KR101847161B1 - Process for the preparation of optically pure substituted (S)-cyclohexylamino acid derivatives - Google Patents

Abstract

The present invention discloses a process for producing optically pure (S) -cyclohexylamino acid derivatives by continuously hydrogenating optically pure (S) -phenyl amino acid derivatives under supported metal supported catalysts. The present invention is an environmentally-friendly and economical method for producing (S) -cyclohexylamino acid derivatives with high yield and high purity.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to optically pure (S) -cyclohexylamino acid derivatives,

A process for the preparation of optically pure (S) -cyclohexylamino acid derivatives is disclosed. More specifically, a method for producing an (S) -cyclohexylamino acid derivative whose optical activity is maintained from an (S) -phenylamino acid derivative by continuous hydrogenation using a metal supported catalyst is disclosed.

The optically pure substituted (S) -cyclohexylamino acid derivative compound is a synthetic derivative having pharmacological activity and is an intermediate for the preparation of various medicines such as hepatitis C treatment agent, renin inhibitors, or thrombin inhibitors (See WO 2005/014526).

Techniques for the preparation of such optically active (S) -cyclohexylamino acid derivatives have been reported in various publications.

U.S. Patent No. 6,316,660 and European Patent No. 0823416 disclose a technique for producing an optically active (S) -cyclohexylamino acid derivative by a batch process using a ruthenium (Ru) single metal on a carbon supported catalyst.

C, 1968, 531; THL, 1991, 32, 3623), a process for producing (S) -cyclohexylamino acid derivatives using a reduced platinum catalyst is known The production yield of the byproduct is increased, and the racemization reaction is easily increased and the optical activity is not maintained.

In the case of a process for producing (S) -cyclohexylamino acid derivatives by hydrogenation using a platinum oxide (PtO ₂ ) catalyst (US Pat. No. 4,788,322; J. Org. Com., 1988, J. Am. Chem. Soc. , 1982, 104, 363, Chem. Berichte, 1986, 119, 2191), the partial racemization reaction easily occurs, and since the reaction time is long in the batch reaction (18 hours) It is difficult to separate the product after hydrogenation and the yield is low.

Synthetic Communications, 1978, 8, 345 discloses a process for hydrogenating Pd (OH) ₂ using a palladium catalyst (Pd (OH) ₂ ) And tends to increase D-isomer production in part.

One aspect of the present invention is to provide a method for preparing an optically pure substituted (S) -cyclohexylamino acid derivative by a continuous hydrogenation process.

One aspect of the present invention is a method for producing an optically pure (S) -cyclohexylamino acid derivative by hydrogenating an (S) -phenylamino acid derivative in the presence of a metal supported catalyst carrying a specific noble metal on an inorganic oxide carrier by a continuous process .

According to one embodiment of the present invention, an (S) -phenyl amino acid derivative represented by the following formula (1) is continuously hydrogenated in a solvent under a metal supported catalyst supported on an inorganic oxide carrier to obtain optically pure (S) -cyclohexylamino acid derivatives can be prepared:

    (1) (2)

Wherein P ¹ and P ² are each independently a hydrogen atom or an amino protecting group, and P ³ is a hydrogen atom or a carboxyl protecting group.

(S) -cyclohexylamino acid derivative represented by the above formula (2) is crystallized in a solvent to increase the optical purity of the optically pure (S) -cyclohexylamino acid derivative, - cyclohexyl amino acid derivative.

The present invention relates to an economical method for producing an optically pure substituted (S) -cyclohexylamino acid derivative in a high purity and a high yield by a simple and environmentally friendly process, and as a method for producing various medicines such as a hepatitis C therapeutic agent, a renin inhibitory agent, or a thrombin inhibitory agent (S) -cyclohexylamino acid derivative which is an intermediate for production can be mass-produced with high optical purity and is industrially useful.

FIG. 1 is a graph showing the yield of the hydrogenation reaction according to the metal supported catalyst. It can be confirmed that the yield of the optically pure (S) -cyclohexylamino acid derivative varies depending on the metal supported catalyst.

One aspect of the present invention provides a method for preparing a substituted (S) -cyclohexylamino acid derivative which is optically active from an (S) -phenyl amino acid derivative substituted by continuous hydrogenation under a certain noble metal supported catalyst.

In one embodiment of the present invention, the substituted (S) -phenyl amino acid derivative compound is hydrogenated in the presence of a metal supported catalyst in which a mixed metal of rhodium (Rh) or rhodium (Ni) (S) -cyclohexylamino acid derivative compound is maintained at a high yield. According to this embodiment, by using a continuous process, the yield is higher than that of the conventional method, and the regeneration and continuous use of the catalyst Optically pure (S) -cyclohexylamino acid derivatives can be prepared in high yields in an economical and environmentally friendly manner without the use of complicated post-treatment processes such as removal of the catalyst by filtration.

In one embodiment of the present invention, the (S) -phenyl amino acid derivative represented by the following formula (1) is continuously hydrogenated in a solvent using a fixed bed reactor packed with a metal supported catalyst to obtain optically pure (S) -cyclohexylamino acid derivative of formula (I).

(1) (2)

Wherein P ¹ and P ² are each independently a hydrogen atom or an amino protecting group, and P ³ is a hydrogen atom or a carboxyl protecting group.

In one embodiment, P ¹ and P ² are each independently a benzyloxycarbonyl group which is a hydrogen or an amino protecting group and / or P ³ is an amine group which is a hydrogen or carboxyl protecting group. For example, P ¹ and P ² may be hydrogen and a benzyloxycarbonyl group, respectively, and P ³ may be hydrogen or an amine group, more specifically hydrogen.

In one embodiment of the present invention, the catalyst comprises a rhodium metal. Rhodium may be used alone or in combination with a metal such as nickel.

The catalyst is supported on the inorganic oxide carrier.

Examples of the inorganic oxide carrier include alumina, silica, silica-alumina, zirconia, titania, zeolite, or molecular sieve. But are not limited thereto. According to one embodiment of the present invention, zirconia may be used as the inorganic oxide carrier. When zirconia is used, one embodiment of the present invention uses a surface area of 10 m ² / g or more as measured by the BET method by nitrogen adsorption. More specifically, zirconia having a BET surface area of 40 to 80 m ² / g can be used.

The carrier particles may be in the form of a circular, cylindrical, granular, or any shape, but in order to have more excellent mechanical properties, Can be used.

Examples of the metal-supported catalyst include alumina, silica, silica-alumina, zirconia, titania, zeolite, or molecular sieve. (Rh) metal or a rhodium (Rh) -nickel (Ni) mixed metal is supported on an inorganic oxide support selected from the group consisting of titanium oxide and titanium oxide. More specifically, for example, rhodium / zirconia (Rh / ZrO 2) or rhodium-nickel / zirconia (Rh-Ni / ZrO 2) is used as the metal-supported catalyst.

In the metal supported catalyst used in one embodiment of the present invention, the metal content can be maintained at 0.1 to 15 wt%, and more specifically 0.5 to 10 wt%. When the content of metal is 0.1 wt% or more, hydrogenation reaction activity and selectivity are further increased. According to an embodiment of the present invention, in consideration of economical aspects of the process, the content of the metal in the metal supported catalyst may be 15 wt% or less.

The metal may be supported on the carrier by any method known in the art such as incipient wetness impregnation, excess water impregnation, spraying or physical mixing.

The supported catalyst should be fired in an air atmosphere or an inert gas atmosphere for 2 hours or more. The firing temperature should be maintained at 300 to 700 ° C, more specifically 300 to 550 ° C. When the firing temperature is higher than 300 ° C, the firing is more likely to occur. In one embodiment of the present invention, the firing temperature can be 700 DEG C or less in consideration of the degree of dispersion of the metal.

After the calcined catalyst is loaded in the fixed bed reactor, the catalyst should be reduced with hydrogen before the reactant is introduced. The reducing conditions are maintained for at least 2 hours at 50 to 500 ° C. depending on the type of the supported metal will be.

In one embodiment of the invention, the hydrogenation reaction is carried out under a metal supported catalyst in a solvent. The solvent should be able to dissolve the starting material compound so that the starting material (S) -phenylamino acid derivative compound can be fed smoothly to the reactor, and it can easily remove the reaction heat generated in the hydrogenation reaction process, ) -Phenylamino acid derivatives and hydrogen. Examples of the solvent include, but are not limited to, 1 to 30% (w / v) potassium hydroxide (KOH) aqueous solution, lithium hydroxide (LiOH) aqueous solution or sodium hydroxide (NaOH) aqueous solution, .

In the production method according to an embodiment of the present invention, the content of the (S) -phenylamino acid derivative in the solvent is 1 to 50% by weight, more specifically 5 to 20% by weight.

In one embodiment of the present invention, the molar ratio of hydrogen to the (S) -phenylamino acid derivative compound may be greater than or equal to 1 to increase the conversion of the substituted (S) -phenylamino acid derivative by hydrogenation, Is not particularly limited. However, in view of the economical efficiency of the production process, the molar ratio of the (S) -phenylamino acid derivative compound to the hydrogen used for hydrogenation can be maintained between 1: 1 and 1:10. At this time, the hydrogen that has passed through the reactor without being used for the reaction can be compressed and recycled to the reactor. Also, the reaction product can be directly separated into desired products according to the reaction conditions, or can be recycled to increase the conversion ratio of the non-conversion reactant and then separate.

In the hydrogenation reaction, the reaction temperature is in the range of 30 to 550 DEG C, more specifically 30 to 150 DEG C, the reaction pressure is in the range of 15 to 4,500 psig, more specifically 500 to 4,500 psig, The speed (LHSV) is in the range of 0.01 to 10 h ^-1 , more specifically in the range of 0.01 to 5 h ^-1 . Hydrogenation conditions can be adjusted to maximize the advantages of the continuous manufacturing process according to one embodiment of the present invention by increasing the yield of the substituted (S) -cyclohexylamino acid derivative product and the deactivation rate of the catalyst.

In one embodiment of the present invention, a fixed bed reaction system is adopted as a method for achieving a higher yield relative to the reaction space time, repeatedly reusing the catalyst without further processing, and greatly simplifying the process. In the fixed bed reaction system, the shape of the reactor, the flow direction of the reactants and the flow direction of the reactants are not particularly limited. However, in order to smoothly contact the reactants, the reactant hydrocarbon and hydrogen flow together from the upper portion to the lower portion of the reactor. A reactor with a trickle-bed type reactor is used.

The reaction product flowing out of the reactor is sent to a device for recovering the solvent, wherein at least some of the solvent is separated from the remaining reaction product. Such a recovery device may be a distillation column, a flash vaporizer, an extractor, or any other device known in the art. The product flowing out from the lower end of the solvent recovery apparatus, or the concentrated reaction product, can be transferred to the purification apparatus and / or the crystallization apparatus, if necessary.

Another aspect of the present invention provides a method for crystallizing an (S) -cyclohexylamino acid derivative to obtain an optically pure (S) -cyclohexylamino acid derivative to increase the optical purity of the (S) -cyclohexylamino acid derivative . This crystallization process can be used to effectively remove the (R) -cyclohexylamino acid derivative which is an optical isomer of the (S) -cyclohexylamino acid derivative which is likely to occur during the hydrogenation of the (S) -phenylamino acid derivative compound according to the present invention .

In one embodiment of the present invention, the crystallization process comprises dissolving a cyclohexyl amino acid derivative in a solvent and adding an additive capable of forming a salt with the cyclohexyl amino acid derivative to form a cyclohexyl amino acid derivative salt (S) -Cyclohexylamino acid or (R) -cyclohexylamino acid derivative salt to obtain an optically pure (e.g., 99.5% ee or more) (S) -phenylamino acid derivative.

Non-limiting examples of the solvent used for the crystallization include an aqueous solution of potassium hydroxide (KOH), an aqueous solution of lithium hydroxide (LiOH), or an aqueous solution of sodium hydroxide (NaOH). In other embodiments, non-limiting examples of solvents used for crystallization include, but are not limited to, aqueous solutions of potassium hydroxide (KOH), lithium hydroxide (LiOH), or sodium hydroxide (NaOH) in an organic solvent such as acetone, acetonitrile, methanol, And mixed solvents in which one or more of them are mixed.

Non-limiting examples of cyclohexyl amino acid derivatives and additives for forming salts include hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ), bromic acid (HBr), hydroiodic acid (HI) acetic acid, glyoxylic acid, o-toluic acid, 4-nitrobenzoic acid, malic acid, malonic acid, oxalic acid, Succinic acid, aspartic acid, crotonic acid, capric acid, trifluoroacetic acid, butyric acid, tartaric acid, tartaric acid, acid, phthalic acid, benzoic acid, citric acid, salicylic acid, mandelic acid, and mixtures thereof.

The additive is used in the range of 0.1 mol to 1000 mol per 1 mol of the cyclohexyl amino acid derivative, more specifically 0.1 mol to 20 mol.

In one embodiment for crystallization, a solution in which a mixture of cyclohexylamino acid derivatives with added additives is dissolved is maintained at a temperature ranging from 30 to 150 DEG C for at least 30 seconds.

In one embodiment of the present invention, a second additive may be further added to further improve the crystallization yield by lowering the solubility of the cyclohexyl amino acid derivative salt. Non-limiting examples of the second additive include sodium chloride, potassium chloride, aluminum chloride, Sodium nitrate, potassium nitrate, sodium nitrate, ammonium carbonate, aluminum sulphate, ammonium sulphate, potassium sulphate, aluminum sulphate, magnesium sulphate, magnesium sulphate, sodium acetate, potassium acetate, sodium oxalate, potassium oxalate, galactose, , Fructose, mannose, sucrose, lactose, maltose, methanol, ethanol, acetone, acetonitrile, propanol or mixtures thereof.

Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited by the examples.

Example

Manufacturing example  1: Rhodium / Zirconia ( Rh / ZrO ₂ ) Preparation of Catalyst

Secondary distilled water was put in a 100 cc capacity flask, and then 17.9 g of rhodium nitrate (Rh (NO ₃ ) ₂ ) was added thereto to prepare an aqueous solution of rhodium nitrate. 100 g (1/8 ") of spherical zirconia was placed in a metal-holding vessel equipped with a motor capable of controlling the rotation speed, and the aqueous solution of rhodium nitrate was uniformly dispersed in the zirconia while rotating the vessel. After the addition of the rhodium nitrate solution is completed, the motor is further rotated at the same speed for about 30 minutes, then the catalyst carrying the rhodium nitrate solution is transferred to a muffle furnace and calcined at 550 ° C. for 6 hours in an air atmosphere. The content of rhodium (Rh) in the catalyst after firing was measured by X-ray fluorescence analysis and found to be 5.0% by weight.

Manufacturing example  2: rhodium-nickel / Zirconia ( Rh - Ni / ZrO ₂ ) Preparation of Catalyst

In the same manner, 1.8 g of nickel nitrate (Ni (NO (NO ₃ ) ₂ ) was added in the same manner as in Example 1, ₃ ) ₂ , 6H ₂ O) was added to prepare a nickel aqueous solution mixed with rhodium nitrate. 100 g (1 / 8˝) of spherical zirconia was put in a metal holding vessel mounted on a motor capable of controlling the rotational speed While rotating the vessel, a solution in which the rhodium nitrate and nickel nitrate were mixed was evenly dispersed in zirconia. After the addition of the solution was completed, the motor was further rotated at the same speed for about 30 minutes, and then rhodium nitrate and nickel nitrate were mixed The catalyst loaded with the solution was transferred to a muffle furnace and fired in an air atmosphere at 550 ° C. for 6 hours. The content of rhodium and nickel in the catalyst after firing was measured by X-ray fluorescence spectrometry to be 4.5% by weight of rhodium, 0.5% Respectively.

Manufacturing example  3: ruthenium / alumina ( Ru / Al ₂ O ₃ ) Preparation of Catalyst

Secondary distilled water is put into a 100 cc capacity flask, and 17.9 g of ruthenium nitrate (Ru (NO ₃ ) ₃ ) is added thereto to prepare an aqueous solution of ruthenium nitrate. 100 g (1/8 ") of spherical alumina was placed in a metal-holding vessel mounted on a motor capable of controlling the rotation speed, and the ruthenium nitrate aqueous solution was uniformly dispersed in alumina while rotating the vessel. After the addition of the ruthenium nitrate solution is completed, the motor is further rotated at the same speed for about 30 minutes, then the catalyst carrying the ruthenium nitrate solution is transferred to the muffle furnace and calcined at 550 ° C. for 6 hours in the air atmosphere. The content of ruthenium (Ru) in the catalyst after firing was measured by X-ray fluorescence analysis and found to be 5.0 wt%.

Manufacturing example  4: platinum / silica ( Pt / SiO ₂ ) Preparation of Catalyst

40 cc of distilled water distilled in a 100 cc capacity flask was charged with 4.21 g of chloroplatinic acid (Aldrich, H ₂ PtCl ₆ xH ₂ O, 47.5% Pt) was added to prepare a chloroplatinic acid aqueous solution. 100 g of silica (specific surface area: 300 m ² / g; pore volume: 0.9 cc / g; average pore diameter: 125 Å) manufactured by Grace Davison Inc. was placed in a metal carrier vessel equipped with a motor capable of controlling the rotation speed, Is rotated at a speed of 50 rpm, the aqueous chloroplatinic acid solution is uniformly dispersed in silica. After the addition of the chloroplatinic acid solution is completed, the motor is further rotated at the same speed for about 30 minutes, then the platinum supported catalyst is transferred to the muffle furnace and calcined at 550 DEG C for 6 hours in the air atmosphere. The content of platinum in the catalyst after firing was measured by X-ray fluorescence analysis and found to be 5.0% by weight.

Example  1-2 and Comparative Example  1-2:

The (S) - Cyclohexyl  Continuous production of amino acid derivative compounds

The hydrogenation reaction of the (S) -phenylamino acid derivative according to Example 1 was carried out using a 10% aqueous solution of potassium hydroxide under the conditions of a temperature of 53 ° C., a hydrogen pressure of 1,000 psig, and an LHSV of 0.09 h ^-1 according to the method described in Production Example 1 The reaction was carried out in a continuous reaction using the catalyst.

The catalyst prepared according to the method described in Production Example 2 was used in Example 2 and the catalyst prepared according to the methods described in Production Examples 3 and 4 was used in Comparative Examples 1 and 2, (S) -cyclohexylamino acid derivative compound was prepared by a continuous reaction as shown in FIG. The types and reaction results of the used catalyst are shown in Table 1 and the reaction yield (%) of each catalyst is shown in Fig.

catalyst Conversion rate,% Selectivity,% Reaction yield,% Example 1 5% Rh / ZrO ₂ 99.9 97.5 97.4 Example 2 5% Rh-Ni / ZrO ₂ 99.7 97.2 96.9 Comparative Example 1 5% Ru / Al ₂ O ₃ 84.2 95.0 79.9 Comparative Example 2 5% Pt / SiO ₂ 41.5 87.1 36.1

Comparative Example  3-4:

(S) - Cyclohexyl  Of amino acid derivative compounds Batch  Produce

As shown in Table 2 below, (S) -cyclohexylamino acid derivative compounds were prepared under the same reaction conditions as in Example 1, except that the kind of catalyst used and the reaction method were different. The catalysts used and the reaction results are shown in Table 2.

catalyst Reaction method Conversion rate,% Selectivity,% Reaction yield,% Comparative Example 3 ¹⁾ 5% Ru / C ^{2 )} Batch 88.2 97.2 85.4 Comparative Example 4 5% 4Pt-Rh / C ^{3 )} Batch 79.5 55.5 44.1

1) Reaction conditions 5 hrs, 850 rpm

2) Degussa products, E 1533 R / W

3) Degussa products, E 101 O / W

(S) - Cyclohexyl  Crystallization of amino acid derivative compounds

(S) -cyclohexyl amino acid derivative compound obtained by using the catalyst of Example 1 in the above-mentioned production method of the (S) -cyclohexyl amino acid derivative compound and 9.47% by weight of the (R) -cyclohexyl amino acid derivative 40 g of aqueous potassium hydroxide solution was added to the reactor, and 10 to 20 g of conc. HCl (35% aqueous HCl solution) was slowly added to cause the pH of the solution to drop below 2. Immediately after the addition of HCl, a white solid was formed in the reactor. The temperature of the reactor was raised to 65 ° C at a rate of 2 ° C per minute and stirred for 1 hour at 65 ° C to allow complete dissolution of the resulting white solid. Again, the reaction was cooled to < RTI ID = 0.0 > 15 C < / RTI > When crystals of (S) -cyclohexylamino acid-hydrochloride salt precipitate during cooling, the temperature of the reactor was maintained at 15 ° C for 3 hours to allow the crystals to fully grow. The precipitated crystals were filtered, vacuum-dried at 50 ° C for 5 hours or more, and analyzed by a flame ionization detector (FID) of liquid chromatograph (60 mx 0.25 mm x 0.25 mm, Beta-DEX column) .

Cyclohexyl amino acid derivative
HCl input per mole (mol) L : D ^{1 )} _- yield(%) 7.2 99.8: 0.2 (99.6% ee) 80

1) The liquid chromatographic peak area ratio of each of (S) -cyclohexylamino acid derivative (L) and (R) -cyclohexylamino acid derivative (D)

Claims (11)

(S) -phenyl amino acid derivative represented by the following formula (1) is reacted with a metal-supported catalyst selected from rhodium / zirconia (Rh / ZrO ₂ ) and rhodium-nickel / zirconia (Rh-Ni / ZrO ₂ ) (S) -cyclohexylamino acid derivative represented by the following formula (2): < EMI ID =

(1) (2)
Wherein P ¹ and P ² are each independently a hydrogen atom or an amino protecting group, and P ³ is a hydrogen atom or a carboxyl protecting group. The method according to claim 1, wherein the metal supporting catalyst is a catalyst in which 0.1 to 15% by weight of rhodium (Rh) metal or rhodium (Ni) mixed metal is supported on a zirconia carrier. delete The method according to claim 1, wherein the solvent is 1 to 30% (w / v) aqueous solution of potassium hydroxide (KOH), lithium hydroxide (LiOH), or sodium hydroxide (NaOH). The method of claim 1, wherein the amino protecting group is a benzyloxycarbonyl group. The method of claim 1, wherein the carboxyl protecting group is an amine group. The process according to claim 1, wherein the continuous hydrogenation is carried out in a fixed-bed reactor in which the metal-supported catalyst is fixed. The process according to claim 1, wherein the molar ratio of the (S) -phenylamino acid derivative to the hydrogen is 1: 1 to 1:10, and the content of the (S) -phenylamino acid derivative in the solvent is 1 to 50% by weight. The method according to claim 1, wherein the (S) -cyclohexylamino acid derivative prepared according to the above method is dissolved in a solvent and an additive capable of forming a salt with the derivative is added to selectively add the (S) ≪ / RTI > further comprising the step of crystallizing. The method of claim 9, wherein the solvent is selected from the group consisting of potassium hydroxide (KOH) aqueous solution, lithium hydroxide (LiOH) aqueous solution, sodium hydroxide (NaOH) aqueous solution, acetone, acetonitrile, methanol, ethanol, The additives may be selected from the group consisting of hydrochloric acid (HCl), sulfuric acid (H ₂ SO ₄ ), nitric acid (HNO ₃ ), bromic acid (HBr), hydroiodic acid (HI), acetic acid, glyoxylic acid, 4-nitrobenzoic acid, malic acid, malonic acid, oxalic acid, succinic acid, aspartic acid, malic acid, But are not limited to, crotonic acid, capric acid, trifluoroacetic acid, butyric acid, tartaric acid, phthalic acid, benzoic acid, Citric acid, salicylic acid, mandelic acid, or a mixture thereof. 11. The method of claim 10, wherein the crystallizing step comprises adding the additive to the additive in the presence of at least one additive selected from the group consisting of sodium chloride, potassium chloride, aluminum chloride, ammonium chloride, ammonium nitrate, potassium nitrate, sodium nitrate, ammonium carbonate, aluminum sulphate, ammonium sulphate, , Sodium acetate, potassium acetate, sodium oxalate, potassium oxalate, galactose, glucose, fructose, mannose, sucrose, lactose, maltose, methanol, ethanol, acetone, acetonitrile, (S) -cyclohexylamino acid derivative is further crystallized by adding a second additive selected from a mixture thereof.

Images