KR100489649B1 - (S) -3-substituted-2-hydroxypropylamine preparation method - Google Patents

Abstract

The present invention relates to a method for preparing (S) -3-substituted-2-hydroxypropylamine represented by the following Chemical Formula 1, and more particularly, (S)-represented by the following Chemical Formula 2 having 4 carbon skeletons Using 4-substituted-3-hydroxybutylhydrazide as starting material and converting hydrazide group to amine group by Curtius Rearrangement, it is useful as intermediate of β-blocker medicine with 3 carbon skeletons It relates to a method for producing (S) -3-substituted-2-hydroxypropylamine derivative represented by the formula (1).

In the formula: R ₁ represents hydrochloride (H.HCl), sulfate (H.H ₂ SO ₄ ) or -C (O) OR, wherein R is an alkyl or benzyl group having 1 to 10 carbon atoms or crushed chain. Or a phenyl group; R ₂ represents a hydrogen atom or an acetyl group; X represents a halogen atom or a hydroxyl group.

Description

(S) -3-Substituted 2-hydroxypropylamine

The present invention relates to a method for preparing (S) -3-substituted-2-hydroxypropylamine represented by the following Chemical Formula 1, and more particularly, (S)-represented by the following Chemical Formula 2 having 4 carbon skeletons Using 4-substituted-3-hydroxybutylhydrazide as starting material and converting hydrazide group to amine group by Curtius Rearrangement, it is useful as intermediate of β-blocker medicine with 3 carbon skeletons It relates to a method for producing (S) -3-substituted-2-hydroxypropylamine derivative represented by the formula (1).

Formula 1

Formula 2

In the above formula:

R ₁ represents hydrochloride (H.HCl), sulfate (H.H ₂ SO ₄ ), or -C (O) OR, wherein R is a linear or pulverized alkyl group, benzyl group or phenyl group having 1 to 10 carbon atoms;

R ₂ represents a hydrogen atom or an acetyl group;

X represents a halogen atom or a hydroxyl group.

In the prior art, in the case of a compound having a chiral hydroxy group at the C-2 position with a carbon skeleton of 3, a microorganism may be derived from a racemic compound having a carbon skeleton of 3 to introduce an oxygen functional group having a chirality at the C-2 position. It is prepared by selective hydrolysis reaction by biological method using enzyme.

For example, in Tetrahedron Lett ., 27 , 2061 (1992), chiral 1- Described are methods for preparing amino-2-propanol derivatives. Selective hydrolysis by this enzyme can theoretically not exceed 50%, and the ratio of the two optical isomers is also very low at 65:35 in optical purity.

And Agric. Biol. Chem. , 48 , 2055 (1984) and Agric. Biol. Chem ., 49 , 1669 (1985) prepared (S) -esters by selective hydrolysis of racemic 2-oxazolidone esters with lipase, but the yield was low to 35% and the resulting (R) -alcohol Inverting chirality with (S) -alcohol adds a five step process.

And Agric. Biol. Chem ., 46 , 1593 (1982), describes the preparation of chiral (S) -2,3-dichloro-1-propyl acetate from selective hydrolysis using lipase from racemic 2,3-dichloro-1-propyl acetate. The method is described. However, the reaction yield is 9 to 22%, which is too low for commercial use, and the reaction process for preparing racemic 2,3-dichloro-1-propyl acetate requires a four-step process from propene.

On the other hand, US Patent No. 4,900,847 (1990) describes a method for preparing chiral (S) -2,3-epoxypropanol by asymmetric epoxylation of allyl alcohol. This method has higher reaction yield than the above-mentioned biologically selective hydrolysis reaction, but has low stereoselectivity of 89% ee.

In the prior art described above, in order to prepare an optically active intermediate having 3 carbon skeletons, a racemate having 3 carbon skeletons is preferentially synthesized, and then a chiral hydroxy group is introduced so that the yield cannot be increased by up to 50%. There is.

Therefore, in the present invention, by using (S) -4-substituted-3-hydroxybutylhydrazide having a high optically active chiral center as a starting material, the manufacturing cost is reduced, and the chiral center introduced in the conventional method is introduced. It is an object of the present invention to provide a breakthrough manufacturing method that can simultaneously solve the problem of low optical purity or low yield generated in the manufacturing method.

The present invention converts the hydrazide group of the compound represented by the following formula (2) to an amine group by Curtisus rearrangement (S) -3-substituted-2-hydroxypropylamine derivative represented by the following formula (1) It relates to a manufacturing method of.

Formula 2

Formula 1

In the above formula:

R ₁ represents hydrochloride (H.HCl), sulfate (H.H ₂ SO ₄ ), or -C (O) OR, wherein R is a linear or pulverized alkyl group, benzyl group or phenyl group having 1 to 10 carbon atoms;

R ₂ represents a hydrogen atom or an acetyl group;

X represents a halogen atom or a hydroxyl group.

The reaction mechanism for the preparation process of (S) -3-substituted-2-hydroxypropylamine derivative represented by Chemical Formula 1 according to the present invention is as follows. All chemical reactions applied in the present invention have no effect on the chirality of the chiral center (S) -hydroxy functional group.

Reported to date, there has been no synthesis of a propylamine derivative having a chiral (S) -hydroxy group at the C-2 position while reducing the carbon skeletal number by the Curtis relocation reaction.

In Scheme 1: R ₁ , R ₂ and X are as defined above, respectively; M represents a metal atom.

According to Scheme 1, (S) -4-substituted-3-hydroxybutylhydrazide represented by Chemical Formula 2 is reacted with a nitrite metal salt or alkyl nitrite to change the hydrazide group to an acyl azide group, which is present in the reaction solvent. When refluxed under, a nitrogen gas is released and repositioned converts the acylnitrene group of the intermediate represented by the formula (4) to an isocyanate group. In the above reaction, the process of changing the hydrazide group of the compound represented by the formula (2) to an acyl azide group is performed at -78 ° C to 10 ° C. When the reaction temperature is less than -78 ° C, the reaction may not be performed properly. And, if the reaction temperature exceeds 10 ℃ there is a problem that the acyl azide is decomposed. It is more preferable to use aromatic hydrocarbons such as benzene and toluene as the refluxing solvent. As the nitrite metal salt used in the reaction, it is preferable to use an alkali metal nitrite salt such as sodium nitrite salt or potassium nitrite salt. As the alkyl nitrite, alkyl nitrite having 1 to 10 carbon atoms, preferably alkyl nitrite having 1 to 6 carbon atoms, is used.

When an inorganic acid such as hydrochloric acid or sulfuric acid is added to the reaction solution containing the intermediate represented by Chemical Formula 5, R ₁ is an inorganic acid salt (for example, hydrochloride (H.HCl), sulfate (H.H _2). A target compound of SO ₄ )) is obtained. On the other hand, when alcohols are added in place of the inorganic acid, R ₁ is a carbamate group.

In addition, (S) -4-substituted-3-hydroxybutylhydrazide used as a starting material in the present invention (S) -3-hydroxybutyrolactone obtained by a known method [US Patent No. 5,374,773, 5,319,110] And No. 5,292,939] were manufactured and used with a high optical purity of at least 99% ee by a very inexpensive and simple method (Japanese Patent Publication No. 64-13069).

The chiral (S) -3-substituted-2-hydroxypropylamine derivative represented by Chemical Formula 1 according to the present invention as described above is a β-blocker useful as an anti-hypertensive drug. It is very useful as a key intermediate in manufacturing. For example, the β-blocker medicament which can be prepared by using (S) -3-substituted-2-hydroxypropylamine or salts thereof as (S) -atenolol [(S) -atenolol], (S) -Metoprolol [(S) -metoprolol], (S) -nadolol [(S) -nadolol], (S) -timolol [(S) -timolol].

The β-blocker hypercoupling agent mentioned above may be prepared by alkylating an amino group of the compound represented by Formula 1 and substituting an end group (X) with an aryloxy group.

In this regard, the reaction mechanism of the manufacturing process of (S)-atenolol from the (S) -3-substituted-2-hydroxypropylamine derivative represented by Chemical Formula 1 according to the present invention is shown in the following Scheme 2. .

In addition, the compound represented by Chemical Formula 1 may be widely applied in industrial fields due to its various uses.

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

Preparation Example 1 Preparation of (S) -3,4-dihydroxybutylhydrazide

Chiral (S) -3-hydroxybutyrolactone (16.32 g, 0.16 mol), hydrazine monohydrate (80% purity, 20 g, 0.32 mol), ethanol in a 500 ml three-necked flask equipped with a thermometer, reflux cooler and stirrer (200 mL) was added and refluxed for 2 hours. The reaction mixture was cooled to room temperature and stirred for 2 hours. The resulting white solid was filtered and dried to give (S) -3,4-dihydroxybutylhydrazide (yield 95%, optical purity> 99% ee).

¹ H-NMR (D ₂ O, ppm): δ3.92 (m, 1H, -CHOH), 3.32 to 3.47 (m, 2H, CH ₂ OH), 2.12 to 2.30 (m, 2H, CH ₂ -CO)

Preparation Example 2 Preparation of (S) -3-acetoxy-4-bromobutylhydrazide bromate

30% hydrogen bromide / acetic acid solution (62 mL, 0.23 mol) was added to a 100 mL three-necked flask equipped with a thermometer and a stirrer, followed by stirring. (S) -3,4-dihydroxybutylhydrazide (13.4g, 0.1 mol) was put into this solution, and it stirred at room temperature for 1 hour. The solid product was filtered off and washed with 50 mL of diethyl ether. The filtered solid product was dried to give (S) -3-acetoxy-4-bromobutylhydrazide bromate (yield 93%, optical purity> 99% ee).

¹ H-NMR (D ₂ O, ppm): δ 5.34 (m, 1H, -CHOAc), 3.50 (m, 2H, CH ₂ Br), 2.75 (m, 2H, CH ₂ -CO), 2.06 (s , OCOCH ₃ )

Example 1: Preparation of (S) -3-bromo-2-hydroxypropylamine hydrochloride

(S) -3-acetoxy-4-bromobutylhydrazide bromate (21.8 g, 0.092 mol), distilled water (80 mL), concentrated hydrochloric acid (40 mL) in a 250 mL three-necked flask equipped with a thermometer and a stirrer; Diethyl ether (100 mL) was added and stirred at 0 ° C. A solution of sodium nitrite (16 g, 0.23 mol) dissolved in distilled water (30 mL) was added dropwise to the reaction solution. At this time, take care that the temperature of the reaction solution does not exceed 10 ℃. When the dropwise addition of the aqueous sodium nitrite solution was completed, the mixture was placed in a separatory funnel and extracted twice with diethyl ether (100 ml). The extract solution was dehydrated with anhydrous magnesium sulfate and filtered. Diethyl ether was distilled under reduced pressure, and toluene (50 ml) was added to the product to reflux for 15 minutes. Nitrogen gas was generated. Concentrated hydrochloric acid (40 ml) was added to the heated toluene solution. After cooling the reaction solution, toluene was distilled under reduced pressure to obtain white (S) -3-bromo-2-hydroxypropylamine hydrochloride (yield 93%, optical purity> 99% ee).

¹ H-NMR (D ₂ O, ppm): δ 4.03 (m, 1H, -CHOH), 3.41 (m, 2H, CH ₂ Br), 3.17 (d, 1H, CH _a N), 2.96 (t, 1H, CH _b N)

Example 2 Preparation of (S) -3-bromo-2-hydroxypropylcarbamate benzyl ester

(S) -3-acetoxy-4-bromobutylhydrazide bromate (21.8 g, 0.092 mol), distilled water (80 mL), concentrated hydrochloric acid (40 mL) in a 250 mL three-necked flask equipped with a thermometer and a stirrer; Diethyl ether (100 mL) was added and stirred at 0 ° C. A solution of sodium nitrite (16 g, 0.23 mol) dissolved in distilled water (30 mL) was added dropwise to the reaction solution. At this time, take care that the temperature of the reaction solution does not exceed 10 ℃. When the dropwise addition of the sodium nitrite aqueous solution was completed, the mixture was placed in a separatory funnel and extracted twice with diethyl ether (200 mL). The extract solution was dehydrated with anhydrous magnesium sulfate and filtered. Diethyl ether was distilled under reduced pressure, and toluene (50 mL) and benzyl alcohol (9.9 g, 0.092 mol) were added to the product, and the mixture was refluxed for 2 hours. Toluene was distilled under reduced pressure to obtain white (S) -3-bromo-2-hydroxypropyl carbamate benzyl ester (yield 94%, optical purity> 99% ee).

¹ H-NMR (CDCl ₃ , ppm): δ 7.39 (s, 5H, Ph), 5.52 (brs, 1H, NH), 5.28 (s, 2H, CH ₂ -Ph), 4.02 (m, 1H, CH -O), 3.48 (m, 2H, CH ₂ -Br), 3.36 (m, 2H, CH ₂ N)

Example 3: Preparation of (S) -3-chloro-2-hydroxypropylamine hydrochloride

(S) -4-chloro-3-hydroxybutylhydrazide (18 g, 0.119 mol) was dissolved in an ethanol solution containing 6 g of hydrogen chloride in a 250 ml three-necked flask equipped with a thermometer and a stirrer. Amyl nitrite (19.3 g, 0.165 mol) was added to this solution, and it heated at 60 degreeC for 2 hours. After cooling, diethyl ether (100 mL) was added thereto, and the resulting solid precipitate was filtered. The solid product was added to 200 ml of concentrated hydrochloric acid and stirred at 90 ° C. for 2 hours. The reaction solution was cooled and diethyl ether (300 mL) was added to obtain (S) -3-chloro-2-hydroxypropylamine hydrochloride (yield 91%, optical purity> 99% ee).

¹ H-NMR (D ₂ O, ppm): δ4.12 (m, 1H, -CHOH), 3.42-3.62 (m, 2H, CH ₂ Cl), 3.20 (d, 1H, CH _a N), 3.02 ( t, 1H, CH _b N)

Example 4: Preparation of (S) -2,3-dihydroxypropylamine sulfate

(S) -3,4-dihydroxybutylhydrazide (13.4 g, 0.1 mol), distilled water (80 ml), concentrated sulfuric acid (30 ml), diethyl ether in a 250 ml three-necked flask equipped with a thermometer and a stirrer (100 mL) was added and stirred at 0 ° C. A solution of sodium nitrite (16 g, 0.23 mol) dissolved in distilled water (30 mL) was added dropwise to the reaction solution. At this time, take care that the temperature of the reaction solution does not exceed 10 ℃. When the dropwise addition of the aqueous sodium nitrite solution was completed, the mixture was placed in a separatory funnel and extracted twice with diethyl ether (150 mL). The extract solution was dehydrated with anhydrous magnesium sulfate and filtered. Diethyl ether was distilled under reduced pressure, and toluene (50 ml) was added to the product to reflux for 15 minutes. Nitrogen gas was generated in a heated toluene solution and refluxed for 1 hour. . After cooling the reaction solution, toluene was distilled under reduced pressure to obtain a white (S) -2,3-dihydroxypropylamine sulfate (yield 93%, optical purity> 99% ee).

¹ H-NMR (D ₂ O, ppm): δ3.92 (m, 1H, -CHOH), 3.53 (m, 2H, CH ₂ OH), 3.15 to 2.93 (m, 2H, CH ₂ N)

As described above, the starting material used in the production method according to the present invention can be synthesized by a simple and inexpensive method, and the Curtis shifting reaction which reduces the carbon skeletal number while preserving the chiral hydroxy group in the starting material By reducing the manufacturing cost, the optical purity and yield is also very high has a useful effect as an intermediate of the β-blocker drug.

Claims (7)

(S) -3-substituted-2-hydroxy represented by the following Chemical Formula 1, which is prepared by converting a hydrazide group of the compound represented by Chemical Formula 2 into an amine group by Curtius Rearrangement. Process for the preparation of propylamine derivatives. Formula 1 Formula 2 In the above formula: R ₁ represents hydrochloride (H.HCl), sulfate (H.H ₂ SO ₄ ), or -C (O) OR, wherein R is a linear or pulverized alkyl group, benzyl group or phenyl group having 1 to 10 carbon atoms; R ₂ represents a hydrogen atom or an acetyl group; X represents a halogen atom or a hydroxyl group. The process for producing (S) -3-substituted-2-hydroxypropylamine derivatives according to claim 1, wherein X is a chlorine atom or a bromine atom. (S) -3-substituted-2-hydroxypropylamine according to claim 1, wherein a nitrite metal salt or a C _{1 to} C ₁₀ alkylnitrite is used for the Curtius rearrangement. Process for the preparation of derivatives. The method for producing (S) -3-substituted-2-hydroxypropylamine derivatives according to claim 3, wherein the metal nitrite salt is sodium nitrite salt or potassium nitrite salt. (S) -3-substituted-2-hydroxypropyl according to claim 3, wherein the metal nitrite salt or C ₁ to C ₁₀ alkylnitrite addition reaction is performed at a temperature range of -78 ° C to 10 ° C. Method for preparing an amine derivative. The reaction solution is refluxed according to claim 3, 4 or 5, wherein the reaction solution is refluxed when the addition of the metal nitrite salt or C ₁ to C ₁₀ alkylnitrite is completed. Preparation of hydroxypropylamine derivatives. The method for producing a (S) -3-substituted-2-hydroxypropylamine derivative according to claim 6, wherein the reflux solvent is an aromatic hydrocarbon.