' ^{7 8} = + 32.5. (C = 1.02 MeOH) ¹ H-NMR (DMSO-d,) δ1.40-1.95 (8Hm), 2.85-3.00 (lHm ), 3.35-3.54 (1H, m), 3.73 (3H, s), 4.56 (1H, s), 6.65—6.85 ( 3 H, m) 7.10-7.25 (4 H, m) 7.35-7.4.5 (2 H, m)

(Reference example 1) (1 R 3 R *) — 3 — (3 — methanol) Cyclohexylamine

 To 2.50 g of the crystals obtained in Example 2, 12 ml of 2N sodium hydroxide and 20 ml of toluene were added, and the mixture was stirred for 10 minutes. The toluene layer was separated by liquid separation, washed with purified water, and concentrated under reduced pressure to give 1.42 g (yield; 98.9%, 99.5% ee) of the title compound. Obtained.

[] _D ^{2 7 5} = +7.3 ° (c = 0.99, CHC 13)

'H-NM (CDC 1 s) δ: 1.25-1.90 (10H, m), 2.85—3.00 (lH, m), 3.25-3 40 (1H, m), 3.78 (3H, s), 6.65-6.90 (3H, m), 7.10-7.30 (1H, m)

4N hydrochloric acid Ethyl acetate was used to make the hydrochloride.

 (As H C 1 salt)

Melting point: 12.5-12.7 ° C

 [] D 13.9 ° (c = 0.999, CHCl 1) The optical purity was measured using HPLC after converting into N-acetyl group using acetic anhydride and pyridine.

H P L C Analysis conditions>

Eluent: n-hexane: ethanol = 4: 1

Flow velocity: 1.0 m1 / min

Detection wavelength: 220 nm

Column: CHIR ALCCELOD 4.6 x 250 mm Column temperature: 40 ° C

<Retention time>

 (1 R *, 3 R *) — 3 — (3 methoxy) Cyclohexylamine: 6 minutes, (15 *, 3 3 *)-3-(3- (Methoxy Fluorine) Cyclohexylamine: 8 minutes

(Example 3) Palladium— (1R3R *)-3 when carbon is used— (3 methoxyphenyl) cyclohexylamine (S) mandelate

 3- (3-Methoxyxenyl) -12-cyclohexene-111 on 2.0 g, (R) -11-phenylenyliramin 1.3.2 g, P-trienesulfo Dissolve 7 mg of phosphoric acid monohydrate in 10 ml of toluene and heat for 5 hours with a disintegrator

3S flow. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in 5 ml of ethanol. To the mixture, 200 mg of radium-carbon was added, and the mixture was stirred at 23 ° C for 7 hours under a hydrogen atmosphere to give a 25:17 mixture of compound 3 and compound 4. Obtained. Further, the mixture was stirred at 60 ° C for 6 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 2.15 g of trans-3- (3-methoxymethoxy) cyclohexylamine as a brown oil. . The obtained oil was treated in the same manner as in Example 1 to obtain 0.82 g (yield; 23.8%) of the title compound as white crystals.

 (Reference example 2)

 3 1 (3 — Hydroxifenyl) 1 2 — Cyclohexene 1

1 won

6.92 g of 3-bromophenol was dissolved in 30 ml of Ν-dimethylformamide, and 17.1 g of potassium carbonate was suspended. 8.0 ml of chloromethyl methyl ether was added dropwise to the yellow suspension under water cooling, and the mixture was stirred for 1 hour. Further, the reaction solution was heated to 80 ° C., stirred for 30 minutes, and then cooled to room temperature. Toluene (150 ml) and purified water (50 ml) were added to the reaction solution, and the mixture was stirred and separated. The organic layer obtained was separated and washed three times with purified water (30 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.10 g of a colorless liquid. Use this liquid for silica gel chromatography. Purification by n-hexane (n-hexane: ethyl acetate = 10: 1) yielded 9.02 g of 3-methoxyethoxymethoxybenzene.

 0.80 g of cut magnesium and a small amount of copper are suspended in 10 ml of tetrahydrofuran, and 7.5 g of 3-methoxymethoxybenzene. A solution of 10 ml of tetrahydrofuran was added dropwise over 30 minutes while heating to 60 ° C. The resulting reaction solution was cooled to 40 ° C, and 3-ethoxy 2-cyclohexene 1 -one 4.90 g of tetrahydrofuran 1 0 ml solution was added dropwise. At this time, the reaction temperature rose to 60 ° C. After stirring the reaction solution for 1 hour, 35 ml of purified water, 10 ml of ethyl acetate and 5 ml of a 4N hydrochloric acid / ethyl acetate solution were added, and the mixture was stirred for 30 minutes. Separation of the ethyl acetate layer by liquid separation operation, washing with purified water, saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, and stirring, 4 ml of 4N hydrochloric acid / ethyl acetate solution was added dropwise while stirring. did. Crystals precipitated after 5 minutes. After further stirring for 20 minutes, the mixture was neutralized by adding an aqueous solution of sodium bicarbonate, and the crystals were collected by filtration and washed with ethyl acetate to obtain 4.58 g of brown crystals. The crystals were recrystallized from methanol to give 2.98 g (yield: 43.7%) of the title compound as yellow crystals.

Elemental analysis

C ₁₂ H ₁₂ 〇 ₂ : C, 76.57; H, 643 (theoretical value)

 C, 76.52; H, 644 (measured) Melting point: 161.5-162.0 ° C

¹ H-NMR (DMSO — d ₆ ) δ: 1.90 — 2.10 (2 Ηm), 2.37 (2H, t, J = 6.76 Hz), 2.7 2 (2H, t, J = 5.77 Hz), 6.24 (1H, s), 6.80 — 7.30 (4H, m), 9.58 (1 H, d, J = 7.10 Hz)

 (Example 4)

3-[(1 R *, 3 R *) _ 3 — [(1 R) — phenylylethylamino] cyclohexylsilyl] phenol

3 — (3 — Hydroxyphenyl) 1 2 — Cyclohexene 1 _ 1 750 mg, (R) — 1 phenylethylamine 53 2 mg, p-toluenesulfonate Twenty-six mg of monohydrate was dissolved in 20 ml of toluene and 5 ml of 1-butanol, and the mixture was refluxed for 1.5 hours with a detacher attached. After the reaction mixture was concentrated under reduced pressure, 15 ml of ethanol and 300 mg of Raneynickel were added, and the mixture was stirred at 40 ° C. for 6.5 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.20 g (yield; 72.6%) of a brown oil. The oil obtained is a diastereomeric compound of two kinds, 3 — {(1R *, 3R *)-3-([1R) —phenylethylamino] cyclohexyl} phene. Nol (compound 5) and 3 — {(1S *, 3S *)-3 — [(1R) —phenylenylethylamino] cyclohexyl} phenol (compound 6 ) And were included in a 2: 1 ratio.

<HPLC analysis conditions>

 Same as (Comparative Example 1).

<Retention time>

 Compound 5: 5.5 minutes, Compound 6: 6.3 minutes.

 This oily mixture was subjected to silica gel chromatography (purified with —hexane: ethyl acetate = 10: 1, then repurified with 5: 1) to give the title compound as a colorless oil. 150 mg (yield: 12.7%) was obtained as a product.

[] To ^{D 2 3 = + 3 4 9} ° (c = 1 3 6, CHC 1 3.) EI - MS (m / z):. 2 9 5 (. C 2 H 2 5 NO)

¹ H-NMR (CDC) δ: 1.25-2.000 (11 H, m), 2.65-2.85 (lH, m), 2.95 (1H, brs), 3.91 (1H, q, J = 6.43 Hz), 4.81 (2H, brs), 6.55 (1H, s), 6.60-6 . 7 0 (2 H, m), 7.00 — 7.13 (lH, m), 7.15-7.40 (5H, m)

 (Example 5)

3-[(1 R *, 3 R *) one 3 — Aminocyclohexyl] phenol

 The purified oil (150 mg) obtained in Example 4 was dissolved in ethanol (10 ml). To this solution was added 20 mg of palladium-carbon containing 10% by weight, and the mixture was stirred at 60 ° C. for 3.5 hours in a hydrogen atmosphere. Then, insolubles were removed by filtration and concentrated under reduced pressure. The obtained residue was dissolved again in 10 ml of ethanol, 100 mg of 10% by weight of palladium-carbon containing 10% by weight was added, and the mixture was heated at 60 ° C for 3 hours in a hydrogen atmosphere. Stirred. After filtration, the reaction solution was concentrated under reduced pressure to obtain 150 mg of brown crystals. After recrystallizing these crystals with ethyl acetate, 5 O mg (yield: 51.5%) of the title compound was obtained as white crystals.

[] _D ^{2 2 1} = — 5.97 ° (c = 1.0 0, MeOH) EI — MS (m Z z): 19 1 (CI ₂ H ₁₇ NO)

Melting point: 167.0-170.0 ° C

'H - NMR (DMSO - d B) δ:..... 1 2 0 - 1 8 0 (8 H m), 2 8 0 - 2 9 5 (l H, m), 3 1 5 - 3. 2 5 (1H, m) 6.50—6.65 (3H, m), 6.95—7.10

(1 H, m)

 (Reference example 3)

 3-(3-ethoxy carbonyl methoxyphenyl) 1 2-cyclohexene 1 1 1

In 20 ml of methylethyl ketone, 3_ (3—hydroxy oxynitrile) 1-2—cyclohexene 1-1—one 1.50 g, ethyl bromate acetate 1.60 g Then, 3.30 g of potassium carbonate was added thereto, and the mixture was heated under reflux for 30 minutes. After the reaction solution was cooled to room temperature, insolubles were filtered through celite and concentrated under reduced pressure to obtain 2.23 g of pale yellow crystals. The crystals were recrystallized from diisopropyl ether to obtain 1.82 g (yield: 81.6%) of the title compound as pale yellow crystals.

Elemental analysis>

 CHO: C, 70.0 6 Η 6 6 1 (theoretical value)

 : C, 70.10 Η 660 (measured value) Melting point: 58.5 — 59.5 ° C

. 'H - NMR (CDC 1 3) δ: 1 3 1 (3 Η t, J = 7.

0 9 Hz), 2.05-2.20 (2H, m), 2.49 (2Ht, J = 6.43Hz), 2.75 (2H, t , J = 5.28 Hz), 4.29 (2H, Q, J = 7.31 Hz) 4.65 (2H, s), 6.39 (1H, s ), 6.85-7400 (4H, m)

 (Example 6)

 3 — [(1 R *, 3 R *)-3-[(1 R) 1 -phenylethylami 2] cyclohexyl] ethyl phenylacetate —ester

3 — (3 — Ethoxyleponyl methoxyphenyl) 1 2 — Cyclohexene 1 1 1 .5 g, (R) 1 1 1 1 -phenylethylamine 0. 73 g, 100 mg of p-toluenesulfonate monohydrate was dissolved in 20 ml of toluene, and the mixture was heated and refluxed for 5 hours with a discharger attached. After cooling, the reaction mixture is depressurized After concentration, 22 ml of ethanol and 500 mg of Raney Nickel were weighed, and the mixture was stirred at 40 ° C under a hydrogen pressure of 1 kgf / cm ^{2 for} 6 hours. After allowing to cool, the reaction solution was allowed to stand overnight, and the next day, the mixture was stirred at 40 ° C under a hydrogen atmosphere for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain 2.33 g of a brown oil. This oil is a mixture of two diastereomers and is 3-[(1R *, 3R *)-3-[(1R)-phenylethylamino] cyclohexyl] Phenyloxyacetic acid ethyl ester (compound 7) and 3 _ [(1S *, 3S *)-3-([1R) -phenylethylamino] cyclohexyl] phenoate It contained ethyl xylacetate (compound 8) in a ratio of about 2.5: 1.

H P L C Analysis conditions>

 Same as (Comparative Example 1).

<Retention time>

Compound 7: 15 minutes, Compound 8: 20 minutes

 The oily mixture was subjected to silica gel chromatography (purified with —hexane: ethyl acetate = 5: 1, then repurified with 10: 1) to give the title compound as a colorless oil. 17 1 mg (8.

2%).

 [a] 22 33. 33 ——— = + 6 1.1 (c =. 00, C H C 1

EI — MS (m / z): 38 1 (C ₂ 4 H 3. NO ₃ )

1 H-NMR (CDC 13) δ: 1.17-1.90 (14H, m), 2.70-2.90 (2H, m), 3.78 (1 H, q, J = 6.60 Hz), 4.18 (2H, q, J = 7.09 Hz) 4.51 (2H, s), 6.55-6 6.5 (lH, m), 6.70-6.80 (2H, m), 7.05-7.25 (6H, m) (Example 7)

3-[(1 R *, 3 R *)-3-Aminocyclohexyl] phenoxyacetic acid ethyl ester

The purified oil (170 mg) obtained in Example 6 was dissolved in ethanol (10 ml). To this solution was added 0.5 ml of a 4N hydrochloric acid-monoacetate solution and 100 mg of paradigm carbon containing 100 mg by weight, and added at 60 ° C in a hydrogen atmosphere at 60 ° C. After stirring for an hour, the reaction solution was filtered. To the filtrate, 100 mg of palladium-carbon containing 10 mg of Omg was added again, and the mixture was stirred at 60 ° C for 6.5 hours under a hydrogen atmosphere. The reaction solution was filtered to remove insolubles and concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue under ice cooling to precipitate crystals. The precipitated crystals were collected by filtration to give 109 mg (yield: 77.9%) of the title compound as white crystals.

[a]. ^{. 2 ϋ 9 = - 9 4} 2 ° (c = 1 0 0, CHC 1 3.) EI - MS (m / z): 2 7 7 (C ι 6 H 2 3 NO 3)

Melting point: 1 0 9 — 110 ° C

^{1 H - NMR (DMSO - d} 6) (5:.... 1 2 2 (3 H, t, J = 7 2 6 H z), 1 5 0 - 2 0 0 (8 H, m), 2 90-3.10 (lH, m), 3.47 (1H, brs), 4.18

(2H, Q, 7.09 Hz), 4.74 (2H, s), 6.70-6.90 (3H, m), 7.15-7.25 ( 1 H, m) 8.2 3 (3 H, brs)

 (Example 8)

 _ (1— R *, 3 R *)-3-(3-1-methoxyphenyl)-cyclohexyl]-[(1R) (1-naphthyl)-ethyl] Min

3 — (3 — methoxy sulfide) 1 2 — Cyclohexene 1 1 1 1 7 g, (R) — 1 — (1 1 naphthyl) ethylamine 1.5 0 g of P-trilensulfonate monohydrate (139 mg) was dissolved in toluene (20 ml), and the mixture was heated and refluxed for 1.5 hours with a discharge unit attached. After concentrating under reduced pressure and leaving it to stand overnight under an argon atmosphere, 20 ml of toluene was added again, and the mixture was heated under reflux for 4 hours. After allowing to cool, the reaction mixture was again concentrated under reduced pressure, and to the concentrated residue was added 19 ml of ethanol containing 20 ml of ethanol and 10% by weight of palladium / carbon, and the mixture was added at room temperature under a hydrogen atmosphere at room temperature. Stirred for hours. After stirring at 40 ° C. for 20 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 3.15 g of a brown oil. The resulting oil was two diastereomeric compounds, [(1 R *, 3 R *) — 3 —

(3—Methoxyxenyl) cyclohexyl] 1-[(1R) — (1—Naphthyl) ethyl] amine (Compound 9) and [(1S *, 3S *)-3 It contained (3—methoxyphenyl) cyclohexyl]-[(1R)-(1-naphthyl) ethyl] amine (compound 10) in a ratio of 3: 2.

<HPLC analysis conditions>

 Same as (Comparative Example 1).

<Retention time>

 Compound 9: 44 minutes, Compound 10: 54 minutes.

 This oily mixture was subjected to silica gel chromatography (3_hexane: ethyl acetate = 20: 1) to give 37 O mg of the title compound as an oil. This oil was converted into a hydrochloride using a 4N hydrochloric acid-ethyl acetate solution, and 150 mg (yield: 7.2%) of the hydrochloride of the title compound was obtained as white crystals.

[α] D ^{2 3 5} = — 59.3 ° (c = 1.0 0 CHC 13) EI — MS (m / z): 35 9 (C ₂₅ H 2 NO)

Melting point: 107.01-110.0. C

¹ H-NMR (CDC 13) δ 1.75 — 2.30 (11 H, m), 3.21 (1H, brs), 3.38 (1H, brs),

3.67 (3H, s) 5.43 (1H, brs), 6.10-6.20 (1H, m) 6.55 (2H, brs), 6.7 0-6.80 (1H, m) 7.5-0.70 (3H, m), 7.

85-8.10 (3Hm), 8.39 (1H, d, J = 6.43Hz), 10.07 (2H, brs)

l ³ C-NMR (CDC la) δ 20.4, 2 2 2

29.6, 31.1, 32.0, 36.3, 51.3, 2.55 5 5 .1, 1 1 1 .0 1 1 2 .8, 1 1 .8, 1 2 .1 .1, 1 2 .5. 7, 1 2 .6 .1 1 2 .6.2, 1 2 .7. 4 , 12.9.1, 19.2.2, 12.9.53 10.3.3, 13.3.6, 13.4.0, 14.5.1,15.9.6

 (Example 9)

1 R *, 3 R *) 3-(3 Toxifenyl) -cyclohexylamine

 From the oil obtained in 1), the same method as in Example 3 (3) or Example 4 (3) was used to obtain (1R *, 3R *)-3-(3 Enyl) Cyclohexylamine is obtained.

 (Reference example 4)

 (1 R *, 3 R *) _ 3 — (3 — methoxyphenyl) cyclohexyl] — [(1 R) — (1 naphthyl) ethyl] amine

[(1 R *, 3 R *)-3-(3-methoxyphenyl) hexylhexyl] ammine (S)-Mandelate 15.0 g, hydroxylated An aqueous solution of sodium was added to make a free form, and extracted with toluene. The organic layer is washed with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is [(1R *, 3 *)-3— (3-methoxyphenyl). ) Cyclohexyl] amine. The obtained residue was dissolved in 100 ml of toluene, and 7.15 g of 1-acetonaphthone and 903 mg of p-toluenesulfonic acid monohydrate were added to this solution. Then, it was heated and refluxed for 8 hours with the installation of a dinner evening device. The reaction solution was cooled, allowed to stand overnight, and further heated under reflux for 9 hours. The reaction solution was concentrated under reduced pressure, and 60 ml of methanol was added to the obtained residue to dissolve it. The mixture was stirred for 5 hours. The reaction solution was concentrated under reduced pressure, 80 ml of purified water was added, extracted with ethyl acetate, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure [[1 R *, 3 R *)-3-(3 — [2- (1-naphthyl) ethyl] amine was obtained as an oily residue in a ratio of 2:11 g.

Retention time>

 [(1 R *, 3 R *)-3-(3-Methoxyfenyl) cyclohexyl] 1 [(1 R)-(1-naphthyl) ethyl] amine: 44 minutes, [(1 R *, 3 R *)-3-(3 -methoxycyclohexyl) cyclohexyl] — [(1 S) — (1 _ naphthyl) ethyl] amine: 54 Minutes.

 This mixture was purified by silica gel chromatography (purified with chloroform and then re-purified with 3-hexane: ethyl acetate = 20: 1) and 4N hydrochloric acid-ethyl acetate. The solution was subjected to hydrochloric acid chloride to obtain 909 mg of the hydrochloride of the title compound (yield: 5.5%). 70 mg of this hydrochloride was converted into a free form with an aqueous solution of potassium carbonate, and again. After purification by silica gel chromatography (3_hexane: ethyl acetate = 10: 1), the hydrochloride of the title compound was obtained by hydrochlorination using a 4N ethyl acetate monohydrochloride solution. 90 mg was obtained as white crystals (recovery rate: 14.2%).

^{[] 1 9 8 = - 5} 8 4 ° (c = 1 0 0, CHC 1 3.) EI - MS (m / z):. 3 5 9 (C 2 5 H 2 9 N 0)

1H-NMR (CDC13) δ: 1.75 — 2.30 (11Η, m), 3.23 (1H, brs), 3.39 (1H, brs),

3.66 (3H, s), 5.45 (1H, brs), 6.10-

6.20 (1H, m), 6.55 (2H, brs), 6.70-

6.80 (1H, m) 7.50-7.65 (3H, m), 7.

8 5-8.10 (3Hm) 8.40 (1H, m) 10

0 7 (2 H, b r s)

' ³ C-NMR (CDC 13) 6: 204, 22.2,

 29.6, 31.0, 32.033.6.351.3, 52.5

55.0, 110.1, 12.8, 11.89.121.2,

25.7, 12.6.1, 12.6.2, 12.4.129.2.1,

29.2, 129.5, 1300 • 3, 132.6 133.4, 45.1, 159.5 Industrial applicability

 The production method of the present invention is excellent in diastereomer selectivity, and can obtain desired optically active cyclamine from inexpensive raw materials.

Claims

The scope of the claims

1. Compound (I) represented by the following formula

(In the formula, R, represents hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl groups or carboxyl groups.)

-Substituted 3 — phenyl obtained by the reductive amination reaction of R ₂ NH ₂ (Π) with an optically active amine compound R ₂ NH ₂ (Π) having a substituent that can be removed on the nitrogen atom. Nylcyclohexylamine compound (m)

(In the formula, R represents hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl groups or carboxyl groups. Represents a removable optically active substituent.)

Manufacturing method.

 2. Compound (I) represented by the following formula

 (In the formula, R, represents hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl groups or carboxyl groups.)

And an optical activity having a substituent that can be removed on the nitrogen atom N-substituted -3-cyclohexylaminate compound (m) obtained by the reductive amination reaction with the active amide compound R ₇ NH 7 (Π)

(In the formula, R i represents hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl groups or carboxyl groups. R ₂ represents Represents a removable optically active substituent.)

Activity by removing the substituent on the nitrogen atom of 3-phenylcyclohexylamine compound (IV)

H ゥ N

(In the formula, R, represents a hydrogen, a hydroxyl group, a lower alkoxy group, or a lower alkoxy group substituted with one or two lower alkoxycarbonyl or a carboxyl group. Represents an asymmetric carbon.)).

3. The process according to claim 1, wherein the compound (I) and the optically active amine compound R ₂ NH ₂ (() are subjected to a catalytic reduction reaction.

4. The method according to claim 1, 2 or 3, wherein Raney nickel is used as a catalyst in the reductive amination reaction.

 5. The following formula (VI)

(Wherein, R is a hydroxyl group, a lower alkoxy group (excluding a methoxy group), or one or two lower alkoxycarbonyl groups) Represents a lower alkoxy group substituted with a carboxyl group. ) 3 — phenyl 1 2 — cyclohexene 1 1 — one-dimensional compound.

Claims of amendment

[November 12, 1999 (12.11.99) Accepted by the International Bureau: Claim 5 as originally filed has been amended; other claims remain unchanged. (2 pages)]

N-substituted 1-3-phenylamine obtained by the reductive amination reaction with the soluble amine compound R ₂ NH ₂ (() )

(In the formula, R, is hydrogen, hydroxyl, lower alkoxy, or lower alkoxy substituted with one or two lower alkoxycarbonyl or carboxyl.) R ₂ represents a removable optically active substituent.)

 Activity by removing the substituent on the nitrogen atom of 3-phenylcyclohexylamine compound (IV)

 (In the formula, R! Is hydrogen, hydroxyl, lower alkoxy, or lower alkoxy substituted with one or two lower alkoxycarbonyl or carboxyl.) * Represents an asymmetric carbon.)).

3. The process according to claim 1, wherein the compound (I) and the optically active amine compound R ₂ NH ₂ (() are subjected to a catalytic reduction reaction. 4. The production method according to claim 1, 2 or 3, wherein Raney nickel is used as a catalyst in the reductive amination reaction.

 5. (After correction) The following formula (VI)

(In the formula, R! Represents a hydroxyl group or a toxicoxycarbonyl group.) Paper captured (Article 19 of the Convention) The compound shown below is a 3-fluoro-2-six-hexene-one compound.

Paper captured (Article 19 of the Convention) Statements under Article 19 of the Convention

References include compounds

 (R represents an alkyl group.)

Is specifically described.

Therefore, the compound (VI) described in Claim 5 is converted to the compound described in Reference Examples 2 and 3 of the present application.

The correction was limited to.

 Clarified that compound (IV) is a compound not described in the literature,