Method for preparing intermediate for synthesizing dipeptidyl peptidase-4 inhibitor

Abstract

The present invention relates to a method for preparing an intermediate of a dipeptidyl peptidase-4 inhibitor and, more specifically, to a method for increasing process efficiency and improving yield of the intermediate by optimizing a metal catalyst and hydrogenation reaction conditions.

Description

Method for preparing an intermediate for the synthesis of a dipeptidyl peptidase-4 inhibitor

[0001] The present invention relates to a method for preparing an intermediate of a dipeptidyl peptidase-4 inhibitor, and more specifically, to a method for increasing process efficiency and improving the yield of the intermediate by optimizing a metal catalyst and hydrogenation reaction conditions.

[0002] Cross-citation with related application(s)

[0003] This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0184155 filed on December 11, 2024, and all contents disclosed in the document of said Korean patent application are incorporated herein as part of this specification.

[0004] Dipeptidyl peptidase-4 (DPP4 or DPPIV), also known as adenosine deaminase complexing protein 2 or CD26, is a protein expressed on the surfaces of most cell types and exists in a soluble form in body fluids such as plasma. DPP4 is a serine exopeptidase that cleaves X-proline or X-alanine dipeptides at the N-terminus of polypeptides and is known to cleave a wide range of substrates, including growth factors, chemokines, neuropeptides, and vasoactive peptides. In particular, DPP4 is known to cleave GLP-1, a protein capable of lowering blood glucose by promoting insulin secretion in the body. Therefore, inhibition of DPP4 can serve as an important mechanism for regulating blood glucose by promoting insulin synthesis and secretion, and inhibiting glucose synthesis.

[0005] The dipeptidyl peptidase-4 inhibitor disclosed in International Application WO2006 / 104356 (the compound of Formula 1 of International Application WO2006 / 104356) is a compound confirmed to exhibit excellent inhibitory activity against DPP4. Therefore, it has been reported that the above DPP4 inhibitor can be utilized for the treatment and prevention of diabetes, obesity, etc. caused by DPP4. International Application WO2006 / 104356 also discloses a compound of Formula 4 below as an essential intermediate of the above DPP4 inhibitor, and discloses a method for preparing a DPP4 inhibitor from Formula 4.

[0006] [Chemical Formula 4]

[0007]

[0008] Meanwhile, the compound of Formula 2 may be used to prepare the compound of Formula 4 above, and Korean Registered Patent No. 10-1378984 discloses a method of performing a hydrogenation reaction on the compound of Formula 1 to prepare the compound of Formula 2 (the compounds of Formulas 1 and 2 are defined in this specification). Specifically, in the above Korean Registered Patent, a hydrogenation reaction is performed using a Palladium hydroxide (Pd(OH)2) catalyst to convert the nitrile group of the compound of Formula 1 into an amine. However, it has been confirmed that the above process has problems such as inconsistent product yield, excessive generation of impurities which impairs product quality, significantly low reaction conversion rates, and excessive delays in process time. Overall, since the conventionally known process is not suitable for mass production of intermediates of DPP4 inhibitors, a process capable of guaranteeing high yield, efficiency, and consistent quality is required.

[0009] [Prior Art Literature]

[0010] [Patent Literature]

[0011] (Patent Document 1) Patent Document 1. International Patent Publication No. WO2006 / 104356

[0012] (Patent Document 2) Patent Document 2. Korean Registered Patent Publication No. 10-1378984

[0013] The present invention was devised to solve the problems of the conventional intermediate manufacturing process of the aforementioned DPP4 inhibitor, and was completed by identifying process conditions that enable mass production of the intermediate by ensuring high yield and quality reproducibility of the intermediate and increasing process efficiency.

[0014] Accordingly, the main objective of the present invention is to provide a method for producing a compound of Formula 2, comprising the step of performing a hydrogenation reaction on a compound of Formula 1 to obtain a compound of Formula 2, wherein the method has improved yield, quality, reproducibility, efficiency, and / or production economics compared to a conventional process.

[0015] [Chemical Formula 1]

[0016]

[0017] [Chemical Formula 2]

[0018]

[0019] In addition, another objective of the present invention is to provide a method for producing a compound of Formula 4, comprising the step of reacting a compound of Formula 2 produced by the above-described method with a compound of Formula 3.

[0020] [Chemical Formula 3]

[0021]

[0022] [Chemical Formula 4]

[0023]

[0024] The definition of each substituent of the above chemical formulas is as defined in this specification.

[0025] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0026] The present disclosure is summarized as follows:

[0027] 1. A method for preparing a compound of Formula 2, comprising the step of performing a hydrogenation reaction on a compound of Formula 1 to obtain a compound of Formula 2:

[0028] [Chemical Formula 1]

[0029]

[0030] [Chemical Formula 2]

[0031]

[0032] (In the above chemical formulas,

[0033] P1 is an amine protecting group;

[0034] P2 is a benzyl group, methyl group, ethyl group, i-propyl group, or t-butyl group)

[0035] A method for manufacturing, wherein the above hydrogenation reaction is carried out using a palladium hydroxide catalyst, and the palladium hydroxide catalyst satisfies one or more of the following characteristics:

[0036] (a) The weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 wt% or less; and

[0037] (b) The molar ratio of metallic palladium to the total molar amount of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 mol% or less.

[0038]

[0039] 2. In the above Paragraph 1,

[0040] P1 is a manufacturing method in which Boc, Cbz, or Fmoc is used.

[0041]

[0042] 3. In any one of the preceding paragraphs,

[0043] A method of preparation in which P2 is an i-propyl group or a t-butyl group.

[0044]

[0045] 4. In any one of the preceding paragraphs,

[0046] A method for manufacturing, wherein the amount of the above palladium hydroxide catalyst used is 0.01 to 0.2 wt% relative to the weight of the compound of Formula 1.

[0047]

[0048] 5. In any one of the preceding paragraphs,

[0049] A manufacturing method in which the above hydrogenation reaction is carried out by pressurizing hydrogen gas to a pressure of 60 to 120 psi.

[0050]

[0051] 6. In any one of the preceding paragraphs,

[0052] A manufacturing method comprising further a step of dissolving the reaction product obtained from the above step in an acid and then washing the aqueous layer of the reaction product with an organic solvent.

[0053]

[0054] 7. In the above paragraph 6,

[0055] A manufacturing method comprising the step of adding a basic solution to the above aqueous layer and then extracting a compound of Formula 2 with an ether-based solvent.

[0056]

[0057] 8. A method for preparing a compound of Formula 4, comprising the step of reacting a compound of Formula 2, prepared by the method of any one of the preceding claims, with a compound of Formula 3:

[0058] [Chemical Formula 2]

[0059]

[0060] [Chemical Formula 3]

[0061]

[0062] [Chemical Formula 4]

[0063]

[0064] (In the above chemical formulas,

[0065] P1 and P2 are as defined in Paragraph 1;

[0066] P3 is a benzyl group, methyl group, ethyl group, i-propyl group, or t-butyl group;

[0067] R1 to R4 are each independently hydrogen, a halogen, or a substituted or unsubstituted C1-C4 alkyl;

[0068] G1O is the leaving group.)

[0069]

[0070] 9. In the above paragraph 8,

[0071] A method for manufacturing the above G1O, which is trilate, mesylate, tosylate, besylate, or nonaplate.

[0072]

[0073] 10. In the above paragraph 8 or 9,

[0074] A method of manufacturing in which R1 and R2 are hydrogen, and R3 and R4 are fluorine.

[0075] This specification relates to a method for preparing an intermediate for the synthesis of a dipeptidyl peptidase-4 inhibitor, and its main purpose is to provide a manufacturing process that offers superior yield, quality, reproducibility, efficiency, and / or production economics compared to conventional processes.

[0076] In this specification, the dipeptidyl peptidase-4 inhibitor may be a compound represented by Chemical Formula 4.

[0077] In this specification, the intermediate may be a compound represented by Chemical Formula 2.

[0078] The process of the present invention will be described in more detail below.

[0079] In the following, unless otherwise noted, “compound represented by chemical formula N” may be simply abbreviated as “compound of chemical formula N” or “compound N”.

[0080]

[0081] Manufacturing process of the present invention

[0082] A method for preparing a compound of Formula 2 is provided, comprising the step of performing a hydrogenation reaction on a compound of Formula 1 to obtain a compound of Formula 2:

[0083] [Chemical Formula 1]

[0084]

[0085] [Chemical Formula 2]

[0086]

[0087] (In the above chemical formulas,

[0088] P1 can be an amine protecting group;

[0089] P2 can be a benzyl group, methyl group, ethyl group, i-propyl group, or t-butyl group)

[0090] In one example, P1 may be Boc (butyloxycarbonyl), Cbz (benzyloxycarbonyl), or Fmoc (9-fluorenylmethyloxycarbonyl). Preferably, P1 may be Boc.

[0091] In one example, P2 may be an i-propyl group or a t-butyl group, preferably a t-butyl group.

[0092] In one example, the compound represented by the above chemical formula 1 may be (S)-t-butyl 3-(t-butoxycarbonylamino)-3-cyanopropanoate ((S)-tert-butyl 3-(tert-butoxycarbonylamino)-3-cyanopropanoate).

[0093] In one example, the compound represented by the above chemical formula 2 may be t-butyl (3S)-4-amino-3-[(t-butoxycarbonyl)amino]butanoate (tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]butanoate).

[0094] In one example, the hydrogenation reaction may refer to a chemical transformation reaction (e.g., a chemical reaction between hydrogen and another compound or element) that adds hydrogen (H2 or an H atom) to a substrate (e.g., a compound of Formula 1).

[0095] The method of the above hydrogenation reaction is not limited to specific means, and any method capable of adding hydrogen to the substrate can be used without restriction. For example, it can be carried out by pressurizing hydrogen gas to react, or by reacting the substrate with other hydrogen donors.

[0096] In one example, the hydrogenation reaction may be for converting a nitrile group of a compound of Formula 1 into an amine group, and more specifically, may be for converting a nitrile group of a compound of Formula 1 into a primary amine group.

[0097] In one example, the hydrogenation reaction can be carried out in the presence of a metal catalyst. That is, the hydrogenation reaction can be carried out using a metal catalyst.

[0098] The metal catalyst for the above hydrogenation reaction is not limited to a specific type and can be used without limitation as long as it is a catalyst capable of promoting the reaction between hydrogen and the substrate; however, in one example of the present invention, the metal catalyst may be a palladium-based, platinum-based, rhodium-based, and ruthenium-based catalyst. More specifically, in one example, the metal catalyst may be a palladium catalyst, a nickel(I) chloride catalyst, a platinum(IV) oxide catalyst, or a palladium hydroxide (Pd(OH)2) catalyst, but is not limited thereto.

[0099] In one example, the metal catalyst may be a palladium hydroxide catalyst (also briefly referred to as a “Pd(OH)2 catalyst”).

[0100] In the present invention, the type or composition of the palladium hydroxide catalyst is not specifically limited, and any catalyst containing palladium hydroxide (Pd(OH)2) may be included without limitation.

[0101] In one example, the palladium hydroxide catalyst may include metallic palladium (Pd) in addition to Pd(OH)2. Additionally, the palladium hydroxide catalyst may include palladium oxide (PdO) in addition to Pd(OH)2 and / or Pd. Furthermore, in one example, the palladium hydroxide catalyst according to the present invention may further include additional elements or particles in addition to the above components.

[0102] In one example, the palladium hydroxide catalyst may further include one or more components selected from the group consisting of C, O, Cl, Al, and Si in addition to the aforementioned Pd(OH)2, Pd, and / or PdO. The constituent elements of such a catalyst can be observed through mapping analysis to analyze the elemental composition contained in the catalyst. The mapping analysis method is not limited to a specific type and may be used without limitation as long as it is a method performed in the art for the analysis of the constituent elements of a material (e.g., microscopic analysis, SEM-EDS, TEM-EDS, EPMA, XRF mapping, etc.). In one example, one or more components selected from the group consisting of C, O, Cl, Al, and Si may be distributed on the palladium hydroxide catalyst (or on the support) in the form of particles with a size of several μm. In one example, the palladium hydroxide catalyst may include metallic palladium, and the metallic palladium may be present and distributed throughout the catalyst (or on the support).

[0103] In the present invention, the shape of the metal catalyst is not limited to a specific type, but in one example, the particle shape of the metal catalyst may be angular or needle-shaped, or may be a mixture of angular particles and needle-shaped particles.

[0104] In one example, the metal catalyst may be supported on a support. The support is not limited to a specific type and may be included without limitation as long as it can physically fix the metal catalyst; however, in one example, the support may be a carbon support.

[0105] In one example, the metal catalyst may be a palladium hydroxide catalyst (Pd(OH)2 / C) supported on a carbon support.

[0106] In one example, the metal catalyst may be a palladium hydroxide catalyst, and the palladium hydroxide catalyst may satisfy one or more of the following features:

[0107] (a) The weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide (e.g., palladium(II) oxide) of the above palladium hydroxide catalyst is 20 wt% or less; and

[0108] (b) The molar ratio of metallic palladium to the total molar amount of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 mol% or less.

[0109] In one example, the weight ratio or molar ratio of the metallic palladium can be confirmed through XRD (X-ray Diffraction) analysis. For instance, the weight ratio or molar ratio of the metallic palladium can be measured according to the method described in Experimental Examples 1-2 of the present invention.

[0110] More specifically, in one example, the weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst may be 20 wt% or less, 19 wt% or less, 18 wt% or less, 17 wt% or less, 16 wt% or less, 15 wt% or less, 14 wt% or less, 13 wt% or less, 12 wt% or less, 11 wt% or less, 10 wt% or less, 9 wt% or less, less than 9 wt%, 8 wt% or less, 7 wt% or less, or 6 wt% or less. Even if a lower limit value for the weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst is not specified, those skilled in the art will clearly understand the present invention and carry it out for the purpose. For example, if the above palladium hydroxide catalyst comprises metallic palladium, it will be understood that the lower limit of the weight ratio of the metallic palladium is not 0 wt%, but a value greater than 0 wt%. However, as a non-limiting example, in one example, the weight ratio of the metallic palladium to the total weight of the metallic palladium and palladium oxide may be 0 wt% or more, greater than 0 wt%, 0.001 wt% or more, 0.01 wt% or more, 0.05 wt% or more, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 5.5 wt% or more, or 6 wt% or more. The weight ratio of the metallic palladium may correspond to any range defined by any combination of the upper and lower limits described above.

[0111] More specifically, in one example, the weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst is 0.001 to 20 wt%, 0.001 to 18 wt%, 0.001 to 16 wt%, 0.001 to 16 wt%, 0.001 to 15 wt%, 0.001 to 14 wt%, 0.001 to 13 wt%, 0.001 to 12 wt%, 0.001 to 11 wt%, 0.001 to 10 wt%, 0.001 to 9 wt%, 0.001 to 8 wt%, 0.001 to 7 wt%, 0.001 to 6 wt%, 0.01 to 20 wt%, 0.01 to 18 wt%, 0.01 to 16 wt%, 0.01 to 16 wt%, 0.01 to 15 wt%, 0.01 to 14 wt%, 0.01 to 13 wt%, 0.01 to 12 wt%, 0.01 to 11 wt%, 0.01 to 10 wt%, 0.01 to 9 wt%, 0.01 to 8 wt%, 0.01 to 7 wt%, 0.01 to 6 wt%, 0.1 to 20 wt%, 0.1 to 18 wt%, 0.1 to 16 wt%, 0.1 to 16 wt%, 0.1 to 15 wt%, 0.1 to 14 wt%, 0.1 to 13 wt%, 0.1 to 12 wt%, 0.1 to 11 wt%, 0.1 to 10 wt%, 0.1 to 9 wt%, 0.1 to 8 wt%, 0.1 to 7 wt%, 0.1 to 6 wt%, 1 to 20 wt%, 1 to 18 wt%, 1 to 16 wt%, 1 to 15 wt%, 1 to 14 wt%, 1 to 13 wt%, 1 to 12 wt%, 1 to 11 wt%, 1 to 10 wt%, 1 to 9 wt%, 1 to 8 wt%, 1 to 7 wt%, 1 to 6 wt%, 3 to 20 wt%, 3 to 18 wt%, 3 to 16 wt%, 3 to 15 wt%, 3 to 14 wt%, 3 to 13 wt%, 3 to 12 wt%, 3 to 11 wt%, 3 to 10 wt%, 3 to 9 wt%, 3 to 8 wt%, 3 to 7 wt%, 3 to 6 wt%, 5 to 20 wt%, 5 to 18 wt%, 5 to 16 wt%, 5 to 15 wt%, 5 to 14 wt%, 5 to 13 wt%, 5 to 12 wt%, 5 to 11 wt%, 5 to 10 wt%, 5 to 9 wt%, 5 to 8 wt%, 5 to 7 wt%, 5 to 6 wt%, 6 to 20 wt%, 6 to 18 wt%, 6 to 16 wt%, 6 to 15 wt%, 6 to 14 wt%, 6 to 13 wt%, 6 to 12 wt%, 6 to 11 wt%, 6 to 10 wt%, 6 to 9 wt%, 6 to 8 It may be wt%, or 6 to 7 wt%.

[0112] In one example, the molar ratio of metallic palladium to the total moles of metallic palladium and palladium oxide of the palladium hydroxide catalyst may be 20 mol% or less, 19 mol% or less, 18 mol% or less, 17 mol% or less, 16 mol% or less, 15 mol% or less, 14 mol% or less, 13 mol% or less, 12 mol% or less, 11 mol% or less, 10 mol% or less, 9 mol% or less, 8 mol% or less, or 7 mol% or less. Even if a lower limit value of the molar ratio of metallic palladium to the total moles of metallic palladium and palladium oxide of the palladium hydroxide catalyst is not specified, those skilled in the art will clearly understand the present invention and carry it out as intended. For example, if the palladium hydroxide catalyst contains metallic palladium, it will be understood that the lower limit value of the molar ratio of metallic palladium is not 0 mol%, but a value greater than 0 mol%. However, as a non-limiting example, in one example, the molar ratio of metallic palladium to the total moles of metallic palladium and palladium oxide may be 0 mol% or more, greater than 0 mol%, 0.001 mol% or more, 0.01 mol% or more, 0.05 mol% or more, 0.1 mol% or more, 0.5 mol% or more, 1 mol% or more, 2 mol% or more, 3 mol% or more, 4 mol% or more, 5 mol% or more, 5.5 mol% or more, 6 mol% or more, or 7 mol% or more. In one example, the molar ratio of metallic palladium may fall within any range defined by any combination of the upper and lower limits described above.

[0113] More specifically, in one example, the molar ratio of metallic palladium to the total molar amount of metallic palladium and palladium oxide of the palladium hydroxide catalyst is 0.001 to 20 mol%, 0.001 to 18 mol%, 0.001 to 16 mol%, 0.001 to 16 mol%, 0.001 to 15 mol%, 0.001 to 14 mol%, 0.001 to 13 mol%, 0.001 to 12 mol%, 0.001 to 11 mol%, 0.001 to 10 mol%, 0.001 to 9 mol%, 0.001 to 8 mol%, 0.001 to 7 mol%, 0.01 to 20 mol%, 0.01 to 18 mol%, 0.01 to 16 mol%, 0.01 to 16 mol%, 0.01 to 15 mol%, 0.01 to 14 mol%, 0.01 to 13 mol%, 0.01 to 12 mol%, 0.01 to 11 mol%, 0.01 to 10 mol%, 0.01 to 9 mol%, 0.01 to 8 mol%, 0.01 to 7 mol%, 0.1 to 20 mol%, 0.1 to 18 mol%, 0.1 to 16 mol%, 0.1 to 16 mol%, 0.1 to 15 mol%, 0.1 to 14 mol%, 0.1 to 13 mol%, 0.1 to 12 mol%, 0.1 to 11 mol%, 0.1 to 10 mol%, 0.1 to 9 mol%, 0.1 to 8 mol%, 0.1 to 7 mol%, 1 to 20 mol%, 1 to 18 mol%, 1 to 16 mol%, 1 to 15 mol%, 1 to 14 mol%, 1 to 13 mol%, 1 to 12 mol%, 1 to 11 mol%, 1 to 10 mol%, 1 to 9 mol%, 1 to 8 mol%, 1 to 7 mol%, 3 to 20 mol%, 3 to 18 mol%, 3 to 16 mol%, 3 to 15 mol%, 3 to 14 mol%, 3 to 13 mol%, 3 to 12 mol%, 3 to 11 mol%, 3 to 10 mol%, 3 to 9 mol%, 3 to 8 mol%, 3 to 7 mol%, 5 to 20 mol%, 5 to 18 mol%, 5 to 16 mol%, 5 to 15 mol%, 5 to 14 mol%, 5 to 13 mol%, 5 to 12 mol%, 5 to 11 mol%, 5 to 10 mol%, 5 to 9 mol%, 5 to 8 mol%, 5 to 7 mol%, 6 to 20 mol%, 6 to 18 mol%, 6 to 16 mol%, 6 to 15 mol%, 6 to 14 mol%, 6 to 13 mol%, 6 to 12 mol%, 6 to 11 mol%, 6 to 10 mol%, 6 to 9 mol%, 6 to 8 mol%, 6 to 7 mol%, 7 to 20 mol%, 7 to 18 mol%, 7 to 16 mol%, 7 to 15 mol%, 7 to 14 mol%, 7 to 13 mol%, 7 to 12 mol%, It may be 7 to 11 mol%, 7 to 10 mol%, 7 to 9 mol%, or 7 to 8 mol%.

[0114] In one example, the weight ratio of palladium oxide to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst may be 80 wt% or more, 81 wt% or more, 82 wt% or more, 83 wt% or more, 84 wt% or more, 85 wt% or more, 86 wt% or more, 87 wt% or more, 88 wt% or more, 89 wt% or more, 90 wt% or more, 91 wt% or more, 92 wt% or more, 93 wt% or more, or 94 wt% or more. In one example, the weight ratio of palladium oxide to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst may be less than 100%, 99 wt% or less, 98 wt% or less, 97 wt% or less, 96 wt% or less, 95 wt% or less, 94 wt% or less, 93 wt% or less, or 92 wt% or less. The weight ratio of palladium oxide may fall within any range defined by any combination of the upper and lower limits described above.

[0115] More specifically, in one example, the weight ratio of palladium oxide to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst is 80 or more and less than 100 wt%, 81 or more and less than 100 wt%, 82 or more and less than 100 wt%, 83 or more and less than 100 wt%, 84 or more and less than 100 wt%, 85 or more and less than 100 wt%, 86 or more and less than 100 wt%, 87 or more and less than 100 wt%, 88 or more and less than 100 wt%, 89 or more and less than 100 wt%, 90 or more and less than 100 wt%, 91 or more and less than 100 wt%, 92 or more and less than 100 wt%, 93 or more and less than 100 wt%, 94 or more and less than 100 wt%, and 80 or more and 99 wt% or less. 81% or more and 99 wt% or less, 82% or more and 99 wt% or less, 83% or more and 99 wt% or less, 84% or more and 99 wt% or less, 85% or more and 99 wt% or less, 86% or more and 99 wt% or less, 87% or more and 99 wt% or less, 88% or more and 99 wt% or less, 89% or more and 99 wt% or less, 90% or more and 99 wt% or less, 91% or more and 99 wt% or less, 92% or more and 99 wt% or less, 93% or more and 99 wt% or less, 94% or more and 99 wt% or less, 80% or more and 98 wt% or less, 81% or more and 98 wt% or less, 82% or more and 98 wt% or less, 83% or more and 98 wt% or less, 84% or more and 98 wt% or less, 85% or more and 98 wt% or less, 86% or more 98 wt% or less, 87 or more and 98 wt% or less, 88 or more and 98 wt% or less, 89 or more and 98 wt% or less, 90 or more and 98 wt% or less, 91 or more and 98 wt% or less, 92 or more and 98 wt% or less, 93 or more and 98 wt% or less, 94 or more and 98 wt% or less, 80 or more and 96 wt% or less, 81 or more and 96 wt% or less, 82 or more and 96 wt% or less, 83 or more and 96 wt% or less, 84 or more and 96 wt% or less, 85 or more and 96 wt% or less, 86 or more and 96 wt% or less, 87 or more and 96 wt% or less,88 or more and 96 wt% or less, 89 or more and 96 wt% or less, 90 or more and 96 wt% or less, 91 or more and 96 wt% or less, 92 or more and 96 wt% or less, 93 or more and 96 wt% or less, 94 or more and 96 wt% or less, 80 or more and 94 wt% or less, 81 or more and 94 wt% or less, 82 or more and 94 wt% or less, 83 or more and 94 wt% or less, 84 or more and 94 wt% or less, 85 or more and 94 wt% or less, 86 or more and 94 wt% or less, 87 or more and 94 wt% or less, 88 or more and 94 wt% or less, 89 or more and 94 wt% or less, 90 or more and 94 wt% or less, 91 or more and 94 wt% or less, 92 or more and 94 wt% or less, or 93 or more It may be 94 wt% or less.

[0116] In one example, the molar ratio of palladium oxide to the total molar amount of metallic palladium and palladium oxide of the palladium hydroxide catalyst may be 80 mol% or more, 81 mol% or more, 82 mol% or more, 83 mol% or more, 84 mol% or more, 85 mol% or more, 86 mol% or more, 87 mol% or more, 88 mol% or more, 89 mol% or more, 90 mol% or more, or 91 mol% or more. In one example, the weight ratio of palladium oxide to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst may be less than 100 mol%, 99 mol% or less, 98 mol% or less, 97 mol% or less, 96 mol% or less, 95 mol% or less, 94 mol% or less, 93 mol% or less, 92 mol% or less, or 91 mol% or less. The weight ratio of the above palladium oxide may fall within any range defined by any combination of the upper and lower limits described above.

[0117] More specifically, in one example, the weight ratio of palladium oxide to the total weight of metallic palladium and palladium oxide of the palladium hydroxide catalyst is 80 or more and less than 100 mol%, 81 or more and less than 100 mol%, 82 or more and less than 100 mol%, 83 or more and less than 100 mol%, 84 or more and less than 100 mol%, 85 or more and less than 100 mol%, 86 or more and less than 100 mol%, 87 or more and less than 100 mol%, 88 or more and less than 100 mol%, 89 or more and less than 100 mol%, 90 or more and less than 100 mol%, 91 or more and less than 100 mol%, 80 or more and 99 mol% or less, 81 or more and 99 mol% or less, 82 or more and 99 mol% or less, 83 or more and 99 mol% or less, 84 or more and 99 mol% or less, and 85 or more and 99 mol%. 86 or more and 99 mol% or less, 87 or more and 99 mol% or less, 88 or more and 99 mol% or less, 89 or more and 99 mol% or less, 90 or more and 99 mol% or less, 91 or more and 99 mol% or less, 80 or more and 98 mol% or less, 81 or more and 98 mol% or less, 82 or more and 98 mol% or less, 83 or more and 98 mol% or less, 84 or more and 98 mol% or less, 85 or more and 98 mol% or less, 86 or more and 98 mol% or less, 87 or more and 98 mol% or less, 88 or more and 98 mol% or less, 89 or more and 98 mol% or less, 90 or more and 98 mol% or less, 91 or more and 98 mol% or less, 80 or more and 96 mol% or less, 81 or more and 96 mol% or less, 82 or more and 96 mol% or less, 83 or more and 96 mol% or less, 84 or more and 96 mol% or less, 85 or more and 96 mol% or less, 86 or more and 96 mol% or less, 87 or more and 96 mol% or less, 88 or more and 96 mol% or less, 89 or more and 96 mol% or less, 90 or more and 96 mol% or less, 91 or more and 96 mol% or less, 80 or more and 94 mol% or less, 81 or more and 94 mol% or less,82 or more and 94 mol% or less, 83 or more and 94 mol% or less, 84 or more and 94 mol% or less, 85 or more and 94 mol% or less, 86 or more and 94 mol% or less, 87 or more and 94 mol% or less, 88 or more and 94 mol% or less, 89 or more and 94 mol% or less, 90 or more and 94 mol% or less, 91 or more and 94 mol% or less, 80 or more and 93 mol% or less, 81 or more and 93 mol% or less, 82 or more and 93 mol% or less, 83 or more and 93 mol% or less, 84 or more and 93 mol% or less, 85 or more and 93 mol% or less, 86 or more and 93 mol% or less, 87 or more and 93 mol% or less, 88 or more and 93 mol% or less, 89 or more and 93 mol% or less, 90 or more and 93 mol% or less, or 91 or more and 93 mol% or less there is.,

[0118] Through experimental examples of the present invention, it was confirmed that in the manufacturing method according to one embodiment of the present invention, when a palladium hydroxide catalyst satisfying conditions (a) and / or (b) is used in the hydrogenation reaction, the hydrogenation reaction time is reduced / reduced or the yield of the compound of Formula 2 is increased compared to when a palladium hydroxide catalyst that does not satisfy both conditions (a) or (b) is used (e.g., when the weight ratio of the metal palladium is 21 wt% or 28 wt%, or the molar ratio is 23 mol% or 31 mol%).

[0119] In one example, the reduction in the hydrogenation reaction time can be achieved by increasing the conversion rate of the nitrile group of the compound of Formula 1 to the amine.

[0120] In one example, when a palladium hydroxide catalyst satisfying conditions (a) and / or (b) is used in the hydrogenation reaction, the reaction time may be 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, 0.5 times or less, 0.4 times or less, 0.3 times or less, 0.3 times or less, 0.25 times or less, 0.2 times or less, 0.18 times or less, 0.15 times or less, or 0.1 times or less than the reaction time when a palladium hydroxide catalyst not satisfying conditions (a) or (b) is used.

[0121] For example, in one example, when a palladium hydroxide catalyst satisfying the conditions of (a) and / or (b) is used in the hydrogenation reaction, the reaction time may be 15 hours or less, 14 hours or less, 13 hours or less, 12 hours or less, 11 hours or less, 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or less, 6 hours or less, 5 hours or less, or 4 hours or less.

[0122] In one example, when a palladium hydroxide catalyst satisfying conditions (a) and / or (b) is used in the hydrogenation reaction, the yield of the compound of Formula 2 may be 1.01 times or more, 1.02 times or more, 1.05 times or more, 1.10 times or more, 1.15 times or more, 1.2 times or more, 1.25 times or more, 1.3 times or more, 1.35 times or more, 1.40 times or more, 1.45 times or more, 1.5 times or more, or 2 times or more than the yield when a palladium hydroxide catalyst not satisfying conditions (a) or (b) is used.

[0123] In one example, when a palladium hydroxide catalyst satisfying conditions (a) and / or (b) is used in the hydrogenation reaction, the yield of the compound of Formula 2 is 80% or more, 81% or more, 82% or more, 82.2% or more, 82.4% or more, 82.6% or more, 82.8% or more, 83% or more, 83.2% or more, 83.4% or more, 83.6% or more, 83.8% or more, 84% or more, 84.2% or more, 84.4% or more, 84.6% or more, 84.8% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, relative to the theoretical yield (the theoretically obtainable yield of the compound of Formula 2). It may be 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, or 100%.

[0124] In addition, through experimental examples of the present invention, it was confirmed that in the manufacturing method according to one embodiment of the present invention, when a palladium hydroxide catalyst satisfying conditions (a) and / or (b) is used in the hydrogenation reaction, the amount of impurities produced is reduced compared to when a palladium hydroxide catalyst that does not satisfy both conditions (a) or (b) is used (e.g., when the weight ratio of the metal palladium is 21 wt% or 28 wt%, or the molar ratio is 23 mol% or 31 mol%).

[0125] In one example, the above impurity may be UK1 represented by the following chemical formula.

[0126]

[0127] In one example, the degree of generation of the UK1 can be confirmed by measuring the relative ratio of the peak area of ​​the UK1 to the total peak area or the peak area of ​​the target compound, i.e., the PAR% (peak area ratio), through HPLC (High Performance Liquid Chromatography) analysis or GC (Gas Chromatography) analysis.

[0128] In one example, in the manufacturing method of the present invention, the degree of generation of the UK1 may be 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less, 0.01 to 0.09%, 0.01 to 0.08%, 0.01 to 0.07%, 0.01 to 0.06%, or 0.01 to 0.05% based on the relative ratio of the peak area of ​​the UK1 to the total peak area in HPLC analysis or GC analysis.

[0129] In one example, the hydrogenation reaction may be carried out in an acidic environment. Accordingly, in one example, the hydrogenation reaction may be carried out using a solvent that provides a weakly acidic environment. More specifically, in one example, the hydrogenation reaction may be carried out using a weakly acidic solvent. The weakly acidic solvent is not limited to a specific type, but in one example, the weakly acidic solvent may be an acetic acid (AcOH) solvent, or other acidic solvent having properties similar to acetic acid, such as an inorganic acid like hydrochloric acid or sulfuric acid, or an organic solvent like formic acid.

[0130] In one example, the amount of weakly acidic solvent (e.g., acetic acid) used in the hydrogenation reaction is 1 to 20 mL / g, 1 to 19 mL / g, 1 to 18 mL / g, 1 to 17 mL / g, 1 to 16 mL / g, 1 to 15 mL / g, 1 to 14 mL / g, 1 to 13 mL / g, 1 to 12 mL / g, 1 to 11 mL / g, 1 to 10 mL / g, 1 to 9 mL / g, 1 to 8 mL / g, 1 to 7 mL / g, 3 to 20 mL / g, 3 to 19 mL / g, 3 to 18 mL / g, 3 to 17 mL / g, 3 to 16 mL / g, 3 to 15 mL / g, and 3 to 14 mL / g relative to the weight of the substrate (e.g., a compound of Formula 1). mL / g, 3 to 13 mL / g, 3 to 12 mL / g, 3 to 11 mL / g, 3 to 10 mL / g, 3 to 9 mL / g, 3 to 8 mL / g, 3 to 7 mL / g, 4 to 20 mL / g, 4 to 19 mL / g, 4 to 18 mL / g, 4 to 17 mL / g, 4 to 16 mL / g, 4 to 15 mL / g, 4 to 14 mL / g, 4 to 13 mL / g, 4 to 12 mL / g, 4 to 11 mL / g, 4 to 10 mL / g, 4 to 9 mL / g, 4 to 8 mL / g, 4 to 7 mL / g, 5 to 20 mL / g, 5 to 19 mL / g, 5 to 18 mL / g, 5 to 17 mL / g, 5 to 16 mL / g, 5 to 15 mL / g, 5 to 14 mL / g, 5 to 13 mL / g, 5 to 12 mL / g, 5 to 11 mL / g, 5 to 10 mL / g, 5 to 9 mL / g, 5 to 8 mL / g, 5 to 7 mL / g, 6 to 20 mL / g, 6 to 19 mL / g, 6 to 18 mL / g, 6 to 17 mL / g, 6 to 16 mL / g, 6 to 15 mL / g, 6 to 14 mL / g, 6 to 13 mL / g, 6 to 12 mL / g, 6 to 11 mL / g, 6 to 10 mL / g,It may be 6 to 9 mL / g, 6 to 8 mL / g, 6 to 7 mL / g, 6.5 to 7.5 mL / g, 7 mL / g, 7 to 20 mL / g, 7 to 19 mL / g, 7 to 18 mL / g, 7 to 17 mL / g, 7 to 16 mL / g, 7 to 15 mL / g, 7 to 14 mL / g, 7 to 13 mL / g, 7 to 12 mL / g, 7 to 11 mL / g, 7 to 10 mL / g, 7 to 9 mL / g, 7 to 8 mL / g, 7 to 7 mL / g, or 7 to 7.5 mL / g.

[0131] In one example, in the hydrogenation reaction, the metal catalyst may be used (added) in an amount of 0.2 wt% or less, 0.19 wt% or less, 0.18 wt% or less, 0.17 wt% or less, 0.16 wt% or less, 0.15 wt% or less, 0.14 wt% or less, 0.13 wt% or less, 0.12 wt% or less, 0.11 wt% or less, or 0.1 wt% or less relative to the weight of the substrate (e.g., a compound of Formula 1). Although the present invention may be appropriately carried out even if a lower limit value for the amount of the metal catalyst used is not specified, in one example, the metal catalyst may be used in an amount of 0.001 wt% or more, 0.01 wt% or more, 0.015 wt% or more, 0.02 wt% or more, 0.03 wt% or more, 0.04 wt% or more, 0.05 wt% or more, 0.06 wt% or more, 0.07 wt% or more, 0.08 wt% or more, or 0.09 wt% or more relative to the weight of the substrate (e.g., a compound of Formula 1). The amount of the metal catalyst used may fall within any range defined by any combination of the upper and lower limits described above.

[0132] More specifically, in one example, the metal catalyst is present in an amount of 0.001 to 0.2 wt%, 0.001 to 0.19 wt%, 0.001 to 0.18 wt%, 0.001 to 0.17 wt%, 0.001 to 0.16 wt%, 0.001 to 0.15 wt%, 0.001 to 0.14 wt%, 0.001 to 0.13 wt%, 0.001 to 0.12 wt%, 0.001 to 0.11 wt%, 0.001 to 0.1 wt%, 0.01 to 0.2 wt%, 0.01 to 0.19 wt%, and 0.01 to 0.18 wt% relative to the weight of the substrate (e.g., a compound of Formula 1). 0.01 to 0.17 wt%, 0.01 to 0.16 wt%, 0.01 to 0.15 wt%, 0.01 to 0.14 wt%, 0.01 to 0.13 wt%, 0.01 to 0.12 wt%, 0.01 to 0.11 wt%, 0.01 to 0.1 wt%, 0.05 to 0.2 wt%, 0.05 to 0.19 wt%, 0.05 to 0.18 wt%, 0.05 to 0.17 wt%, 0.05 to 0.16 wt%, 0.05 to 0.15 wt%, 0.05 to 0.14 wt%, 0.05 to 0.13 wt%, 0.05 to 0.12 wt%, 0.05 to 0.11 wt%, 0.05 to 0.1 wt%, 0.08 to 0.2 wt%, 0.08 to 0.19 wt%, 0.08 to 0.18 wt%, 0.08 to 0.17 wt%, 0.08 to 0.16 wt%, 0.08 to 0.15 wt%, 0.08 to 0.14 wt%, 0.08 to 0.13 wt%, 0.08 to 0.12 wt%, 0.08 to 0.11 wt%, 0.08 to 0.1 wt%, 0.09 to 0.2 wt%, 0.09 to 0.19 wt%, 0.09 to 0.18 wt%, 0.09 to 0.17 wt%, 0.09 to 0.16 wt%, 0.09 to 0.15 wt%, 0.09 to 0.14 wt%, 0.09 to 0.13 wt%, 0.It can be used (added) in an amount of 0.9 to 0.12 wt%, 0.09 to 0.11 wt%, 0.09 to 0.1 wt%, or about 0.1 wt%.

[0133] Through experimental examples of the present invention, it was confirmed that in the manufacturing method according to one embodiment of the present invention, when the metal catalyst is used in an amount of 0.2 wt% or less relative to the weight of the substrate (e.g., compound of Formula 1) in the hydrogenation reaction, the yield of the compound of Formula 2 increases compared to when the same catalyst is used in an amount higher than 0.2 wt% relative to the weight of the substrate (e.g., 0.25 wt%).

[0134] In one example, when the metal catalyst is used in the hydrogenation reaction at an amount of 0.2 wt% or less relative to the weight of the substrate (e.g., the compound of Formula 1), the yield of the compound of Formula 2 is 1.01 times or more, 1.02 times or more, 1.03 times or more, 1.04 times or more, 1.05 times or more, 1.06 times or more, 1.07 times or more, 1.08 times or more, 1.09 times or more, 1.1 times or more, 1.11 times or more, 1.12 times or more, 1.13 times or more, 1.14 times or more, 1.15 times or more, 1.16 times or more, 1.17 times or more, 1.18 times or more, 1.19 times or more, and 1.2 times or more than the yield when the same catalyst is used at an amount greater than 0.2 wt% relative to the weight of the substrate. It may be 1.3 times or more, 1.4 times or more, 1.5 times or more, or 2 times or more.

[0135] In one example, when the metal catalyst is used in the hydrogenation reaction at an amount of 0.2 wt% or less relative to the weight of the substrate (e.g., the compound of Formula 1), the yield of the compound of Formula 2 is 80% or more, 81% or more, 82% or more, 82.2% or more, 82.4% or more, 82.6% or more, 82.8% or more, 83% or more, 83.2% or more, 83.4% or more, 83.6% or more, 83.8% or more, 84% or more, 84.2% or more, 84.4% or more, 84.6% or more, 84.8% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, relative to the theoretical yield (the theoretically obtainable yield of the compound of Formula 2). It may be 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more, or 100%.

[0136] In one example, the hydrogenation reaction can be carried out by treating a compound of Formula 1 with hydrogen gas.

[0137] In one example, when the hydrogenation reaction is carried out by pressurizing hydrogen gas, the hydrogen gas may be pressurized to a pressure of 60 psi or more, 65 psi or more, 70 psi or more, 75 psi or more, 80 psi or more, 83 psi or more, 85 psi or more, 90 psi or more, 95 psi or more, 100 psi or more, 105 psi or more, 110 psi or more, 115 psi or more, or 120 psi or more. In one example, when the hydrogenation reaction is carried out by pressurizing hydrogen gas, the hydrogen gas may be pressurized to a pressure of 120 psi or less, 115 psi or less, 110 psi or less, 105 psi or less, 100 psi or less, 97 psi or less, 95 psi or less, 90 psi or less, or 85 psi or less. The pressure of the hydrogen gas mentioned above may correspond to any range defined by any combination of the upper and lower limits described above.

[0138] In one example, when the hydrogenation reaction is performed through the pressurization of hydrogen gas, the hydrogen gas is 60 to 120 psi, 60 to 115 psi, 60 to 110 psi, 60 to 105 psi, 60 to 100 psi, 60 to 97 psi, 60 to 95 psi, 60 to 90 psi, 60 to 85 psi, 70 to 120 psi, 70 to 115 psi, 70 to 110 psi, 70 to 105 psi, 70 to 100 psi, 70 to 97 psi, 70 to 95 psi, 70 to 93 psi, 70 to 92 psi, 70 to 91 psi, 70 to 90 psi, 70 to 85 psi, 80 to 120 psi, 80 to 115 psi, 80 to 110 psi, 80 to 105 psi, 80 to 100 psi, 80 to 97 psi, 80 to 95 psi, 80 to 94 psi, 80 to 93 psi, 80 to 92 psi, 80 to 91 psi, 80 to 90 psi, 80 to 85 psi, 83 to 120 psi, 83 to 115 psi, 83 to 110 psi, 83 to 105 psi, 83 to 100 psi, 83 to 97 psi, 83 to 95 psi, 83 to 94 psi, 83 to 93 psi, 83 to 92 psi, 83 to 91 psi, 83 to 90 psi, 83 to 85 psi, 85 to 120 psi, 85 to 115 psi, 85 to 110 psi, 85 to 105 psi, 85 to 100 psi, 85 to 97 psi, 85 to 95 psi, 85 to 94 psi, 85 to 93 psi, 85 to 92 psi, 85 to 91 psi, 85 to 90 psi, 87 to 120 psi, 87 to 115 psi, 87 to 110 psi, 87 to 105 psi, 87 to 100 psi, 87 to 97 psi,It may be pressurized to a pressure of 87 to 95 psi, 87 to 94 psi, 87 to 93 psi, 87 to 92 psi, 87 to 91 psi, 87 to 90 psi, 88 to 120 psi, 88 to 115 psi, 88 to 110 psi, 88 to 105 psi, 88 to 100 psi, 88 to 97 psi, 88 to 95 psi, 88 to 94 psi, 88 to 93 psi, 88 to 92 psi, 88 to 91 psi, or 88 to 90 psi.

[0139] A person skilled in the art would be able to perform the task by converting the aforementioned hydrogen gas pressure into MPa.

[0140] For example, when the above hydrogenation reaction is performed by pressurizing hydrogen gas, the hydrogen gas may be pressurized to a pressure of 0.4 MPa or more, 0.45 MPa or more, 0.5 MPa or more, 0.55 MPa or more, 0.6 MPa or more, 0.65 MPa or more, 0.7 MPa or more, 0.75 MPa or more, 0.8 MPa or more, or 0.82 MPa or more, but is not limited thereto. In one example, the hydrogen gas may be pressurized to a pressure of 0.8 MPa or less, 0.75 MPa or less, 0.70 MPa or less, 0.65 MPa or less, 0.60 MPa or less, 0.55 MPa or less, or 0.50 MPa or less. The pressure of the hydrogen gas may correspond to any range defined by any combination of the upper and lower limits described above.

[0141] In one example, when the hydrogenation reaction is performed through the pressurization of hydrogen gas, the hydrogen gas is 0.4 to 0.8 MPa, 0.4 to 0.75 MPa, 0.4 to 0.7 MPa, 0.4 to 0.65 MPa, 0.4 to 0.6 MPa, 0.4 to 0.55 MPa, 0.4 to 0.5 MPa, 0.45 to 0.8 MPa, 0.45 to 0.75 MPa, 0.45 to 0.7 MPa, 0.45 to 0.65 MPa, 0.45 to 0.6 MPa, 0.45 to 0.55 MPa, 0.45 to 0.5 MPa, 0.5 to 0.8 MPa, 0.5 to 0.75 MPa, 0.5 to 0.7 MPa, 0.5 to It may be pressurized to a pressure of 0.65 MPa, 0.5 to 0.6 MPa, 0.5 to 0.55 MPa, 0.55 to 0.8 MPa, 0.55 to 0.75 MPa, 0.55 to 0.7 MPa, 0.55 to 0.65 MPa, 0.55 to 0.6 MPa, 0.41 to 0.83 MPa, 0.48 to 0.83 MPa, 0.55 to 0.83 MPa, 0.55 to 0.76 MPa, 0.55 to 0.69 MPa, 0.57 to 0.69 MPa, 0.55 to 0.67 MPa, or 0.57 to 0.67 MPa.

[0142] Through experimental examples of the present invention, it was confirmed that when the hydrogenation reaction is performed by pressurizing hydrogen gas in a manufacturing method according to one embodiment of the present invention, the yield of the compound of Formula 2 increases when the hydrogen gas is pressurized to a pressure of 60 psi or higher (e.g., 90 psi) compared to when it is pressurized to a lower pressure (e.g., 45 psi).

[0143] In one example, when the hydrogenation reaction is carried out by pressurizing hydrogen gas, the yield of the compound of Formula 2 when the hydrogen gas is pressurized to a pressure of 60 psi or higher is at least 1.01 times, 1.02 times, 1.03 times, 1.04 times, 1.05 times, 1.06 times, 1.07 times, 1.08 times, 1.09 times, 1.1 times, 1.11 times, 1.12 times, 1.13 times, 1.14 times, 1.15 times, 1.16 times, 1.17 times, 1.18 times, 1.19 times, and 1.2 times higher than the yield when the hydrogen gas is pressurized to a lower pressure. It may be 1.3 times or more, 1.4 times or more, 1.5 times or more, or 2 times or more.

[0144] In one example, when the hydrogenation reaction is carried out by pressurizing hydrogen gas, the yield of the compound of Formula 2 when the hydrogen gas is pressurized to a pressure of 60 psi or more is 80% or more, 81% or more, 82% or more, 82.2% or more, 82.4% or more, 82.6% or more, 82.8% or more, 83% or more, 83.2% or more, 83.4% or more, 83.6% or more, 83.8% or more, 84% or more, 84.2% or more, 84.4% or more, 84.6% or more, 84.8% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% It may be 97% or more, 98% or more, or 99% or more, or 100%.

[0145] In one example, the hydrogenation reaction may proceed until the residual amount of the compound of Formula 1 is 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less relative to the compound of Formula 1 used in the reaction, but is not limited thereto. Here, the ratio of the residual amount of the compound of Formula 1 may be a value measured as the ratio of the area of ​​the compound of Formula 1 to the total peak area in GC (Gas Chromatography) analysis, but is not limited thereto.

[0146] In one example, the manufacturing method may further include a step of filtering the product after the hydrogenation reaction is completed. Through the filtration step, the catalyst used in the hydrogenation reaction can be removed. The filter for filtration is not limited to a specific type and can be used without limitation as long as it is capable of separating the catalyst used in the hydrogenation reaction from the product; however, in one example, the filtration may be performed using celite.

[0147] In one example, the above manufacturing method may further include the step of filtering the product and distilling the filtrate after the hydrogenation reaction is completed.

[0148] In one example, the manufacturing method may further include the step of dissolving the product obtained from the hydrogenation reaction in an acid and then washing the aqueous layer of the product with an organic solvent. In one example, the product may have undergone the filtration step described above after the hydrogenation reaction is completed. In one example, the product may have undergone the filtration and distillation steps described above after the hydrogenation reaction is completed. At this time, the compound of Formula 2 may be dissolved in the aqueous layer.

[0149] Here, the acid may be selected from hydrochloric acid or sulfuric acid, and preferably may be hydrochloric acid, but is not limited thereto. In one example, the acid may be hydrochloric acid, and the concentration of the hydrochloric acid solution is 0.1 to 5N, 0.1 to 4N, 0.1 to 3N, 0.1 to 2N, 0.1 to 1N, 0.1 to 0.9N, 0.1 to 0.8N, 0.1 to 0.7N, 0.1 to 0.6N, 0.1 to 0.5N, 0.2 to 5N, 0.2 to 4N, 0.2 to 3N, 0.2 to 2N, 0.2 to 1N, 0.2 to 0.9N, 0.2 to 0.8N, 0.2 to 0.7N, 0.2 to 0.6N, 0.2 to 0.5N, 0.3 to 5N, 0.3 to 4N, 0.3 to It may be 3N, 0.3 to 2N, 0.3 to 1N, 0.3 to 0.9N, 0.3 to 0.8N, 0.3 to 0.7N, 0.3 to 0.6N, 0.3 to 0.5N, 0.4 to 5N, 0.4 to 4N, 0.4 to 3N, 0.4 to 2N, 0.4 to 1N, 0.4 to 0.9N, 0.4 to 0.8N, 0.4 to 0.7N, 0.4 to 0.6N, or 0.4 to 0.5N, but is not limited thereto.

[0150] Here, the acid is 1 to 10 g / g, 1 to 9 g / g, 1 to 8 g / g, 1 to 7 g / g, 1 to 6 g / g, 1 to 5 g / g, 1 to 4 g / g, 2 to 10 g / g, 2 to 9 g / g, 2 to 8 g / g, 2 to 7 g / g, 2 to 6 g / g, 2 to 5 g / g, 2 to 4 g / g, 3 to 10 g / g, 3 to 9 g / g, 3 to 8 g / g, 3 to 7 g / g, 3 to 6 g / g, 3 to 5 g / g, 3 to 4 g / g, 3 to 3.9 g / g, 3 to 3.8 g / g, 3 to 3.75 g / g, based on the weight of the substrate (e.g., the compound of Formula 1). It may be used (added) in a volume of 3.5 to 4 g / g, 3.5 to 3.9 g / g, 3.5 to 3.8 g / g, or 3.5 to 3.75 g / g, but is not limited thereto.

[0151] In one example, organic impurities and / or other residual solvents contained in the aqueous layer can be removed through washing using the organic solvent. In one example, the organic solvent may be selected from toluene, ethyl acetate, paraformaldehyde, dimethyl carbonate, etc., and preferably may be toluene.

[0152] In one example, the amount of toluene used is 0.1 to 10 mL / g, 0.1 to 10 mL / g, 0.1 to 9 mL / g, 0.1 to 8 mL / g, 0.1 to 7 mL / g, 0.1 to 6 mL / g, 0.1 to 5 mL / g, 0.1 to 4 mL / g, 0.1 to 3 mL / g, 0.1 to 2 mL / g, 0.5 to 10 mL / g, 0.5 to 10 mL / g, 0.5 to 9 mL / g, 0.5 to 8 mL / g, 0.5 to 7 mL / g, 0.5 to 6 mL / g, 0.5 to 5 mL / g, 0.5 to 4 mL / g, 0.5 to 3 mL / g, 0.5 to 2 mL / g, 1 to 10 mL / g, 1 to 10 mL / g, 1 to 9 mL / g, 1 to 8 mL / g, 1 to 7 mL / g, 1 to 6 mL / g, 1 to 5 mL / g, 1 to 4 mL / g, 1 to 3 mL / g, 1 to 2 mL / g, 1 to 1.9 mL / g, 1 to 1.8 mL / g, 1 to 1.7 mL / g, 1 to 1.6 mL / g, 1 to 1.5 mL / g, 1.2 to 10 mL / g, 1.2 to 10 mL / g, 1.2 to 9 mL / g, 1.2 to 8 mL / g, 1.2 to 7 mL / g, 1.2 to 6 mL / g, 1.2 to 5 mL / g, 1.2 to 4 mL / g, It may be 1.2 to 3 mL / g, 1.2 to 2 mL / g, 1.2 to 2 mL / g, 1.2 to 1.9 mL / g, 1.2 to 1.8 mL / g, 1.2 to 1.7 mL / g, 1.2 to 1.6 mL / g, or 1.2 to 1.5 mL / g.

[0153] In one example, the washing using the organic solvent may be performed one or more times or two or more times, specifically, one to five times, one to four times, one to three times, one to two times, two to five times, two to four times, or two to three times, but is not limited thereto.

[0154] In one example, the above manufacturing method may further include a step of extracting a compound of Formula 2 after completing the washing step.

[0155] In one example, the extraction step may be performed after the washing step is completed and after the washed aqueous layer is made into a basic state.

[0156] In one example, the conversion of the above-mentioned aqueous layer to a basic state can be performed by adding (introducing) a basic solution to the above-mentioned aqueous layer after washing. Here, the base may be sodium hydroxide (NaOH) or ammonium hydroxide (NH4OH), and preferably ammonium hydroxide, but is not limited thereto.

[0157] In one example, the basic solution may be added until the pH of the aqueous layer becomes pH 8 or higher, pH 8.5 or higher, pH 9 or higher, pH 9.5 or higher, or pH 10 or higher.

[0158] In one example, the extraction of the compound of Formula 2 above may be performed using an ether-based solvent. Here, the ether-based solvent may be selected from MTBE (methyl t-butyl ether), iso-octane, or 2-MTHF (2-methyltetrahydrofuran), and preferably MTBE, but is not limited thereto.

[0159] In one example, the amount of MTBE used is 1 to 10 mL / g, 1 to 9 mL / g, 1 to 8 mL / g, 1 to 7 mL / g, 1 to 6 mL / g, 1 to 5 mL / g, 1 to 4.5 mL / g, 1 to 4 mL / g, 1 to 3.5 mL / g, 1 to 3 mL / g, 1 to 2.5 mL / g, 1 to 2 mL / g, 1 to 1.5 mL / g, 1 to 1.3 mL / g, 2 to 10 mL / g, 2 to 9 mL / g, 2 to 8 mL / g, 2 to 7 mL / g, 2 to 6 mL / g, 2 to 5 mL / g, 3 to 10 mL / g, 3 to 9 mL / g, 3 to 8 mL / g, and 3 to 7 mL / g relative to the total weight of the compound of Formula 1. It may be mL / g, 3 to 6 mL / g, 3 to 5 mL / g, 4 to 10 mL / g, 4 to 9 mL / g, 4 to 8 mL / g, 4 to 7 mL / g, 4 to 6 mL / g, or 4 to 5 mL / g.

[0160] The above extraction step may be performed one or more times, two or more times, or three or more times, but is not limited thereto.

[0161] In one example, the extraction step may be performed three or more times, and the type and / or amount of ether-based solvent used in each extraction step may be different or the same.

[0162] In one example, the extraction step may be performed two or three times, wherein MTBE may be used as an ether-based solvent for extraction, and the amount of MTBE used in the first extraction step may be 2 to 10 mL / g, 2 to 9 mL / g, 2 to 8 mL / g, 2 to 7 mL / g, 2 to 6 mL / g, 2 to 5 mL / g, 3 to 10 mL / g, 3 to 9 mL / g, 3 to 8 mL / g, 3 to 7 mL / g, 3 to 6 mL / g, 3 to 5 mL / g, 4 to 10 mL / g, 4 to 9 mL / g, 4 to 8 mL / g, 4 to 7 mL / g, 4 to 6 mL / g, or 4 to 5 mL / g relative to the total weight of the compound of Formula 1; The amount of MTBE used in the second extraction step (and the third extraction step) may be 1 to 2 mL / g, 1 to 1.5 mL / g, 1 to 1.3 mL / g, 0.5 to 2 mL / g, 0.5 to 1.5 mL / g, or 0.5 to 1.3 mL / g relative to the total weight of the compound of Formula 1, but is not limited thereto.

[0163] In one example, the above manufacturing method may further include the step of obtaining a compound of Formula 2 by distilling the ether-based solvent after completing the extraction step using the ether-based solvent.

[0164] A manufacturing method according to one example of the present invention satisfies one or more conditions selected from the group consisting of the following, or satisfies all conditions, wherein

[0165] (i) The hydrogenation reaction is carried out using a palladium hydroxide catalyst, wherein the palladium hydroxide catalyst satisfies one or more of the following characteristics:

[0166] (a) The weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 wt% or less; and

[0167] (b) The molar ratio of metallic palladium to the total molar amount of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 mol% or less,

[0168] (ii) The amount of the palladium hydroxide catalyst used is 0.01 to 0.2 wt% relative to the weight of the compound of Formula 1; and

[0169] (iii) The above hydrogenation reaction is carried out by pressurizing hydrogen gas to a pressure of 60 to 120 psi,

[0170] One or more features selected from the group consisting of the following can be satisfied:

[0171] (1) The reaction time of the hydrogenation reaction is reduced compared to the conventional process;

[0172] (2) The yield of the compound of Formula 2 is increased compared to the conventional process;

[0173] (3) The amount of impurities is reduced compared to the conventional process; and

[0174] (4) Compared to conventional processes, the amount of waste from catalysts (e.g., metal catalysts) for hydrogenation reactions is reduced.

[0175] In one example, a manufacturing method according to one example of the present invention may additionally satisfy the following feature (iv) in addition to one or more features selected from the group consisting of (i) to (iii):

[0176] (iv) The solvent for the hydrogenation reaction is a weak acidic solvent (e.g., acetic acid), and the amount of the weak acidic solvent used is 1 to 20 mL / g relative to the weight of the compound of Formula 1.

[0177] In one example, the above conventional process may be a process that does not satisfy one or more, two or more, or three or more of the conditions (i) to (iii), or does not satisfy all of the above conditions.

[0178] For example, the above-mentioned conventional process may satisfy one or more of the following features, or satisfy all of the following features, but is not limited thereto:

[0179] (I') The hydrogenation reaction is carried out using a palladium hydroxide catalyst, wherein the palladium hydroxide catalyst corresponds to one or more of the following:

[0180] (a') The weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 21 wt% or more; and

[0181] (b') The molar ratio of metallic palladium to the total molar amount of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 23 mol% or more,

[0182] (ii') the amount of the palladium hydroxide catalyst used is greater than 0.2 wt% (e.g., 0.25 wt% or more) relative to the weight of the compound of Formula 1; and

[0183] (iii') The above hydrogenation reaction is carried out by pressurizing the hydrogen gas to a pressure of less than 60 psi (e.g., 45 psi or less).

[0184] In one example, a decrease in the reaction time of the hydrogenation reaction may mean that the conversion rate of the nitrile group of the compound of Formula 1 to the amine has increased.

[0185] Accordingly, the hydrogenation reaction time of the manufacturing method according to one example of the present invention may be 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, 0.5 times or less, 0.4 times or less, 0.3 times or less, 0.3 times or less, 0.25 times or less, 0.2 times or less, 0.18 times or less, 0.15 times or less, or 0.1 times or less of the hydrogenation reaction time of the conventional process, but is not limited thereto.

[0186] In addition, the hydrogenation reaction time of the manufacturing method according to one example of the present invention may be 15 hours or less, 14 hours or less, 13 hours or less, 12 hours or less, 11 hours or less, 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or less, 6 hours or less, 5 hours or less, or 4 hours or less, but is not limited thereto.

[0187] In addition, the yield of the compound of Formula 2 in the manufacturing method according to one example of the present invention may be 1.01 times or more, 1.02 times or more, 1.03 times or more, 1.04 times or more, 1.05 times or more, 1.06 times or more, 1.07 times or more, 1.08 times or more, 1.09 times or more, 1.1 times or more, 1.11 times or more, 1.12 times or more, 1.13 times or more, 1.14 times or more, 1.15 times or more, 1.16 times or more, 1.17 times or more, 1.18 times or more, 1.19 times or more, 1.2 times or more, 1.25 times or more, 1.3 times or more, 1.35 times or more, 1.4 times or more, 1.45 times or more, 1.5 times or more, or 2 times or more than the yield of the conventional process, but is not limited thereto.

[0188] In addition, the yield of the compound of Formula 2 in the manufacturing method according to an example of the present invention is 80% or more, 81% or more, 82% or more, 82.2% or more, 82.4% or more, 82.6% or more, 82.8% or more, 83% or more, 83.2% or more, 83.4% or more, 83.6% or more, 83.8% or more, 84% or more, 84.2% or more, 84.4% or more, 84.6% or more, 84.8% or more, 85% or more, 86% or more, 87% or more, 88% or more, 89% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, relative to the theoretical yield (the yield of the compound of Formula 2 that can be obtained theoretically). It may be 98% or more, or 99% or more, or 100%, but is not limited thereto.

[0189] In addition, the manufacturing method according to one example of the present invention may have a lower degree of impurity generation compared to conventional processes.

[0190] In one example, the degree of impurity generation can be measured through HPLC analysis or GC analysis.

[0191] In one example, the impurity may be the UK1 described above; or a dimer component and / or trimer component of the compound of Formula 2. When the compound of Formula 2 is prepared by the method according to the present invention, the aldimine structure and primary amine structure of the intermediate generated during the preparation of Compound 2 may couple to produce a dimer component and further a trimer component (see Reaction Scheme 2 of this specification).

[0192] In one example, when preparing a compound of Formula 2 by a manufacturing method according to one example of the present invention, the degree of UK1 generation may be 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less, 0.01 to 0.09%, 0.01 to 0.08%, 0.01 to 0.07%, 0.01 to 0.06%, or 0.01 to 0.05% based on the relative ratio (PAR%) of the peak area of ​​UK1 to the total peak area in HPLC analysis or GC analysis.

[0193] In one example, when preparing a compound of Formula 2 by a manufacturing method according to one example of the present invention, the degree of formation of dimer byproducts may be 7% or less, 6.5% or less, 6% or less, 5.5% or less, 5% or less, 4.5% or less, 4% or less, 4 to 7%, 4 to 6.5%, 4 to 6, 4 to 5.5%, 4 to 5, or 4 to 4.5% based on the relative ratio (PAR%) of the peak area of ​​the dimer byproducts to the total peak area in HPLC analysis or GC analysis.

[0194] In one example, when manufacturing a compound of Formula 2 by a manufacturing method according to one example of the present invention, the amount of waste metal catalyst (e.g., palladium hydroxide catalyst) may be 99% or less, 95% or less, 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, or 60% or less of the amount of waste in the process.

[0195] In addition, the present invention provides a method for preparing a compound of Formula 4, comprising the step of reacting a compound of Formula 2 prepared by the above-described manufacturing method with a compound of Formula 3:

[0196] [Chemical Formula 3]

[0197]

[0198] [Chemical Formula 4]

[0199]

[0200] (In the above chemical formulas,

[0201] P1 can be an amine protecting group;

[0202] P3 can be a benzyl group, methyl group, ethyl group, i-propyl group, or t-butyl group;

[0203] R1 to R4 may each independently be hydrogen, a halogen, or a substituted or unsubstituted C1-C4 alkyl;

[0204] G1O can be the departure phase.)

[0205] In the present invention, the compound of Formula 4 is an intermediate of a dipeptidyl peptidase-4 inhibitor according to the present invention. In one example, the dipeptidyl peptidase-4 inhibitor may be represented by the structure of Formula 1 of International Application WO2006 / 104356.

[0206] In one example, R1 and R2 may be hydrogen, and R3 and R4 may be fluorine. That is, in one example, the compound of Formula 4 may be 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo-piperidin-1-yl)-butyric acid.

[0207] In one example, when the C1-C4 alkyl group is substituted, it may be substituted with a halogen, and more specifically, with fluorine, but is not limited thereto.

[0208] In one example, the compound of Formula 4 is prepared by reacting the compound of Formula 2 and the compound of Formula 3 according to the present invention, and at this time, after reacting the two compounds, a process of removing the carboxylic acid protecting group derived from the compound of Formula 2 may be included.

[0209] In one example, G1 can function as a good leaving group with oxygen. In one example, G1O is trifluoromethanesulfonate, mesylate, tosylate, besylate, or nonafluorobutanesulfonate, and preferably can be trifluoromethanesulfonate or nonafluorobutanesulfonate.

[0210] The method for preparing the compound of Chemical Formula 4 above is specifically

[0211] (a) A step of coupling reaction by adding a base to the compound of Formula 2 and the compound of Formula 3,

[0212] (b) a step of obtaining the following intermediate compound (Formula 4a) by carrying out a cyclization reaction by adding acid, and

[0213] (c) may include the step of hydrolyzing the above intermediate compound to remove the carboxylic acid protecting group to obtain the compound of Formula 4.

[0214] The method for preparing the compound of Chemical Formula 4 above can be illustrated by the following reaction schemes 3 and 4.

[0215] [Reaction Equation 3]

[0216]

[0217] [Reaction Equation 4]

[0218]

[0219] In the above formula,

[0220] a can be a base such as Et3N, Hunig's base, etc., and

[0221] b can be an acid such as AcOH and an organic solvent such as CH2Cl2;

[0222] c may vary depending on the protecting group, but typically, when P1 is Boc and P2 is a t-butyl group, (1) H2SO 4　Strong acids such as CH2Cl2, aq. NaOH, Boc2O, or (2) NaOH, EtOH, H2O, reflux may be selected, and in the case where P1 is Boc and P2 is a benzyl group, methyl group, ethyl group and i-propyl group, hydrolysis conditions using the base specified in condition (2) above may be used. R1 to R4, P1, P2, P3 and G1 are as defined in this specification.

[0223] The present invention will be explained in more detail through the following examples, but these are intended only to aid in understanding the invention and do not limit the scope of the invention in any way.

[0224] The present invention relates to a method for preparing an intermediate for the synthesis of dipeptidyl peptidase-4 inhibitors. When the intermediate is synthesized using the method of the present invention, the yield of the intermediate can be increased, process time can be reduced through improved reaction conversion rate, and the generation of impurities can be reduced. In particular, the method of the present invention can achieve high quality and yield with only a smaller amount of catalyst compared to conventional technology, thereby reducing production costs and waste volume.

[0225] Figure 1 is a photograph showing the mapping of the components of a Pd(OH)2 / C catalyst according to an example of the present invention through SEM-EDS analysis.

[0226] Figure 2 shows the results of analyzing the surfaces of catalyst-1 and catalyst-3 using XRD.

[0227] Figure 3 shows the results of comparing the yield of Compound 2 according to the Pd content of the palladium hydroxide catalyst. In each process, the hydrogen gas pressure and the amount of catalyst used were set to be the same, and the comparison was made by varying only the type of catalyst.

[0228] Figure 4 shows the results of an IPC chart analysis using GC analysis of compound 2 obtained according to the process of the example.

[0229] Figure 5 shows the results of an IPC chart analysis using GC analysis of compound 2 obtained according to the comparative example process.

[0230] Figure 6 shows the results of tracking UK1 impurity using HPLC in the process of the example and comparative example.

[0231] The present invention will be explained in more detail below through examples. However, the following examples are provided merely to aid in understanding the invention and do not limit the scope of the invention.

[0232]

[0233] Example: Novel manufacturing process of Compound 2

[0234] Compound 2 (t-butyl (3S)-4-amino-3-[(t-butoxycarbonyl)amino]butanoate) was obtained through the hydrogenation reaction of Compound 1 ((S)-t-butyl 3-(t-butoxycarbonylamino)-3-cyanopropanoate). Pd(OH)2 / C (carbon-supported Pd(OH)2 catalyst) was used as the catalyst for the hydrogenation reaction, and AcOH was used as the solvent. The preparation mechanism of Compound 2 is briefly illustrated below.

[0235] [Reaction Equation 1]

[0236]

[0237] The specific reaction process is as follows: Compound 1 (reference substance) and AcOH (7.0 mL / g of Compound 1) were introduced into a reactor, and the internal temperature was raised to 40°C. Pd(OH)2 / C catalyst (1.0 mg / g of Compound 1) was introduced, and H2 gas was pressurized to 90 psi to proceed with the reaction until the remaining amount of Compound 1 was 0.5% or less. At this time, the Pd(OH)2 / C catalyst (Catalyst-1) purchased from Evonik was used. After the reaction was completed, Pd(OH)2 was removed by Celite filtration, and the filtrate was distilled. After distillation, the reaction product was dissolved in a 0.5N HCl solution (3.75 g / g per weight of Compound 1), and the aqueous layer was washed twice using Tol (toluene, 1.5 mL / g of Compound 1). NH4OH was added to the aqueous layer to adjust the pH to 9 or higher, and the mixture was extracted once with MTBE (Methyl tert-butyl ether) (5.0 mL / g of Compound 1) and further extracted twice using MTBE (1.25 mL / g of Compound 1). The MTBE layer was distilled to obtain the final compound.

[0238]

[0239] Comparative Example: Conventional manufacturing process of Compound 2

[0240] Comparative example was prepared by the same process as the above example to produce compound 2, but with differences in the relative ratio of metallic palladium (Pd) in the elemental composition of the Pd(OH)2 / C catalyst, the amount of Pd(OH)2 / C used, and the hydrogen pressure compared to the process of the above example. The ratio of Pd was calculated by measuring the weight or molar ratio of metallic palladium relative to the total weight or total molar amount of palladium oxide (PdO) and metallic palladium present in the Pd(OH)2 / C catalyst.

[0241] The reaction processes of the above examples and comparative examples are compared in Table 1 below.

[0242] PdO ratio in Pd(OH)2 catalyst (weight ratio) Pd ratio in Pd(OH)2 catalyst (weight ratio) Pd(OH)2 catalyst usage amount (weight ratio) H2 (psi) Comparative Example 72~79 21~29 0.25 wt% 45 Example >91 <90.1 wt% 83~97

[0243] Here, the Pd ratio of the catalysts in the examples and comparative examples was varied by using different types of Pd(OH)2 / C catalysts.

[0244] Specifically, as described above, the process of the example basically used a Pd(OH)2 / C catalyst (catalyst-1) purchased from Evonik, and in some comparative experiments described later, either catalyst-1 or a Pd(OH)2 / C catalyst (catalyst-2) purchased from Sigma-Aldrich was used. In the process of the comparative example, a Pd(OH)2 / C catalyst (catalyst-3) purchased from Johnson Matthey UK or a Pd(OH)2 / C catalyst (catalyst-4) purchased from Johnson Matthey India was used. All catalysts were in the form of wet powder, and their visual appearance was identical. As confirmed in the experimental examples described later, the proportion of Pd in ​​the Pd(OH)2 / C catalyst used in the example process (less than 9% by weight) is relatively low compared to the proportion of Pd in ​​the catalyst used in the comparative example (21-29% by weight).

[0245]

[0246] Experimental Example 1. Comparison of characteristics of palladium hydroxide catalysts in the Examples and Comparative Examples

[0247] 1-1. Analysis of Composition and Morphology of Palladium Hydroxide Catalyst

[0248] First, the components of the four types of Pd(OH)2 / C catalysts described above were analyzed. The shape and composition of each particle were observed using SEM-EDS (Scanning Electron Microscope-Energy Dispersive Spectroscopy).

[0249] As a representative example, the analysis results of the component mapping image of Catalyst-1 are shown in Figure 1, and the analysis results of each catalyst are shown in Table 2. In each catalyst, C, O, Cl, Pd (total palladium components including metallic palladium and palladium oxide), Al, and Si components were observed. As a result of analyzing the distribution of palladium components (including palladium oxide and metallic palladium) in the carbon support for each catalyst, it was found that palladium components were evenly distributed in the carbon for all catalysts, and no clear difference in the distribution of palladium components between catalysts was observed. Notably, in the case of Catalyst-2 and Catalyst-3, it was confirmed that Al and Si components were distributed in trace amounts in the form of particles of several μm in size.

[0250] Pd(OH)2 Catalyst Classification | Shape | Composition | Pd | Distribution | Specifics Catalyst-1 | Needle-shaped | C, O, Cl, Pd observed generally | Catalyst-2 | Angular particles | C, O, Cl, Pd, Al, Si observed generally | Al and Si distributed in trace amounts as particles of several µm in size | Catalyst-3 | Angular particles | C, O, Cl, Pd, Al, Si observed generally | Al and Si distributed in trace amounts as particles of several µm in size | Catalyst-4 | Needle-shaped, angular particles | C, O, Cl, Pd observed generally | Pd composition is higher compared to other samples

[0251] 1-2. Analysis of Metallic Palladium Content in Palladium Hydroxide Catalysts

[0252] The metallic palladium (Pd) content of each Pd(OH)2 / C catalyst in Table 2 above was confirmed through X-ray Diffraction (XRD) analysis. As described above, the ratio of Pd was calculated by measuring the relative weight or molar ratio of Pd based on the total weight or total moles of PdO and Pd present in the Pd(OH)2 / C catalyst. An appropriate amount of sample was taken and prepared in a Powder Sample Holder or Film Sample Holder, mounted on a sample measuring device, analyzed according to the instrument's SOP, and the diffractogram was verified. The ratio of Pd was calculated by determining the area ratio of the peaks corresponding to each phase of the XRD analysis.

[0253] The surface analysis results of catalyst-1 and catalyst-3 are shown in FIG. 2, and the quantitative analysis results of the metallic palladium content for each of the four types of catalysts are shown in Table 3 below.

[0254] Normalized weight fraction Normalized mole fraction Crystallite size (cry size L, nm) Pd(OH)2 catalyst classification PdPdOPdPdOPdPdO catalyst -18% 92% 9% 91%~ 12~ 3 catalyst -26% 94% 7% 93%~ 43~ 3 catalyst -3 21% 79% 23% 77%~ 33~ 3 catalyst -4 28% 72% 31% 69%~ 27~ 3

[0255] As can be seen from the results, the weight ratio of Pd to the total weight of PdO and Pd in ​​Catalyst-3 and Catalyst-4 was 21% and 28%, respectively, whereas the weight ratio of Pd in ​​Catalyst-1 and Catalyst-2 was only 8% and 6%, respectively (Table 3). When comparing the molar ratios, the molar ratio of Pd to the total molar amount of PdO and Pd in ​​Catalyst-3 and Catalyst-4 was 23% and 31%, respectively, while the molar ratio of Pd in ​​Catalyst-1 and Catalyst-2 was 9% and 7%, respectively (Table 3). Overall, it was confirmed that the proportion of metallic palladium in the Pd(OH)2 catalyst was significantly lower in the catalysts of the examples (Catalyst-1 and Catalyst-2) compared to the catalysts used in the comparative examples (Catalyst-3 and Catalyst-4).

[0256]

[0257] Experimental Example 2. Comparison of yields of Compound 2 according to palladium hydroxide catalyst usage and hydrogen pressure

[0258] In the process of manufacturing Compound 2, the yield was compared according to the amount of Pd(OH)2 catalyst used and the difference in hydrogen gas pressure.

[0259] First, the process of the example was performed for each group, using catalyst-1 in common and keeping other conditions the same except for varying the amount of catalyst used to compare the yield of compound 2. The results are shown in Table 4.

[0260] Group Compound 1 (g)AcOH (fold)Pd(OH)2 / C (wt%) Pressure (psi) Temperature (°C) Yield (%) 1 20 70.25 90 40 83.6 2 20 70.15 90 40 85.6 2 320 70.10 90 40 90.70 420 70.05 90 40 90.11

[0261] When 0.25 wt% of the Pd(OH)2 / C catalyst was used relative to the weight of the reference substance (Compound 1), the yield of Compound 2 was approximately 83%, and when 0.15 wt% of the Pd(OH)2 / C catalyst was used, the yield of Compound 2 was approximately 85% (see Table 4). On the other hand, when the Pd(OH)2 / C catalyst was used at a dose of 0.10 wt% relative to the reference substance, the yield of Compound 2 increased significantly to 90%.

[0262] The above results show that compound 2 can be obtained in a higher yield when the palladium hydroxide catalyst is used at 0.2 wt% or less relative to the reference material, and in particular, compound 2 can be obtained in an even higher yield when used at around 0.1 wt%.

[0263]

[0264] Next, the yield of Compound 2 was compared by performing the same process as in the example but varying the hydrogen gas pressure and / or catalyst usage for the hydrogenation reaction. Catalyst-1 was commonly used as the palladium hydroxide catalyst, and the process was carried out on a 15 g scale of Compound 1. Specific process conditions and the corresponding yields are summarized in Table 5 below.

[0265] Group AcOH (fold) Pd(OH)2 (wt%) H2 Pressure (psi) Yield (g) Yield (%) 1 3 0.15 40 1 2.5 28 2.3 7 29 0.25 6 5 1 2.79 8 4.15 3 1 5 0.15 90 1 3.95 9 1.78 4 1 5 0.35 40 1 2.17 8 0.72 5 3 0.35 40 1 0.52 6 9.21 6 1 5 0.15 40 1 3.55 8 9.15 7 1 5 0.35 90 1 2.77 8 4.02 8 3 0.15 90 1 3.53 8 9.02 9 3 0.35 90 1 1.17 7 3.49 10 7 0.25 45 1 2.63 8 2.98 1 17 0.25 90 1 2.93 8 4.95

[0266] As can be seen in the table above, Group 11 showed an increase in the yield of Compound 2 as the hydrogen gas pressure was increased to 90 psi compared to Groups 2 (H2 pressure 65 psi) and 10 (H2 pressure 45 psi). Additionally, Group 3 also showed a greater increase in yield when only the hydrogen gas pressure was increased to 90 psi while maintaining identical other conditions compared to Group 6 (H2 pressure 40 psi); furthermore, the difference in yield was found to be even greater when compared to Group 4, which used 0.35 wt% of catalyst and had a hydrogen gas pressure of 40 psi. These results demonstrate that in the manufacturing process of Compound 2, not only the amount of catalyst but also the pressure of the hydrogen gas for the hydrogenation reaction affects the yield of Compound 2. Meanwhile, according to the results, the amount of acetic acid (AcOH) used also affects the yield of Compound 2; however, considering productivity, it was determined that using 7 times the amount of the reference substance is the most appropriate.

[0267]

[0268] Experimental Example 3. Comparison of Process Efficiency and Yield According to Differences in Metallic Palladium Ratio of Palladium Hydroxide Catalysts

[0269] In this example, it was determined whether there were differences in yield and process efficiency depending on the Pd content of the catalyst. For comparison, the same process as in the example was performed in each group, but the catalyst usage was set to 0.25 wt% relative to the weight of the reference material (Compound 1), hydrogen gas was supplied at 45 psi, and different types of catalysts (Catalyst-1 to Catalyst-4) were used for each group. As confirmed in Experimental Example 1-2, Catalyst-1 to Catalyst-4 are palladium hydroxide catalysts with different metallic palladium contents. Additionally, a process using a Pd / C (Palladium on carbon) catalyst (Catalyst-5) instead of the Pd(OH)2 / C catalyst was also compared (catalyst usage and hydrogen gas pressure were the same as the other groups). The Pd / C catalyst is a catalyst supported mainly with metallic palladium on a carbon support and was purchased from Evonik.

[0270] The results are shown in Figure 3. When using Catalyst-3 and Catalyst-4, which have a relatively high proportion of metallic palladium (Pd) in the catalyst, the reaction time was very long, exceeding 20 hours, and the yield of Compound 2 was only around 70%. Furthermore, in the process using Catalyst-5, which has a higher proportion of Pd compared to the Pd(OH)2 / C catalyst, not only was the reaction time long at 15 hours, but the yield was also very low at 56%. On the other hand, when using Catalyst-1 or Catalyst-2, which have a relatively low proportion of metallic palladium, the reaction time was significantly shortened to less than 5 hours, and the yield increased greatly to over 80%. The above results demonstrate that the proportion of metallic palladium in the palladium hydroxide catalyst used in the manufacturing process of Compound 2 affects the efficiency and yield of the Compound 2 manufacturing process. Table 6 below compares the process results according to the Pd content of the Pd(OH)2 / C catalyst.

[0271] Catalyst Type PdO (weight ratio) Pd (weight ratio) Result (net Yield %) Catalyst-3 or Catalyst-4 72~79 21~29 68~73 Catalyst-1 or Catalyst-2 >9 1<9 85

[0272] Experimental Example 4. Comparison of Dimer Impurity in Examples and Comparative Examples

[0273] Looking specifically at the mechanism of the preparation process for Compound 2, an Aldimine structure is formed by bonding H22 groups to a Nitrile structure through a primary hydrogen reaction, and a Primary amine, which is the structure of Compound 2, is synthesized through a secondary reaction. At this time, the intermediate Aldimine and the generated Primary amine structure are coupled to form a minor component with a Dimer structure, and furthermore, a Trimer minor component can be formed (Reaction Scheme 2).

[0274] [Reaction Equation 2]

[0275]

[0276] Accordingly, a comparison was made to determine whether differences in the conditions of the manufacturing processes of the examples and comparative examples resulted in differences in the degree of dimer byproduct formation. Specifically, reaction in-process control (IPC) analysis was performed using Gas Chromatography (GC), and the dimer impurity in the manufacturing processes of the examples and comparative examples was compared. The specific GC analysis conditions and experimental methods are shown in Table 7. The processes of the examples and comparative examples were carried out according to the conditions in Table 1, and as the palladium hydroxide catalyst, Catalyst-1 was used in the example process, and Catalyst-4 was used in the comparative process.

[0277] ColumnAT-1, 15 m×ID 0.53 mm, Film Thickness: 1.2 ㎛Injector / Detector typeCapillary split mode / FIDTmperatureInjector250℃Detector270℃Column initial value100℃Initial time5 minProgram rate10℃ / minFinal value270℃Final time10 minFlow rateCarrier Gas(N2)4.0 mL / minMake up(N2)30 mL / minHydrogen30 mL / minAir300 mL / minSplit ratio40:1Reaction timeCompound 1about 13.4 minutesCompound 2about 14.0 minutes

[0278] As a result, as shown in Figures 4 and 5, when Compound 2 is prepared according to the manufacturing process of the Comparative Example, the dimer impurity was found to be high at 8 to 11%, whereas when prepared according to the manufacturing process of the Example, the dimer impurity was found to be reduced to 4 to 7%. The above results demonstrate that dimer impurity can be reduced when Compound 2 is prepared using the process according to the Example of the present invention.

[0279]

[0280] Experimental Example 5. Comparison of UK impurities in Examples and Comparative Examples

[0281] Finally, the UK1 impurity of the HPLC example and comparative example processes was compared. The structure of UK1 is as follows. The example and comparative example processes were carried out according to the conditions in Table 1, and as the palladium hydroxide catalyst, catalyst-1 was used in the example process and catalyst-4 was used in the comparative example process.

[0282] [API UK1 Structure]

[0283]

[0284] Specific HPLC analysis conditions are shown in Table 8.

[0285] Device model nameHPLCColumnACE C18 (4.6 mm × 250 mm, Particle size 5 ㎛)Column temperature10℃Eluent solutionA: AN / ultrapure water / TFA = 37 / 63 / 0.1 (v / v)B: AN / ultrapure water / TFA = 80 / 20 / 0.1 (v / v)UV Absorbance256 nmF / r0.7 mL / minInjection volume10 ㎕Run Time55 minGradient TableTime (min)A (%)B (%)Initial1000251000350100401000551000Total Run Time55 min

[0286] As a result, as shown in Fig. 6, it was confirmed that UK1 impurities were present in the comparative example process at 0.097–0.103 PAR (peak area ratio)%, whereas in the example process, UK1 impurities were found to have been significantly reduced to 0.01–0.05 PAR%. The above results demonstrate that the occurrence of impurities can be minimized when compound 2 is prepared according to the example process of the present invention.

Claims

1. A method for preparing a compound of Formula 2, comprising the step of performing a hydrogenation reaction on a compound of Formula 1 to obtain a compound of Formula 2: [Chemical Formula 1] [Chemical Formula 2] (In the above chemical formulas, P1 is an amine protecting group; P2 is a benzyl group, methyl group, ethyl group, i-propyl group, or t-butyl group) A method for manufacturing, wherein the above hydrogenation reaction is carried out using a palladium hydroxide catalyst, and the palladium hydroxide catalyst satisfies one or more of the following characteristics: (a) The weight ratio of metallic palladium to the total weight of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 wt% or less; and (b) The molar ratio of metallic palladium to the total molar amount of metallic palladium and palladium oxide of the above palladium hydroxide catalyst is 20 mol% or less.

2. In Paragraph 1, P1 is a manufacturing method in which Boc, Cbz, or Fmoc is used.

3. In Paragraph 1, A method of preparation in which P2 is an i-propyl group or a t-butyl group.

4. In Paragraph 1, A method for manufacturing, wherein the amount of the above palladium hydroxide catalyst used is 0.01 to 0.2 wt% relative to the weight of the compound of Formula 1.

5. In Paragraph 1, A manufacturing method in which the above hydrogenation reaction is carried out by pressurizing hydrogen gas to a pressure of 60 to 120 psi.

6. In Paragraph 1, A manufacturing method comprising further a step of dissolving the reaction product obtained from the above step in an acid and then washing the aqueous layer of the reaction product with an organic solvent.

7. In Paragraph 6, A manufacturing method comprising the step of adding a basic solution to the above aqueous layer and then extracting a compound of Formula 2 with an ether-based solvent.

8. A method for preparing a compound of Formula 4, comprising the step of reacting a compound of Formula 2, prepared by the method of any one of Claims 1 to 7, with a compound of Formula 3: [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] (In the above chemical formulas, P1 and P2 are as defined in Paragraph 1; P3 is a benzyl group, methyl group, ethyl group, i-propyl group, or t-butyl group; R1 to R4 are each independently hydrogen, a halogen, or a substituted or unsubstituted C1-C4 alkyl; G1O is the leaving group.) 9. In Paragraph 8, A method for manufacturing the above G1O, which is trilate, mesylate, tosylate, besylate, or nonaplate.

10. In Paragraph 8, A method of manufacturing in which R1 and R2 are hydrogen, and R3 and R4 are fluorine.

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