WO2009133778A1

WO2009133778A1 - Method for the production of tert-butyl 3-aminopiperidine-1-carboxylate, and intermediates thereof

Info

Publication number: WO2009133778A1
Application number: PCT/JP2009/057811
Authority: WO
Inventors: 安岡順一; 池本哲哉
Original assignee: 住友化学株式会社
Priority date: 2008-04-30
Filing date: 2009-04-14
Publication date: 2009-11-05
Also published as: JP2009286778A

Abstract

Disclosed is a method for the production of tert-butyl 3-aminopiperidine-1-carboxylate wherein a base is reacted with tert-butyl 3-(alkoxycarbonylamino)-piperidine-1-carboxylate.

Description

Description t ter t-Butyl 3-aminobiperidine mono-carboxylate production method and intermediates thereof Technical Field

The present invention relates to a method for producing t tert -butyl 3-aminobiperidine monocarboxylate and an intermediate thereof. Background art

As a method for producing tert-butyl 3-aminobiperidine_1-carboxylate, for example, a method of reducing tert-butyl 3-azidopiperidine mono-carboxylate is known (see Patent Document 1). However, this method is not industrially satisfactory in terms of safety of the azide compound.

[Patent Document 1] International Publication No. 2000 00 No. 0 0 0 3 0 5 Disclosure of Invention

Under such circumstances, the present inventors have studied a production method of industrially advantageous tert-butyl 3-aminopiperidine 1-1-carboxylene, and the alkoxy moiety is primary or 2 Tert-butyl 3- (alkoxycarbonylamino) piperidine 1-carboxylate, which is a primary alkoxy group, reacts with a base to form a carbamate protecting group on the nitrogen atom at position 1; Among the carbamate protecting groups on the amino group bonded to the position, the carbamate protecting group on the amino group bonded to the 3-position is selectively removed, and tert-butyl 3-aminobiperidine 1-carboxylate It was found that a good yield was obtained. That is, the present invention provides the inventions described in the following [1] to [10].

(In the formula, R ¹ and R ² each independently represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.)

Tert-Butyl 3- (alkoxycarbonylamino) piveridiboxylate represented by the formula (3)

A method for producing tert-butyl 3-aminobiperidine mono-carboxylate represented by the formula:

[2] The production method according to [1], wherein the base is a metal hydroxide or a metal alkoxide having 1 to 4 carbon atoms.

[3] The production method according to [1], wherein the base is an alkali metal hydroxide.

[4] tert-butyl 3- (alkoxycarbonyl) represented by the formula (2)

1 One carboxylate is represented by the formula (2,)

(In the formula, R ¹ and R ² each have the same meaning as above, and * represents that the carbon atom is an optically active center.)

The optically active tert-butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate represented by the formula (3), and the tert-butyl 3-aminopiperidine mono 1-carboxylate represented by the formula (3) Formula (3 '

(In the formula, * represents that the carbon atom is an optically active center.)

The production method according to any one of items [1] to [3], which is an optically active tert-butyl 3-aminobiperidine mono-carboxylate represented by the formula:

(In the formula, R ¹ and R ² each have the same meaning as above.)

Tert-butyl 3-(alkoxycarbonylamino) piperidine represented by the formula (2) is converted to tert-butylcarboxylate.

(Alkoxycarbonylamino) The method according to any one of [1] to [3], further comprising a step of obtaining piperidine mono-carboxylate.

1-position of optically active 3- (alkoxycarbonylamino) piperidine represented by tert-butylcarboxylate is converted to tert _ represented by the formula (2 ') [4] The production method according to item [4], further comprising a step of obtaining butyl 3- (alkoxycarbonylamino) piperidine 1-carboxylate.

[7] tert-Butylcarboxylation is a 3- (alkoxycarbonylamino) piperidine represented by the formula (1) or an optically active 3- (alkoxycarbonyl) represented by the formula (1 '). [Amino] The production method according to [5] or [6], wherein the reaction is performed by reacting piperidine with ditert-butyl dicarbonate.

[8] The production method according to any one of [1] to [7], wherein both R ¹ and R ² forces are methyl groups.

[9] t tert-Butyl 3- (isopropoxycarbonylamamino) piberidine 1-force nolevoxylate.

[10] Optically active tert-butyl 3_ (isopropoxycarbonylamino) piperidine mono 1-carboxylate. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

First, tert-butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate represented by the above formula (2) (hereinafter tert-butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate (2 ) And a manufacturing method thereof will be described. In the formula, examples of the alkyl group having 1 to 8 carbon atoms represented by R ¹ and R ² include a methyl group, an ethyl group, a pill group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, Examples thereof include tert-butynole group, pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group, heptyl group, isoheptyl group, octyl group, isooctyl group and the like. R ¹ and R ² are independently preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a butyl group, and more preferably a methyl group for both R ¹ and R ² forces. tert-Butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate (2) is, for example, tert-butyl 3- (ethoxycarbonylamino) piperidine mono-monocarboxylate, tert-butyl 3 — (Propoxycarbonylamino) piperidine _ 1 _carboxylate, tert butyl 3— (isobutoxycarbonylamino) piperidine 1-force ruboxylate, tert-butyl 3 _ (isopropoxycarbonylamino) pi Examples include peridine monocarboxylate. These compounds may be any acid addition salts. The production method of tert-butyl 3 — (alkoxycarbonylamino) piperidine mono 1-carboxylate (2) is not particularly limited, and can be produced by any known method and used in the present invention. Here, as a preferred example, 3- (alkoxycarbonylamino) piperidine (hereinafter, ¾- (alkoxycarbonylamino) piperidine (1) represented by the above formula (1) is abbreviated. ) And di-tert-butyl dicarbonate (hereinafter abbreviated as Bocation reaction). '

Examples of 3- (alkoxycarbonylamino) piperidine (1) include ethyl piperidine-3-ylcarbamate, propylpiperidine-3-yl Carbamate, 3-butyl piperidine 3-ylcarbamate, isopropyl piperidine 3-ylcarbamate, isobutyl piperidine 3-ylcarbamate, 2-ethylhexyl piperidine 3-ylcarbamate, etc. Can be mentioned. These compounds may be any acid addition salt.

3- (Alkoxycarbonylamino) piperidine (1) can be obtained, for example, by catalytic hydrogen reduction of 3- (alkoxycarbonylamino) pyridine. Further, 3- (alkoxycarbonylamino) piperidine (1) is used, for example, optically active acid such as optically active tartaric acid, optically active mandelic acid, optically active camphorsulfonic acid, optically active lactic acid or the like. By optical resolution, an optically active 3- (alkoxycarbonylamino) piperidine represented by the above formula (1 ') (hereinafter optically active 3- (alkoxycarbonylamino) piperidine (1') This is abbreviated as). When performing such optical resolution, it is preferable to use optically active tartaric acid when both R ¹ and R ² are methyl groups, and optically active mandelic acid when R ¹ is a methyl group and R ² is a hydrogen atom. Is preferably used. The amount of ditert-butyl dicarbonate used is usually 0.9 to 3 moles, preferably 1 to 2 moles, relative to 3- (alkoxycarbonylamino) piperidine (1).

The B o cation reaction is usually carried out in the presence of a solvent. Examples of the solvent include water; ether solvents such as tetrahydrofuran and tert-butyl methyl ether; nitrile solvents such as acetonitrile; ester solvents such as ethyl acetate; aromatic solvents such as toluene; Examples include alcohol solvents such as 1-butanol, 2-propanol, and 2-methyl_2-propanol. These solvents may be used alone or in combination of two or more. The amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 20 L, relative to 1 kg of 3-(alkoxycarbonylamino) piperidine (1). Further, such B ocification reaction may be carried out in the presence of a base. Examples of the base include alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydrogen carbonates such as sodium carbonate and carbonic acid lithium; sodium hydroxide and hydroxide Alkali metal hydroxides such as potassium; organic bases such as triethylamine, disobutylethylamine, pyridine; and the like. These bases may be used alone or in combination of two or more. The amount of the base used is usually 1 to 5 mol times, preferably 1 to 2 mol times with respect to diter t-ptyl dicarbonate. When an acid addition salt is used as the 3_ (alkoxycarbonylamino) piperidine (1), the amount of the base used is determined in consideration of the amount necessary to neutralize the acid contained in the salt. Just decide.

The reaction temperature for the B o cation reaction is usually 10 to 80 ° C, preferably 0 to 50 ° C. The reaction time is usually 15 minutes to 12 hours, preferably 30 minutes to 5 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The progress of the reaction can be confirmed by usual means such as gas chromatography and high performance liquid chromatography.

The mixing order in the B ocification reaction is not particularly limited. As a preferred embodiment Te is, for example, 3- (alkoxycarbonyl - Ruamino) and aspects will in addition to the piperidine (1) a base and di-te _r t _ butyl concurrently, 3- (alkoxides aryloxycarbonyl § Mino) An embodiment in which ditert-butyl dicarbonate is added to a mixture of piperidine (1) and a base.

The mixture after completion of the B ocification reaction contains tert-butyl 3- (alkoxycarbonylamino) piperidine _ 1 _carboxylate (2) or its acid-added salt. The mixture may be subjected to a reaction, but usually the mixture is subjected to a usual post-treatment such as filtration, neutralization, extraction, washing and the like, and then subjected to the next reaction. Of course, the mixture after the above-mentioned post-treatment may be subjected to the following reaction after subjecting it to a normal isolation treatment such as distillation or crystallization. Furthermore, recrystallization; extraction purification; rectification; activated carbon, silica, Adsorption treatment of alumina, etc .; Silica gel column chromatography, etc. Chromatography method, etc .;

When optically active 3- (alkoxycarbonylamino) piperidine (1 ') is used in the Bocation reaction, optically active tert-butyl 3- (alkoxycarbonyl) represented by the above formula (2') is usually used. (Amino) piperidine monocarboxylate (hereinafter abbreviated as optically active tert-butyl 3- (alkoxycarbonylamino) piperidine monocarboxylate (2 ′)). Next, the above formula (3) according to the reaction of tert-butyl 3- (alkoxycarbonylamino) piperidine_1-carboxylate (2) with a base (hereinafter also referred to as the present deprotection reaction). A method for producing tert-butyl 3-aminopiperidine — 1 —carboxylate (hereinafter abbreviated as tert-butyl 3-aminobiperidine 1-carboxylate (3)) will be described. As the base used in this deprotection reaction, metal hydroxide, metal alkoxide, metal amide, metal carbonate, etc. are used. Examples of such metal hydroxides include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide. Is mentioned. As the metal alkoxide, for example, an alkyl group metal alkoxide having 1 to 4 carbon atoms such as sodium methoxide, strong tert-butoxide and the like can be mentioned. Examples of the metal amide include alkali metal amides such as sodium amide and lithium amide. Examples of the metal carbonate include alkali metal carbonates such as cesium carbonate and potassium carbonate. From the viewpoint of reactivity, metal hydroxides and metal alkoxides are preferable, alkali metal hydroxides, alkaline earth metal hydroxides, and Al 1-4 metal alkoxides having 1 to 4 carbon atoms are more preferable, alkaline metal water. More preferred are oxides. These bases may be used alone or in combination of two or more. The amount of the base used is usually 1 to 10 moles, preferably 2 to 5 moles per tert-butyl 3- (alkoxycarbonylamino) piperidine 1-carboxylate (2). is there. This deprotection reaction is usually carried out in the presence of a solvent. Solvents include, for example, water; tetrahydrofuran, etherol solvent such as tert-butylmethylol ether Medium: Aromatic solvents such as toluene, xylene, monochrome benzene, 1,2-dichloro benzene, etc .; 1-butanol, 2-propanol, 2-methyl-2-propanol, 4-methyl-2-pentanol, etc. Alcohol solvent: dimethyl sulfoxide, sulfolane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-1 3 , 4, 5, 6—Tetrahydrol 2 (1 H) 1-pyridinone and other non-proton polar solvents; Water, ether solvent and alcohol solvent are preferred. These solvents may be used alone or in combination of two or more. The amount of the solvent to be used is usually 1 to 50 L, preferably 2 to 20 L with respect to 1 kg of tert_butyl 3- (alkoxycarbonylamino) piperidine mono 1 -carboxylate (2). The reaction temperature of this deprotection reaction is usually 0 to 160 ° C, preferably 50 to 120 ° C. The reaction time is usually 15 minutes to 12 hours, preferably 30 minutes to 5 hours, although it depends on the reaction temperature and the amount of reaction reagent used. The progress of the reaction can be confirmed by usual means such as gas chromatography and high performance liquid chromatography. The mixing order in this deprotection reaction is not particularly limited. Preferred embodiments include, for example, an embodiment in which a base is added to tert-butyl 3- (alkoxycarbonylamino) piperidine-1-carboxylate (2), and tert-butyl 3- (alkoxycarbonyl) to the base. Amino) Piperidin 1 1 Carboxylate (2) is added. The mixture after completion of the deprotection reaction contains tert-butyl 3_aminobiperidine-1-carboxylate (3) or an acid addition salt thereof, and the mixture is filtered, if necessary. Tert-butyl 3 _ aminobiperidine _ 1-carboxylate (3) or its acid addition by subjecting to normal post-treatment such as summation, extraction, washing, etc., followed by usual isolation treatment such as distillation and crystallization The salt can be isolated. The isolated tert-butyl 3-aminobiperidine 1-carboxylate (3) is further recrystallized; extraction and purification; rectification; adsorption treatment of activated carbon, silica force, alumina, etc .; It may be purified by a conventional purification process such as a chromatographic method; -When optically active tert-butyl 3- (alkoxycarbonylamino) piperidine 1_carboxylate (2,) is used in this deprotection reaction, the optical activity represented by the above formula (3 ') is usually used. Tert-butyl 3-aminobiveridine 1-carboxylate is obtained. According to the present invention, tert-butyl 3-aminobiperidine monocarboxylate can be obtained safely and with high yield, which is industrially advantageous. Example

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these Examples. Reference Example 1: (R) —Isopropylpiperidine 1-ylcarbamate L 1 tartrate

A solution consisting of 200 g (1.11 mo 1) of isopropylpyridine-3-ylcarbamate, lOO g of oxalic acid (1.66 mo 1) and 300 g of water, and palladium carbon (1 0 %) 20. 0 g was mixed, and the resulting mixture was stirred at a hydrogen pressure of 0.5 to 0.9 MPa at 85 to 95 ° C. for 1 hour. After completion of the reaction, palladium carbon was filtered off to obtain a reaction solution. The palladium carbon was washed with 100 g of water to obtain a washing solution, and the reaction solution and the washing solution were combined. 1-Butanol 8 O OmL was added to the resulting solution and concentrated until the internal volume reached about 80 OmL. The obtained concentrated residue was mixed with 400 ml of 1-butanol and 192.1 g (1.28 m o 1) of L monotartaric acid. The resulting mixture was stirred at 70 ° C. for 3 hours, and then gradually cooled to 10 ° C. while continuing to stir. Crystals precipitated from the middle. The crystals were collected by filtration and dried to obtain (R) -isopropylpiperidine-1-ylcarbamate L monotartrate 1 1 6.9 g as white crystals. Yield 3 1.3%. Reference Example 2: (S) —Isopropylpiperidine 1-3-ilcarbamate D—Tartrate

In Reference Example 1, (R) -isopropylpiperidine-3-ylcarbamate L--tartrate was filtrated to concentrate the filtrate, and 494 g of water was added to the resulting residue. The obtained mixture was adjusted to 35 ° C., and 224 g (2.1 1 m o 1) of sodium carbonate was added in portions thereto. To the obtained mixture, 260 g of ethyl oxalate was added and mixed, and an organic layer was obtained by liquid separation treatment. The aqueous layer was extracted with 244 g of ethyl acetate, and the obtained organic layer and the previously obtained organic layer were combined. The obtained organic layer was dried over 135 g of anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the resulting solution was concentrated. Ethanol (453 g) and D-tartaric acid (168 g, 0.87 mo 1) were added to the resulting residue, and the resulting mixture was stirred at 70 ° C for 3 hours. When it was gradually cooled, crystals precipitated from the middle. The crystals were collected by filtration and washed with 176 g of ethanol. The obtained crystals were dried to obtain 74. l g of (S) -isopropylpiberidin-3-ylcarbamate D-tartrate as white crystals. The crystals were suspended in 75 g of ethanol, and the resulting suspension was stirred at 70 ° C. for 1 hour, and then cooled to 10 ° C. Crystals were collected from the resulting suspension by filtration, and the crystals were washed with 59 g of ethanol. The obtained crystals were dried to obtain 72.1 g of (S) monoisopropylpiperidine-3-ylcarbamate D-tartrate as white crystals. Yield 19.3% from isopropylpyridine 3-ylcarbamate. The obtained (S) -isopropyl piperidine 3-ylcarbamate D—reacts a portion of tartrate with triethylamine to remove isopropyl piperidine 3-ylcarbamate, which is taken as 3,5-dinitroben When derivatized with zoyl chloride and analyzed by high performance liquid chromatography, the optical purity of isopropyl piperidine 3-ylcarbamate in the salt was 99.4% ee (S form). there were.

Optical purity analysis conditions>

Column: CH I RALCE L (registered trademark) AS—RH 4. 6 X 1 50 mm, 5 μ

(Daicel Chemical Industries, Ltd.)

Mobile phase: A = water, B-acetonitrile, A / B = 70 Z3 0

Flow rate: 1. O ml / min

Detector: U V 2 5 4 nm

Retention time: S form = 19.1 minutes, 1 form = 3 1.5 minutes Example 1: (S) — tert-butyl 3 _ (isopropoxycarbonylamino) piperidine _1 carboxylate

(S) —Isopropylpiperidine-3-ylcarbamate D—tartrate 10 0 O g (29. 7 mmol, 99.4% ee) and tetrahydrofuran 5 obtained in Reference Example 2 0 mL and 5 mL of water were mixed, and a mixed solution of 6.3 g (59.4 mm o 1) of sodium carbonate and 25 mL of water was added dropwise thereto over 1 hour. The internal temperature of the mixture during the dropping was 10 to 20 ° C. After completion of the dropwise addition, the resulting mixture was stirred at 20 ° C. for 30 minutes. To the resulting mixture, a mixed solution of 6.5 g (29.7 mm o 1) of diterbi-carbonate and 10 ml of tetrahydrofuran was added dropwise over 1 hour. The internal temperature of the mixture during the dropwise addition was 10 to 20 ° C. The resulting mixture was stirred at room temperature for 1 hour. Water 5 O mL was added to the obtained mixture and mixed, and an organic layer was obtained by liquid separation treatment. The aqueous layer was extracted with Tetrahydrofuran 3 O mL, and the obtained organic layer and the previously obtained organic layer were combined, and then 2 times with 20 wt% aqueous citrate solution 2 O mL, saturated saline. Washed once with 2 O mL of water. The obtained organic layer was dehydrated with sodium sulfate. After sodium sulfate was filtered off and the resulting solution was concentrated, 1 O mL of heptane was added to the resulting oily substance, and crystals were precipitated. The crystals were collected by filtration and washed with 5 m 1 of heptane. The obtained crystals were dried to obtain 7.65 g of (S) -tert-butyl 3- (isopropoxycarbonylamino) piperidine_1 carboxylate as white crystals. Yield 90%

¹ H-NMR (CDC 1 a> 4 0 0 MHz) δ ppm: 5. 0 0-4. 8 2 (1 H, m) 4. 7 3 (1 H, brs), 3. 6 7— 3. 2 4 (4 H, m), 1. 8 9— 1. 6 2 (2 H, m), 1. 5 9— 1. 4 4 (2 H, m), 1. 4 6 (9 H, s ), 1. 2 9 (6 H, d, J = 5.2 H z)

1 ³ C-NMR (CDC 1 a, 10 OMH z) 6 ppm: 1 5 5. 3, 1 5 4 .9, 7 9. 7, 7 2. 3, 6 8. 0, 4 8. 9, 4 6. 4, 4 3. 9, 30. 1, 2 8. 4, 2 2. 4, 1 7. 9 Example 2: (S) — tert-butyl 3-aminobiperidine mono 1-carboxylate

(S) — tert-butyl 3 _ (isopropoxycarbonylamino) piperidine monocarboxylate 5. 0 0 g (17.5 mm o 1) and 1 —butanol 2 O obtained in Example 1 The resulting mixture was adjusted to 100 ° C. Thereto, 2.94 g (52.5 mm o 1) of lithium hydroxide was added over 5 minutes. The resulting mixture was stirred at 100 ° C. for 1 hour, then cooled to room temperature, 5 mL of water was added thereto, and an organic layer was obtained by liquid separation treatment. The aqueous layer was extracted with 1-butanol 1 O mL, and the obtained organic layer and the previously obtained organic layer were combined, and then washed twice with 1 O mL of water. The obtained organic layer was concentrated to give (S) -tert-butyl 3-aminobiperidine 1_

The transfer buoyant poxylate 3.08 g was obtained. Yield 8 8%

Movable amount

When (S) -tert-butyl 3-aminobiperidine 1-carboxylate was derivatized with 3,5-dinitrobenzoyl chloride and analyzed by high-performance liquid chromatography, its optical purity was 9 9. 4% ee (S body).

Column: CH I RAL CE L (registered trademark) AS—RH

4. 6 X 1 50 mm, 5 m

(Daicel Chemical Industries, Ltd.)

Phase: A = water, B = acetonitrile, AZB = 60/40

: 1. Om l Z min

Instrument: UV 2 5 4 nm

Time: S body-1 1.4 minutes, Scale = 1 2.3 minutes Example 3: (S) — t tert -Butyl 3-aminobiperidine 1 _ carboxy silicate

(S) —tert-Butyl 3 _ (Isopropoxycarbonamino) piperidine monocarboxylate 5 7 3 mg (2.0 0 mm o 1) and 2-propanol 3 obtained in Example 1 Then, 33.7 mg of potassium hydroxide (6.00 mm o 1) was added to the resulting mixture. The resulting mixture was stirred in an autoclave at 100 ° C for 3 hours. The internal pressure during stirring was 0.2 MPa. The obtained mixture was cooled to room temperature, 1-butanol 1 OmL and 5 mL of water were added thereto, and an organic layer was obtained by liquid separation treatment. The aqueous layer was extracted with 1-butanol 1 OmL, and the obtained organic layer and the previously obtained organic layer were combined, and then washed twice with 5 mL of water. The obtained organic layer was concentrated to give (S) -tert-butyl 3-aminobiperidine 1 1-carboxylate 3 52 mg as a pale yellow oil. Yield 8 8% When analyzed by high performance liquid chromatography as in Example 2, the optical purity of (S) -tert-butyl 3-aminopiperidine 1-carboxylate was 9 9. It was 4% ee (S body). Example 4 (S) — tert-butyl 3-aminobiperidine 1-carboxylate hemifumarate

(S) -tert monobutyl 3-aminobiberidine mono 1-carboxylate, 2-propanol 20 ml and fumaric acid 1 16 g (1.00 mo 1) obtained in the same manner as in Example 3. Mixed. The resulting mixture was stirred at 80 ° C for 1 hour and cooled to 10 ° C, whereupon crystals were precipitated. The crystals were collected by filtration and washed with 5 mL of 2-propanol. The obtained crystals were dried to obtain (S) -tert-butyl 3-aminobiperidine 1-1 monocarboxylate 413 mg of mifumarate as white crystals. Yield 80% (S) -tert-Butyl 3-amino- (S) -tert-Butyl 3-aminobiperidine mono 1-Carboxylate By reacting part of hemifumarate with triethylamine (S) — tert-butyl 3-amino Biperidine 1 1 _carboxylate This was derivatized with 3,5-dinitrobenzoyl chloride and analyzed by high performance liquid chromatography under the same conditions as in Example 2. (S) 1 tert-butyl 3-aminobiperidine 1 —The optical purity of the carboxylate was 99.8% ee (S form). Industrial applicability

tert-Butyl 3-aminopiperidine monocarboxylate is useful, for example, as an optically active compound as a synthetic intermediate for Alzheimer's therapeutics (see International Publication No. WO 2000 00 0 0 3 0 5) It is an important compound. The present invention is industrially applicable as a method for producing such a compound and its intermediate.

Claims

Claim scope Claim 1

(In the formula, R ¹ and R ² each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.)

Tert_Butyl 3- (alkoxycarbonylamino) piveridibase represented by the formula (3)

A method for producing t tert -butyl 3 -aminopiperidine mono 1-carboxylate represented by the formula: Claim 2

The production method according to claim 1, wherein the base is a metal hydroxide or a metal alkoxide having 1 to 4 carbon atoms. Claim 3

2. The production method according to claim 1, wherein the base is an alkali metal hydroxide. Claim 4

Tert-butyl 3- (alkoxycarbonylamino) rate represented by the formula (2) is represented by the formula (2,)

The optically active tert-butyl 3- (alkoxycarbonylamino) piperidine mono 1-carboxylate represented by the formula (3), and the tert-butyl 3-aminobiperidine mono 1-carboxylate represented by the formula (3), Formula (3 ')

The production method according to any one of claims 1 to 3, wherein the optically active t-tert-butyl 3-aminobiperidine is represented by Claim 5

Formula (1).

(In the formula, R ¹ and R ² each have the same meaning as above.)

3-(Alkoxycarbonylamino) piperidine represented by the formula 1 tert-butylcarboxylate and the tert 3 -butyl 3— represented by the formula (2)

The production method according to claim 1, further comprising a step of obtaining (alkoxycarbonylamino) piperidine mono-carboxylate. Claim 6

The 1-position of the optically active 3- (alkoxycarbonylamino) piperidine represented by tert-butylcarboxylate is converted to the tert-butyl 3- (alkoxycarbonylamino) pirpine represented by the formula (2 '). 5. The method according to claim 4, further comprising a step of obtaining peridine mono 1-carboxylate. Claim 7

tert-butylcarboxylation is carried out with 3- (alkoxycarbonylamino) piperidine represented by the formula (1) or optically active 3- (alkoxycarbonylamino) piperidine represented by the formula (1 ') and The production method according to claim 5 or 6, which is carried out by reacting with ditert-butyl dicarbonate. Claim 8

The production method according to claim 1, wherein both R ¹ and R are methyl groups. Claim 9

tert-Butinole 3- (Isopropoxycarbonylamino) piperidine One carboxylate. Claim 1 0

Optically active tert-butyl 3- (isopropoxycarbonylamino) piperidine 1-carboxylate.