Method for preparing chiral benzodiazepine derivatives

Abstract

The present invention provides a method for preparing a compound of formula (I), said compound represented by the structure of formula (I), wherein: each R1 is independently F, Cl, Br, I, OCH3, CN, or NO2; each R2 is independently the same or different C1-C5 alkyl; n1 is an integer from 1 to 5; and n2 is an integer from 1 to 4. Additionally, the present invention provides a compound represented by the following structural compound (1a) and compound (2), wherein X comprises: chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, Phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof.

Description

Technology Field

[0001] The present invention provides a method for preparing a compound of formula (I) as well as other compounds derived therefrom, wherein the compound is represented by the structure of formula (I) below:

[0002]

[0003] In the above formula:

[0004] R 1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0005] R 2 Each is independently the same or different C1-C5 alkyl;

[0006] n 1 is an integer from 1 to 5; and

[0007] n 2 is an integer from 1 to 4.

[0008] In addition, the present invention relates to a compound represented by the following structure,

[0009]

[0010] Provides pharmaceutically acceptable salts of the same, and combinations thereof.

[0011] In addition, the present invention provides a compound represented by the following structure:

[0012]

[0013] The above X includes the following:

[0014] Chloride, Acetate, Adipate, Alginate, Ascorbate, Aspartate, Benzoate, Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphorate, Camposulfonate, Cyclopentanepropionate, Digluconate, Dodecylsulfate, Ethanesulfonate, Fumarate, Glucoheptanoate, Glycerophosphate, Hemisulfate, Heptanoate, Hexanoate, Hydroiodide, Maleate, 2-Hydroxyethanesulfonate, Lactate, Methanesulfonate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oxalate, Pectinate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Salicylate, Succinate, Sulfate, Sulfonate, Tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof. Background Technology

[0015] Benzodiazepinene compounds are useful as pharmaceutically active ingredients in the pharmaceutical and fine chemical industries. For example, the following gamma-secretase inhibitor (GSI) (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide shows promising results in current clinical trials for the treatment of various cancers, particularly those with defective Notch regulation (see U.S. Patent 9,273,014 incorporated herein by reference):

[0016]

[0017] Since (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide is chiral, efficient and diastereoselective preparation of the chiral compound in its pure form is required.

[0018] U.S. Patent 9,273,014 discloses a precursor for (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide, which is a compound represented by the following structure:

[0019]

[0020] In U.S. Patent 9,273,014, compound (1) is prepared as described in Reaction Scheme 1 below. In short, compound (a) is divided using chiral supercritical fluid chromatography (SFC) to form chiral compound (b); This is then hydrolyzed to produce compound (1). However, chiral chromatography methods, such as SFC and high-performance liquid chromatography (HPLC), are expensive, time-consuming, and tedious methods for producing chiral compounds. Furthermore, these methods have a theoretical yield of only 50%.

[0021] Reaction Scheme 1: Preparation of compound (3) using chiral SFC conditions.

[0022]

[0023] In one embodiment, the present invention provides a method for preparing a compound of the following formula (Ib), and

[0024]

[0025] In the above formula:

[0026] R 1 Each is independently Cl, F, Br, I, OCH3, CN, or NO2;

[0027] R 2 Each is independently the same or different C1-C5 alkyl;

[0028] n 1 is an integer from 1 to 5; and

[0029] n 2 is an integer from 1 to 4;

[0030] Compounds of the following formula (Ia) with or without a catalyst in the presence or absence of a solvent

[0031]

[0032] React with the following L-pyroglutamic acid (L-PGA)

[0033]

[0034] It includes the step of obtaining a compound of the chemical formula (Ib).

[0035] In another embodiment, the present invention provides a method for preparing a compound of the following chemical formula (Id), and

[0036]

[0037] In the above formula

[0038] R 1 Each is independently Cl, F, Br, I, OCH3, CN, or NO2;

[0039] R 2 Each is independently the same or different C1-C5 alkyl;

[0040] n 1 is an integer from 1 to 5; and

[0041] n 2 is an integer from 1 to 4;

[0042] Compounds of the following formula (Ia) in the presence of a solvent and with or without a catalyst

[0043]

[0044] React with the following D-pyroglutamic acid (D-PGA)

[0045]

[0046] It includes the step of obtaining a compound of the chemical formula (Id).

[0047] In another embodiment, the present invention provides a method for preparing a compound of the following formula (Ic), and

[0048]

[0049] a) A compound of the following chemical formula (Ib)

[0050]

[0051] A step of reacting with a base and a solvent to provide a compound of the following chemical formula (I); and

[0052]

[0053] b) the compound of the above chemical formula (I)

[0054] React with the following S (+) camphor sulfonic acid (CSA)

[0055]

[0056] The method includes the step of providing a compound of the chemical formula (Ic),

[0057] In the above formula

[0058] R 1 Each is independently Cl, F, Br, I, OCH3, CN, or NO 2이고 ;

[0059] R 2 Each is independently the same or different C1-C5 alkyl;

[0060] n 1 is an integer from 1 to 5; and

[0061] n 2 is an integer from 1 to 4.

[0062] In another embodiment, the present invention provides a compound represented by the following structure, a pharmaceutically acceptable salt thereof, or a combination thereof:

[0063]

[0064] The above salts are chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, It includes sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof.

[0065] In another embodiment, the present invention provides a compound represented by the following structure:

[0066]

[0067] The above X includes the following: chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof. Brief explanation of the drawing

[0068] Fig. 1 Shows an HPLC chromatogram showing the chiral purity of the compound (1b). Fig. 2 1c shows an HPLC chromatogram showing the chiral purity of the compound. Specific details for implementing the invention

[0069] In the following detailed description, numerous specific details are provided to provide a complete understanding of the invention. However, it will be understood by those skilled in the art that the invention may be practiced without these specific details. In other examples, well-known methods, procedures, and components are not described in detail to avoid obscuring the invention.

[0070] Method for preparing a compound of chemical formula (I) and its salt

[0071] In one embodiment, the present invention provides a method for preparing a compound of formula (Iz), wherein the compound of formula (Ia) is prepared.

[0072]

[0073] X 1 Overreact

[0074] The method comprises the step of providing a compound of the following chemical formula (Iz).

[0075]

[0076] In the above formula

[0077] X 1 is a chiral salt;

[0078] R 1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0079] R 2 Each is independently the same or different C1-C5 alkyl;

[0080] n 1 is an integer from 1 to 5; and

[0081] n 2 is an integer from 1 to 4.

[0082] In one embodiment, the chiral salt comprises L-pyroglutamic acid (L-PGA), L-aspartic acid, L-leucine, S-mandelic acid, N-acetyl-L-tyrosine, N-acetyl-L-valine, S(+)CSA (camposulfonic acid), and L-glutamic acid. Each possibility represents an individual embodiment of the present invention.

[0083] In another embodiment, the present invention provides a method for preparing a compound of formula (Ib), wherein the compound of formula (Ia) is prepared.

[0084]

[0085] Overreact,

[0086] The method comprises the step of providing a compound of the following chemical formula (Ib).

[0087]

[0088] In the above formula

[0089] R1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0090] R 2 Each is independently the same or different C1-C5 alkyl;

[0091] n 1 is an integer from 1 to 5; and

[0092] n 2 is an integer from 1 to 4.

[0093] Each possibility represents an individual embodiment of the present invention.

[0094] In one embodiment, the compounds of formulas (Iz), (Ia), and (Ib) are represented as the compounds of the following formulas (Iz-1), (Ia-1), and (Ib-1), respectively:

[0095]

[0096] Each possibility represents an individual embodiment of the present invention.

[0097] In another embodiment, compounds of formulas (Iz), (Ia), and (Ib) are represented as compounds (1z), (1a), and (1b), respectively, having the following structures:

[0098]

[0099]

[0100] Each possibility represents an individual embodiment of the present invention.

[0101] In another embodiment, the present invention provides a method for preparing a compound of formula (I), (I-1) or compound (1), wherein the compound of formula (Iz), (Iz-1) or (1z)

[0102]

[0103]

[0104]

[0105] The step of reacting with a base to provide a compound of the following chemical formula (I), (I-1) or compound (1), respectively:

[0106]

[0107]

[0108]

[0109] In the above formula

[0110] X 1 L-pyroglutamic acid ( L-PGA ), selected from L-aspartic acid, L-leucine, S-mandelic acid, N-acetyl-L-tyrosine, N-acetyl-L-valine, S(+)CSA (camposulfonic acid) and L-glutamic acid;

[0111] R 1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0112] R 2 Each is independently the same or different C1-C5 alkyl;

[0113] n 1 is an integer from 1 to 5; and

[0114] n 2 is an integer from 1 to 4.

[0115] Each possibility represents an individual embodiment of the present invention.

[0116] In another embodiment, the present invention provides a method for preparing a compound of formula (I), (I-1) or compound (1), wherein the compound of formula (Ib), (Ib-1) or (1b)

[0117]

[0118]

[0119]

[0120] A method comprising reacting with a base to provide a compound of the following chemical formula (I), (I-1) or compound (1), respectively:

[0121]

[0122]

[0123]

[0124] In the above formula

[0125] R 1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0126] R 2 Each is independently the same or different C1-C5 alkyl;

[0127] n 1 is an integer from 1 to 5; and

[0128] n 2 is an integer from 1 to 4.

[0129] Each possibility represents an individual embodiment of the present invention.

[0130] In another embodiment, the method further comprises the step of converting a free-base compound of formula (I), (I-1) or compound (1) into a pharmaceutically acceptable salt thereof by adding, for example, each acid, for example hydrochloric acid, to the compound to obtain a chloride salt. In another embodiment, the salt is chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, pyroglutamate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, Picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof. Each possibility represents an individual embodiment of the present invention.

[0131] Surprisingly, L-PGA is X in the splitting of the racemic compound (1a) and the provision of the pure compound (1). 1The chiral acid was the most successful. In another embodiment, the S(+) enantiomer CSA (camphosulfonic acid) salt of formula (Ia), (Ia-1) or compound (1a) (represented by formula (Ic), (Ic-1a) or compound (1c); see below) was formed by reacting a compound represented by formula (Ib), (Ib-1) or compound (1b) (structure provided herein) with a base, and then reacting it with S(+)CSA. The formed S(+)CSA salt (represented by the structure of formula (Ic), (Ic-1) or compound (1c)) was obtained with a high chiral purity of greater than 99%, greater than 99.1%, greater than 99.2%, greater than 99.3%, greater than 99.4%, greater than 99.5%, greater than 99.6%, or greater than 99.7%. In one embodiment, the chiral purity of the CSA salt (e.g., represented by formula (Ic)) is higher than the chiral purity of the PGA salt (e.g., represented by formula (Ib)). In another embodiment, the chiral purity of the CSA salt is lower than, similar to, or equal to the chiral purity of the PGA salt. Each possibility represents an individual embodiment of the present invention.

[0132]

[0133] In another embodiment, the present invention provides a method for preparing a compound of formula (Ic), (Ic-1) or compound (1c), and

[0134] a) Compounds of the above formulas (Ib), (Ib-1) or (1b)

[0135]

[0136]

[0137]

[0138] A step of reacting with a base to provide a compound of the following chemical formula (I), (I-1) or compound (1), respectively.

[0139]

[0140]

[0141]

[0142] b) The following S (+) CSA

[0143]

[0144] The method includes the step of reacting with a compound of chemical formula (I), (I-1) or compound (1) to provide a compound of chemical formula (Ic), (Ic-1) or compound (1c), respectively.

[0145]

[0146]

[0147]

[0148] In the above formula

[0149] R 1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0150] R 2 Each is independently the same or different C1-C5 alkyl;

[0151] n 1 is an integer from 1 to 5; and

[0152] n 2 is an integer from 1 to 4.

[0153] Each possibility represents an individual embodiment of the present invention.

[0154] In another embodiment, the present invention provides a method for preparing a compound of formula (I), (I-1) or compound (1), comprising the step of reacting a compound of formula (Ic), (Ic-1) or compound (1c) with a base as described herein for the method of formula (I), (I-1) or compound (1b).

[0155] In this regard, it should be noted that in the method of the present invention, the reaction of a racemic compound (represented by the structure of formula (Ia), formula (Ia-1), or compound (1a)) with a chiral CSA does not cause the cleavage of the racemic compound. Instead, the chiral CSA is a chiral amine free-base In-situ ( in-situ Replaces chiral PGA within a chiral salt (a compound represented by the chemical formula (Ib), (Ib-1), or compound (1b)) through the formation of ).

[0156] In some embodiments, reacting a compound represented by formula (Ia), (Ia-1) or compound (1a) with an acid having reverse chirality (e.g., D-PGA instead of L-PGA) in a method according to the present invention as described herein above results in the formation of a remanent isomer salt of a compound represented by formula (Ib), (Ib-1) or compound (1b). This compound is represented by the structure of the following formula (Izi), (Izi-1a) or compound (1zi) and

[0157]

[0158]

[0159]

[0160] In the above formula

[0161] X 1i is selected from D-pyroglutamic acid (D-PGA), D-aspartic acid, D-leucine, R-mandelic acid, N-acetyl-D-tyrosine, N-acetyl-D-valine, R(-)CSA (camphosulfonic acid) and D-glutamic acid;

[0162] R 1 Each is independently F, Cl, Br, I, OCH3, CN, or NO2;

[0163] R 2 Each is independently the same or different C1-C5 alkyl;

[0164] n 1is an integer from 1 to 5; and

[0165] n 2 is an integer from 1 to 4.

[0166] Each possibility represents an individual embodiment of the present invention.

[0167] In some embodiments, in the method according to the present invention as described herein, reacting the compound represented by formula (Ia), (Ia-1) or compound (1a) with D-PGA instead of L-PGA results in the formation of a remanent isomer salt of the compound represented by formula (Ib), (Ib-1) or compound (1b). This compound is represented by the structure of the following formula (Id), (Id-1a) or compound (1d):

[0168]

[0169]

[0170]

[0171] Each possibility represents an individual embodiment of the present invention.

[0172] In some embodiments, a method for preparing a compound of formulas (Iz), (Izi), (Iz-1), (Izi-1) or compound (1z) or (1zi) further comprises the steps of adding an anti-solvent to a reaction mixture, followed by quenching the reaction; and reacting the mixture with the anti-solvent, wherein formulas (Iz), (Izi), (Iz-1), (Izi-1) or compound (1z) or (1zi) are as defined herein. In one embodiment, the method comprises the following steps:

[0173] a. A compound of chemical formula (Ia), (Ia-1) or compound (1a) X 1 or X 1iA step of reacting with to provide a compound of the chemical formula (Iz), (Izi), (Iz-1), (Izi-1) or compound (1z) or (1zi);

[0174] b. A step of quenching the reaction of step (a);

[0175] c. A step of adding a semi-solvent to the reaction mixture of step (b); and

[0176] d. A step of reacting the mixture from step (b) with a semi-solvent,

[0177] The above chemical formulas (Ia), (Ia-1), (Iz), (Izi), (Iz-1), (Izi-1) and compounds (1a), (1z) and (1zi) are as defined in the above invention.

[0178] In some embodiments, a method for preparing a compound of formula (Ib), (Ib-1) or compound (1b) comprises the steps of adding a semi-solvent to a reaction mixture, followed by quenching the reaction; and reacting the mixture with the semi-solvent, wherein formula (Ib), (Ib-1) and compound (1b) are as defined herein. In one embodiment, the method comprises the following steps:

[0179] a. A step of reacting a compound of formula (Ia), (Ia-1) or compound (1a) with L-pyroglutamic acid (L-PGA) to provide a compound of formula (Ib), (Ib-1) or compound (1b);

[0180] b. A step of quenching the reaction of step (a);

[0181] c. A step of adding a semi-solvent to the reaction mixture of step (b); and

[0182] d. A step of reacting the mixture from step (b) with a semi-solvent,

[0183] The above chemical formulas (Ia), (Ia-1), (Ib), (Ib-1) and compounds (1a) and (1b) are as defined in the above invention.

[0184] In some embodiments, a method for preparing a compound of formulas (Iz), (Izi), (Iz-1), (Izi-1) or compound (1z) or (1zi) further comprises the step of adding a semi-solvent and a catalyst to a reaction mixture and reacting the mixture with the semi-solvent and the catalyst, wherein formulas (Iz), (Izi), (Iz-1), (Izi-1) or compound (1z) or (1zi) are as defined herein. In one embodiment, the method comprises the following step:

[0185] a. Compound of chemical formula (Ia), (Ia-1) and compound (1a) X 1 or X 1i A step of reacting with for a certain period to provide a compound of the chemical formula (Iz), (Izi), (Iz-1), (Izi-1) or compound (1z) or (1zi);

[0186] b. Adding a catalyst to the reaction mixture of step (a) and reacting the reaction mixture of step (a) with the catalyst for an additional period;

[0187] c. A step of quenching the reaction of step (b);

[0188] d. A step of adding a semi-solvent to the reaction mixture of step (c); and

[0189] e. A step of reacting the mixture of step (c) with a semi-solvent,

[0190] The above chemical formulas (Ia), (Ia-1), (Iz), (Izi), (Iz-1), (Izi-1) and compounds (1a), (1z) and (1zi) are as defined in the above invention.

[0191] In some embodiments, a method for preparing compounds of formulas (Ib), (Ib-1) and compound (1b) further comprises the step of adding a semi-solvent and a catalyst to a reaction mixture and reacting the mixture with the semi-solvent and the catalyst, wherein formulas (Ib), (Ib-1) and compound (1b) are as defined herein. In one embodiment, the method comprises the following steps:

[0192] a. A step of reacting compounds of formulas (Ia), (Ia-1) and compound (1a) with L-pyroglutamic acid (L-PGA) for a certain period of time to provide compounds of formulas (Ib), (Ib-1) and compound (1b);

[0193] b. Adding a catalyst to the reaction mixture of step (a) and reacting the reaction mixture of step (a) with the catalyst for an additional period;

[0194] c. A step of quenching the reaction of step (b);

[0195] d. A step of adding a semi-solvent to the reaction mixture of step (c); and

[0196] e. A step of reacting the mixture of step (c) with a semi-solvent,

[0197] The above chemical formulas (Ia), (Ia-1), (Ib), (Ib-1) and compounds (1a) and (1b) are as defined in the above invention.

[0198] In one embodiment, the anti-solvent is cyclohexane, heptane, hexane, or petroleum ether. In one embodiment, quenching is performed by cooling to 25 to 35°C. Each of these possibilities represents an individual embodiment of the present invention.

[0199] In one embodiment, the yield of a preferred chiral salt (e.g., compounds of formulas (Iz), (Ib), (Id), or (Izi), or compounds of (1z), (1b), (1d), or (1zi)) is less than 50%. In one additional embodiment, the yield of a preferred chiral salt (e.g., compounds of formulas (Iz), (Ib), (Id), or (Izi), or compounds of (1z), (1b), (1d), or (1zi)) is greater than 50%. In another embodiment, the yield is greater than 55%. In another embodiment, the yield is greater than 60%. In another embodiment, the yield is greater than 65%. In another embodiment, the yield is greater than 70%. In another embodiment, the yield is greater than 75%. In another embodiment, the yield is greater than 80%. In another embodiment, the yield is greater than 85%. In another embodiment, the yield is greater than 90%. In another embodiment, the yield is greater than 95%. In another embodiment, the yield is greater than 99%. In some embodiments, when the yield of a desired chiral salt (e.g., formulas (Iz), (Ib), (Id), or (Izi), or compounds of compounds (1z), (1b), (1d), or (1zi)) is less than 50%, the reaction is said to proceed by a chiral cleavage mechanism. Chiral cleavage is, (e.g., Dale, JA et al., J. Org. Chem. 1969, 34(9): 2543-2549) For example, this is found when a racemic mixture reacts with a chiral acid / base to provide a chiral salt from the initial racemic mixture in a yield of up to 50% (one stereoisomer of the chiral salt precipitate in solution and the other enantiomer of the other enantiomer in the racemate are dissolved in or not formed at all). In some embodiments, when the yield of the desired chiral salt (e.g., compounds of formulas (Iz), (Ib), (Id), or (Iz), or compounds of compounds (1z), (1b), (1d), or (1zi)) exceeds 50%, the reaction is carried out via dynamic kinetic splitting (DKR). (Pellisier et al., Tetrahedron 2003, 59, 8291-8327). Using DKR, a racemic mixture reacts with a chiral acid / base to provide a chiral salt, and if the yield exceeds 50%, at least a portion of the opposite, undesirable enantiomer (in the racemic mixture) is dynamically converted (i.e., epimerized) into the desired enantiomer during the process. In one embodiment, DKR occurs in the absence of a catalyst. In another embodiment, DKR occurs in the presence of a catalyst. In one embodiment, the catalyst is an aldehyde catalyst. In another embodiment, the catalyst is benzaldehyde, salicylaldehyde, 3,5-dichlorosalicylaldehyde, or p-nitrobenzaldehyde. Each possibility represents an individual embodiment of the present invention.

[0200] In another embodiment, the fixed period and additional period of each step (a) and (b) are each independently 0.5 to 48 hours. In another embodiment, the period or additional period is 1 to 3, 3 to 5, 5 to 10, 10 to 24, or 24 to 48 hours. Each possibility represents an individual embodiment of the present invention.

[0201] In one embodiment, Example 2 provides a method for preparing compound (1).

[0202] In some embodiments, the method as described herein produces, for example, a chiral compound or salt of formulas (I), (Ib), (Iz), (Ic), (Id), or (Izi) with a chiral purity of greater than 99%. In another embodiment, the chiral purity is greater than 99.4%. In yet another embodiment, the chiral purity is greater than 99.5%. Each possibility represents an individual embodiment of the present invention.

[0203] In some embodiments, the base used in the method of the present invention comprises an inorganic or organic base or any combination thereof. In one embodiment, the inorganic base comprises: an alkali metal hydroxide, an alkali metal hydride, an alkali metal alkoxide, an alkali metal carboxylate, an alkali metal carbonate or bicarbonate, or any combination thereof. In another embodiment, non-limiting examples of the alkali metal hydroxide include: lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof. In another embodiment, non-limiting examples of the alkali metal hydride include: sodium hydride, potassium hydride, or a combination thereof. In another embodiment, non-limiting examples of the alkali metal alkoxide include: sodium methoxide, sodium ethoxide, lithium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, or a combination thereof. In another embodiment, non-limiting examples of alkali metal carboxylates include: sodium formate, potassium formate, sodium acetate, potassium acetate, or combinations thereof. In another embodiment, non-limiting examples of alkali metal carbonates or bicarbonates include: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or combinations thereof. In one embodiment, the organic base includes: primary amine, secondary amine, aromatic amine, tertiary amine, or any combination thereof. In another embodiment, non-limiting examples of amines include: triethylamine, tributylamine, diisopropylethylamine, diethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, or combinations thereof. In another embodiment, the alkali metal bicarbonate is sodium bicarbonate.In another embodiment, the alkali metal bicarbonate is aqueous or non-aqueous sodium bicarbonate. Each possibility represents an individual embodiment of the present invention.

[0204] In some embodiments, a solvent is used within the method of the present invention. In one embodiment, the solvent comprises an alcoholic solvent, an ester solvent, an ether solvent, a hydrocarbon solvent, a polar aprotic solvent, a ketone solvent, a chloro-based solvent, a nitrile solvent, a polar solvent, or any combination thereof. In another embodiment, non-limiting examples of an alcoholic solvent include: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or a combination thereof. In another embodiment, non-limiting examples of an ester solvent include: ethyl acetate, methyl acetate, isopropyl acetate, or a combination thereof. In another embodiment, non-limiting examples of an ether solvent include: tetrahydrofuran, diethyl ether, methyl tert-butyl ether, or a combination thereof. In another embodiment, non-limiting examples of hydrocarbon solvents include: toluene, hexane, heptane, cyclohexane, or combinations thereof. In another embodiment, non-limiting examples of polar aprotic solvents include: dimethylacetamide, dimethylformamide, dimethyl sulfoxide, or combinations thereof. In another embodiment, non-limiting examples of ketone solvents include: acetone, methyl ethyl ketone, methyl isobutyl ketone, or combinations thereof. In another embodiment, non-limiting examples of chlorogenic solvents include: methylene chloride, chloroform, ethylene dichloride, or combinations thereof. In another embodiment, non-limiting examples of nitrile solvents include: acetonitrile, propionitrile, or combinations thereof. In another embodiment, non-limiting examples of polar solvents include water. In another embodiment, the solvent is ethanol. In another embodiment, the solvent is isopropyl acetate.In another embodiment, when a solvent such as water is used, for example, in the basing step within the method described herein, the product (e.g., compound of formula (I), (I-1), or compound (1)) is isolated directly, for example, by filtration. In another embodiment, the basing step using an aqueous base (e.g., KHCO3(aq)) is carried out in the presence of a non-aqueous solvent, such as methylene chloride, and then the non-aqueous solvent is separated from the product (e.g., compound of formula (I), (I-1), or compound (1)) and then evaporated. Each possibility represents an individual embodiment of the present invention.

[0205] In another embodiment, the method of the present invention involves the use of a catalyst. In another embodiment, the catalyst is optionally used in the chiral salt formation step (providing a compound of formula (Ib), (Ib-1), (Iz), (Iz-1), (Ic), (Ic-1), (Id), (Id-1), (Izi), (Izi-1) or compounds (1b), (1z), (1c), (1d) or (1zi)) (i.e., may or may not be used). In another embodiment, the catalyst is an aromatic aldehyde catalyst. In another embodiment, the catalyst is benzaldehyde, salicylaldehyde, 3,5-dichlorosalicylaldehyde, p-nitrobenzaldehyde, or any combination thereof. In another embodiment, the catalyst is 3,5-dichlorosalicylaldehyde. In another embodiment, 0.001 to 1.0 molar equivalents of a catalyst are used relative to a compound of formula (Ia), (Ia-1), or compound (1a). In another embodiment, 0.03 molar equivalents of a catalyst are used relative to a compound of formula (Ia), (Ia-1), or compound (1a). Each possibility represents an individual embodiment of the present invention.

[0206] Without being bound by any mechanism or theory, the anti-solvent and / or catalyst in the method of the present invention is considered to provide a higher yield and / or purity of the provided chiral acid salt (e.g., compounds of formulas (Iz), (Ib), (Izi), (Iz-1), (Ib-1) or compounds of (1z), (1zi), or (1b).

[0207] In another embodiment, the reaction within the method of the present invention (e.g., a salt-forming step and / or basing to provide a chiral product) is carried out at a temperature of -5 to 100°C. In another embodiment, the temperature range is 60 to 65°C. In another embodiment, the temperature range is 0 to 45°C. In another embodiment, the temperature range is -5 to 45°C. In another embodiment, the temperature range is 5 to 10°C. In another embodiment, the temperature range is -5 to 35°C. In another embodiment, the temperature range is 0 to 35°C. In another embodiment, the temperature is 60°C. In another embodiment, the temperature range is 0 to 100°C. In another embodiment, the salt-forming step is carried out at -5 to 35°C or 60 to 65°C. In another embodiment, basicization to provide a chiral product is performed at 0 to 45°C or 5 to 10°C. Each possibility represents an individual embodiment of the present invention.

[0208] Compounds (1a) to (1d)

[0209] In another embodiment, the present invention is a compound represented by the following structure

[0210]

[0211] and / or any pharmaceutically acceptable salt thereof is provided.

[0212] In another embodiment, the present invention is a compound represented by the following structure

[0213]

[0214] and provides any pharmaceutically acceptable salt thereof.

[0215] In another embodiment, the present invention is a compound represented by the following structure

[0216]

[0217] Or provide any pharmaceutically acceptable salt thereof.

[0218] In another embodiment, the present invention is a compound represented by the following structure

[0219]

[0220] Provides a pharmaceutically acceptable salt of this, or a combination thereof.

[0221] In another embodiment, the present invention provides a mixture or combination comprising a) a compound (1a) in the form of a free base and b) a compound (1a) in the form of a pharmaceutically acceptable salt, wherein the compound (1a) is as described herein.

[0222] In another embodiment, the present invention provides a compound represented by the structure of compound (2):

[0223]

[0224] The above X includes the following: chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt, or any combination thereof.

[0225] In one embodiment, the compound described herein, which is compound (1a), is a free base. In another embodiment, the compound is a pharmaceutically acceptable salt form. In one embodiment, the free base comprises a compound in which the amine moiety of compound (NH2) is not protonated. In one embodiment, the pharmaceutically acceptable salt form comprises a compound in which the amine moiety of compound (NH2) is protonated and the entire compound is positively charged. In one embodiment, a counter anion is used to balance the charge. In another embodiment, compound (1a) is chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, pyroglutamate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, Phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonate, tartrate, thiocyanate, toluenesulfonate, or undecanoate salt forms, or any combination thereof. Each possibility represents an individual embodiment of the present invention.

[0226] In another embodiment, the present invention provides a compound represented by the following structure:

[0227]

[0228] In another embodiment, the present invention provides a compound represented by the following structure:

[0229]

[0230] The above S-(+)-camphosulfonic acid (CSA)

[0231]

[0232] In another embodiment, the present invention provides a compound represented by the following structure:

[0233]

[0234] Each possibility represents an individual embodiment of the present invention.

[0235] In some embodiments, the present invention provides compounds (1a)-(1c) for use as intermediates in the preparation of (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide as presented below:

[0236]

[0237] In one embodiment, the chiral compound (1) is prepared from compounds (1a) to (1c) using the method of the present invention as described below in “Method for preparing the compound of formula (I) and its salt”.

[0238]

[0239] In one embodiment, the chiral compound (2) is prepared from compounds (1a) to (1c) using the method of the present invention as described below in “Method for preparing the compound of formula (I) and its salt”.

[0240]

[0241] The preparation of (2R,3S)-N-[(3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinimide from compound (1) is further detailed in U.S. 9,273,014, the whole of which is incorporated herein by reference.

[0242] definition

[0243] In some embodiments, each R 1 is independently F, Cl, Br, I, OCH3, CN, or NO2. In one embodiment, n 1 When this is greater than 1, each R 1 It is the same or different. Each possibility represents an individual embodiment of the present invention.

[0244] In some embodiments, each R 2 is independently a C1-C5 alkyl. In one embodiment, the term "alkyl" refers to a branched-chain and straight-chain saturated aliphatic hydrocarbon group containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 5 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears as a subscript following the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-5 "Alkyl" refers to straight-chain and branched-chain alkyl groups having 1 to 5 carbon atoms. Each possibility represents an individual embodiment of the present invention.

[0245] In some implementations, n 1n is an integer from 1 to 5. In one embodiment, n 1 is 1, 2, 3, 4, or 5. Each possibility represents an individual embodiment of the present invention.

[0246] In some embodiments, n 2 is an integer from 1 to 4. In one embodiment, n 1 It is 1, 2, 3, or 4. Each possibility represents an individual embodiment of the present invention.

[0247] In the context of the present invention, the term "reacting" is defined as providing one or more conditions (e.g., heating, reflux) sufficient for the reactants to chemically react.

[0248] In some embodiments, when the following moiety is found in a compound as described herein (e.g., a compound represented by the chemical formulas (Ib), (Id), (Ib-1), (Id-1) and the structures of compounds (1b) and (1d)

[0249]

[0250] It should be understood that at least some of the moiety can be represented by the following ion pair structures.

[0251]

[0252] In some embodiments, when the following moiety is found in a compound as described herein (e.g., a compound represented by the structure of formula (Ic), (Ic-1) and compound (1c)

[0253]

[0254] It should be understood that at least some of the moiety can be represented by the following ion pair structures.

[0255]

[0256] In one embodiment, all (or almost all, e.g., more than 99%) of the amine within the structure / embodiment is protonated and all (or almost all, e.g., more than 99%) of the carboxylic acid / sulfonic acid is deprotonated. In some embodiments, notation " " means "arbitrary moiety".

[0257] The following examples are presented to more fully illustrate preferred embodiments of the present invention. However, they should not be construed as limiting the broad scope of the present invention.

[0258] Examples

[0259] Example 1

[0260] Synthesis of Compound (1) - Method A

[0261]

[0262] Compound (1a) (0.5 g, 1.0 eq; see Synthesis thereof below) was dissolved in EtOH (10 mL, 20 vol) and stirred at 25 to 35°C for 10 minutes. L-pyroglutamic acid or (S)-(-)-2-pyrrolidone-5-carboxylic acid (0.23 g, 1.0 eq) was added (a clear solution followed by a solid precipitate at 25 to 35°C), the contents were heated to 60 to 65°C, stirred for 1.0 hour, and then cooled to 25 to 35°C. Then, cyclohexane (20 mL, 40 vol) was added, and the solid precipitate was filtered and washed with cyclohexane (5 mL, 10 vol). The washed solid was dried at 45°C to obtain compound (1b) (0.5 g; 68.4% yield from (1a)). The chiral HPLC purity of compound (1b) was 99.4%, and the purity of the other isomer was 0.6% (Fig. 1). Chiral purity was measured using an HPLC with the following: a ChiralPack OJ-RH column (50 x 4.6 mm, 5 μ), a mobile phase of 10 mM ammonium acetate in water:acetonitrile (80:20), ammonium hydroxide, methanol diluent, a flow rate of 1.2 ml / min, and a pH of 7.5 adjusted to an isolytic gradient. Under these conditions, the retention time of compound (1b) was 9.54 minutes. When 0.5 g of compound (1a) was used, 0.5 g of compound (1b) was obtained; when 2 g of compound (1a) was used, 1.72 g of compound (1b) was obtained; and when 5 g of compound (1a) was used, 4.5 g of compound (1b) was obtained.

[0263] 0.5 g of compound (1b) was dissolved in water (5 mL, 10 vol) and the pH was adjusted to 8.0 to 8.5 with a 10% NaHCO3 solution at 25 to 35°C. The aqueous layer was extracted with EtOAc (270 mL). The combined organic layer was dried over Na2SO4, filtered, and the organic layer was distilled off under vacuum at 30 to 35°C. Cyclohexane was added to the dried organic layer (5 mL, 10 vol), and the resulting solution was stirred for 12 hours. The resulting precipitate was filtered, washed with cyclohexane (2.5 mL, 5.0 vol), and then dried at 50 to 55°C for 16 hours to obtain 0.2 g of compound (1) as the S isomer of compound (1a). When 0.2 g of compound (1b) was used, 0.13 g of compound (1) was obtained.

[0264] The separation of compound (1a) using pyroglutamic acid in ethanol provided excellent separation of R & S isomers due to the difference in solubility of the formed diastereomer salts. The S-isomer of compound (1a), i.e., compound (1), was isolated with a chiral purity of over 99.4% after treating the diastereomer salt of the S-isomer with aqueous NaHCO3.

[0265] Example 2

[0266] Synthesis of compound (1d)

[0267]

[0268] Compound (1a) (500 mg, 1.0 eq.) was dissolved in EtOH (10 ml) and stirred for 10 minutes. Next, D-pyroglutamic acid (D-PGA; 0.228 gr, 1.0 eq) was added, the contents were heated to 60 to 65°C and then stirred for 1.0 hour, followed by cooling to 25 to 35°C. Cyclohexane (20 mL) was subsequently added, the resulting mixture was stirred at 25 to 35°C for 1.0 hour, and filtered. The obtained solid was washed with cyclohexane and dried at 50 to 55°C to obtain compound (1d) in a yield of 0.43 gr / 59.1%.

[0269] Example 3

[0270] Non-PGA salts do not divide compound (1a)

[0271] L-aspartic acid, L-leucine, S-mandelic acid, N-acetyl-L-tyrosine, N-acetyl-L-valine, S(+)CSA (camphosulfonic acid), and L-glutamic acid were used in a manner similar to that in Method A of Example 1 using L-PGS. L-aspartic acid, L-leucine, and N-acetyl-L-tyrosine did not form salts with compound (1a). Salt formation of N-acetyl-L-valine, S(+)CSA, and L-glutamic acid was observed with compound (1a), but splitting was not observed by chiral HPLC after isolation of the salts (a 50:50 mixture of R:S isomers).

[0272] Example 4

[0273] Synthesis of compound (1c)

[0274]

[0275] 1.0 gr (1.0 eq.) of compound (1b) was dissolved in water (10 vol), and the pH was adjusted to 8.0 to 8.5 with a 5% NaHCO3 solution (0.5 gr, 0.5 w / w% 10 vol) at 25 to 35°C. The mixture was stirred for 30 minutes. AcOiPr (40 ml) was added, and the resulting mixture was stirred for 30 minutes, after which the two layers were separated. The aqueous layer was extracted with AcOiPr (15 ml). The combined organic layer was dried over NaSO4 (2.0 g), filtered, washed with AcOiPr (5 ml), and then the filtrate was dissolved in a round-bottom flask (RBF). S-CSA (0.56 gr / 1.0 eq.) was added to the RBF, and the resulting mixture was stirred for 4 hours. The resulting solid was filtered, the compound was washed with AcOiPr (5.0 ml), and dried at 60 to 65°C for 16 hours. The yield of compound (1c) was 0.95 gr / 60.8%, and the chiral purity was 99.88%. When the reaction was upscaled by a factor of 5 (i.e., using 5.0 eq. (5.0 gr) of compound (1b) and a corresponding amount of other reagent / solvent), compound (1c) was obtained in a 75% yield, which had an HPLC chiral purity of 99.64% (Fig. 2). Chiral purity was measured using an HPLC with the following: a ChiralPack OJ-RH column (50 x 4.6 mm, 5 μ), a mobile phase of 10 mM ammonium acetate in water:acetonitrile (80:20), ammonium hydroxide, methanol diluent, a flow rate of 1.0 ml / min, and a pH of 7.5 adjusted to an isolytic gradient. Under these conditions, the retention time of compound (1c) was 8.03 min.

[0276] Example 5

[0277] Synthesis of compound (1) - Method B (adding cyclohexane)

[0278] Example 1 was repeated using a modified procedure to prepare compound (1b):

[0279] 2.0 gr of compound (1a) (1.0 eq.) was dissolved in EtOH (10 ml) and the solution was stirred for 10 minutes. Then, L-pyroglutamic acid (0.91 gr, 1.0 eq) was added, the contents were heated to 60 to 65°C and stirred for 8.0 hours, and then cooled to 25 to 35°C. Then, cyclohexane (80 ml) was added, the resulting mixture was stirred at 25 to 35°C for 12 hours and filtered. The obtained solid was washed with cyclohexane (80 ml) and dried at 50 to 55°C to produce compound (1b) in a yield of 1.72 gr / 59.1%. Compound (1) was prepared from compound (1b) as in Example 1.

[0280] Example 6

[0281] Synthesis of compound (1) - Method C (addition of 3,5-dichlorosalicylate)

[0282] Example 1 was repeated using a modified procedure for the preparation of compound (1b):

[0283] 2.0 gr of compound (1a) (1.0 eq.) was dissolved in EtOH (40 ml) and the solution was stirred for 10 minutes. Then, L-pyroglutamic acid (0.91 gr, 1.0 eq) was added, the contents were heated to 60 to 65°C and stirred for 4.0 hours. Then, 3,5-dichlorosalicylaldehyde (0.03 eq) was added, the contents were maintained at 60 to 65°C for 4.0 hours, and then cooled to 25 to 35°C. Then, cyclohexane (80 ml) was added. The resulting mixture was stirred at 25 to 35°C for 12 hours and filtered. The obtained solid was washed with cyclohexane (80 ml) and dried at 50 to 55°C to produce compound (1b) in a yield of 2.38 gr / 79.9%. Compound (1) was prepared from compound (1b) as in Example 1.

[0284] Example 7

[0285] Synthesis of compound (1a)

[0286]

[0287]

[0288] Step 1

[0289]

[0290] The experiment was performed on a 150 g scale: 150 gr (1 eq.) 1ab, 200.3 gr (1.05 eq.) 1aa, 144.2 gr (1.25 eq.) glyoxalic acid, and 4.5 L toluene were mixed at 55 to 60°C for 6 hours. The progress of the reaction was monitored by TLC. The starting material was present at approximately 2 to 3% after 4 hours. After the reaction was complete, the mixture was cooled to 25 to 30°C, and purified water (10 vol) was added. The resulting mixture was stirred for 1.0 hour, and the contents were filtered. The obtained slurry was washed with water (15 vol) and then washed with toluene (5 vol) and MTBE (10 vol). Subsequently, the slurry was dried in a vacuum oven at 70 to 75°C with a purity of 97.11% (HPLC) and a yield of 375 gr / 91.3%.

[0291] Step 2A

[0292]

[0293] The experiment was performed on a 10 g scale: 10 gr (1 eq.) 1 ad, 12.9 gr (2.0 eq.) methoxymethylamine, 23.3 gr (1.1 eq.) TBTU, 40.1 ml (3.4 eq.) DIPEA, and 100 ml THF were mixed at 25 to 35°C for 8 hours. The progress of the reaction was monitored by TLC, and the starting material was present at less than ~1.0% after 8 hours. After the reaction was complete, 10% aq NaHCO3 solution (10 vol) was added and the mixture was stirred for 30 minutes, then isopropyl acetate (10 vol) was added and the resulting mixture was stirred for 30 minutes. The two layers were separated. The organic layer was washed with a 10% aq NaHCO3 solution (2 x 5 vol), water (5 vol), and a brine solution (5 vol), then dried over Na2SO4, filtered, and concentrated under vacuum to obtain the compound, which was confirmed by HNMR and mass. The yield was 13.1 gr.

[0294] Step 2

[0295]

[0296] The experiment was performed on a 13 g scale: 13 gr (1 eq.) 1 ae, 51.9 gr (3.5 eq.) 3-fluoro-1-iodo-benzene, 93.5 ml (3.5 eq.) 2.5 M n-BuLi, and 104 ml THF were mixed at -78 to -73 °C for 1 hour. The progress of the reaction was monitored by TLC, and the starting material was present at less than ~1.0% after 1 hour. After the reaction was complete, 20% aq ammonium chloride (13 vol) was added, and the mixture was stirred for 30 minutes; then, ethyl acetate (7 vol) was added, and the resulting mixture was stirred for 30 minutes. The two layers were separated. The organic layer was washed with a saturated brine solution (5 vol), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a crude compound, which 1 It was confirmed by ¹H NMR and mass spectrometry. The yield was 9.5 gr / 53.7%.

[0297] Step 3A

[0298]

[0299] The experiment was performed on a 9 g scale: 9 gr (1 eq.) 1af, 13.2 gr (1.2 eq.) 1c, 6.2 gr (1.2 eq.) POCl3, 18 ml (2.0 eq.) pyridine, and 45 ml THF were mixed at -345 to -30°C for 0.25 hours, and then mixed at 0 to 15°C for 1 hour. After the reaction was complete, the reaction mass was quenched with ice-cold water (5 vol) and stirred for 30 minutes, then ethyl acetate (10 vol) was added, and the resulting mixture was stirred for 30 minutes. The two layers were separated. The organic layer was washed with 1N HCl solution (10 vol), water (10 vol), 10% sodium bicarbonate solution (10 vol), water (10 vol), and saturated brine solution (4 vol), and then the resulting mixture was dried over Na2SO4, filtered, and concentrated under vacuum. Subsequently, IPA (5 vol) was added to obtain the compound, which 1 It was confirmed by HNMR and Mass. The yield was 16 gr / 88%.

[0300] Steps 3B and 3

[0301]

[0302] The experiment was performed on a scale of 15 g (1 ag). After NH3 gas purging and ammonia gas purging reactions in methanol (6.0 vol) for 1 hour at 0 to 5°C, the resulting mixture was distilled with the solvent to 4.0 vol, 5 to 6 vol methanol was added, and co-distilled to 3 to 4 vol. Acetic acid (4.0 vol) was added to the organic layer, and the solution was stirred at 25 to 30°C for 16 hours. After the reaction was complete, the solvent was distilled to 4.0 vol, the mixture was cooled to 25 to 30°C, and then IPA (6.0 vol) and water (6.0 vol) were added. The solid was filtered and washed with a mixture of IPA (6.0 vol) and purified water (10.0 vol). The product was analyzed, and the yield was 7.5 gr / 53%.

[0303] Step 4A

[0304]

[0305] The experiment was performed on a 7 g scale: 7 gr (1 eq.) compound ( 1ai ), 35 ml (5 vol) HBr in AcOH, and 175 ml MTBE were mixed at 25 to 35°C for 1 to 2 hours. The progress of the reaction was monitored by TLC, and the starting material was absent after 1 hour. After the reaction was complete, MTBE (15.0 vol) was added, the mixture was stirred for 2 hours, the contents were filtered, the slurry was washed with MTBE (10 vol), vacuum dried for 1 hour, and dried at 45 to 50°C to obtain a compound with a yield of 6.0 gr / 98%. ( 1aj I obtained ).

[0306] Step 4

[0307]

[0308] The experiment was performed on a scale of 90 g of 1 aj. Compound (1 aj) was dissolved in water (10 vol), and the pH was adjusted to 8.0 to 8.5 with a 10% NaHCO3 solution (5.0 vol) at 25 to 35°C. After pH adjustment, a heterogeneous mixture was observed. The contents were stirred at 25 to 35°C for 2.0 hours, filtered, washed with purified water (5.0 vol), and suction dried under vacuum. The wet material was extracted with EtOAc (1.0 vol) at 25 to 35°C for 30 minutes, the compound was filtered, washed with EtOAc (1.0 vol), and dried at 50 to 55°C for 16 hours. The yield was 52 gr / 85.2%.

[0309] Example 8

[0310] Dynamic kinetic splitting study of compound (1a)

[0311] Compound (1a) is converted into an S isomer (compound (1)) in one step (with high yield and high chiral purity) using a catalytic amount of benzaldehyde, salicylaldehyde, 3,5-dichlorosalicylaldehyde or p-nitrobenzaldehyde and a solvent, such as cyclohexane / EtOH or other suitable solvent system.

Claims

Claim 1 A method for preparing a compound of the following chemical formula (Ib), In the above equation, R 1 Each is independently Cl, F, Br, I, OCH3, CN, or NO2; R 2 Each is independently identical or different C 1- C5 alkyl and; n 1 is an integer from 1 to 5; n 2 is an integer from 1 to 4; a compound of the following formula (Ia) in the presence of a solvent and with or without a catalyst React with the following L-pyroglutamic acid (L-PGA) A method comprising the step of obtaining a compound of the chemical formula (Ib). Claim 2 In claim 1, the compound of formula (Ia) is represented by the following compound (1a), and the compound of formula (Ib) is represented by the following compound (1b): Claim 3 A method according to claim 1, wherein the yield of the compound of the formula (Ib) is greater than 50%. Claim 4 A method for preparing a compound of the following chemical formula (Id), In the above equation, R 1 Each is independently Cl, F, Br, I, OCH3, CN, or NO2; R 2 Each is independently identical or different C 1- C5 alkyl and; n 1 is an integer from 1 to 5; n 2 is an integer from 1 to 4; a compound of the following formula (Ia) in the presence of a solvent and with or without a catalyst react with D-pyroglutamic acid (D-PGA) A method comprising the step of obtaining a compound of the chemical formula (Id). Claim 5 A method according to claim 4, wherein the yield of the compound of the above chemical formula (Id) is greater than 50%. Claim 6 A method according to any one of claims 1 to 5, wherein the catalyst comprises at least one selected from the group consisting of benzaldehyde, salicylaldehyde, 3,5-dichlorosalicylaldehyde and p-nitrobenzaldehyde. Claim 7 In claim 6, the method wherein the catalyst comprises 3,5-dichlorosalicylaldehyde. Claim 8 A method according to any one of claims 1 to 5, wherein 0.001 to 1.0 molar equivalents of a catalyst relative to a compound of formula (Ia) are used. Claim 9 A method according to claim 8, wherein 0.03 molar equivalents of a catalyst are used relative to the compound of formula (Ia). Claim 10 A method according to any one of claims 1 to 5, wherein the solvent comprises at least one selected from the group consisting of an alcoholic solvent, an ester solvent, an ether solvent, a hydrocarbon solvent, a polar aprotic solvent, a ketone solvent, a chloro solvent, a nitrile solvent, and a polar solvent. Claim 11 In paragraph 10, the above alcoholic solvent is ethanol. Claim 12 A method according to any one of claims 1 to 5, wherein the reaction is performed at a temperature of 0 to 100°C. Claim 13 In paragraph 12, the method wherein the temperature is 60 to 65℃. Claim 14 A method for preparing a compound of the following chemical formula (Ic), a) A compound of the following chemical formula (Ib) A step of reacting with a base and a solvent to provide a compound of the following chemical formula (I); and b) React the compound of the above chemical formula (I) with the following S (+) camphosulfonic acid (CSA) The method comprises the step of providing a compound of the chemical formula (Ic), wherein R in the formula 1 Each is independently Cl, F, Br, I, OCH3, CN, or NO2; R 2 Each is independently identical or different C 1- C5 alkyl and; n 1 is an integer from 1 to 5; n 2 A method that is an integer from 1 to 4. Claim 15 In claim 14, the compound of formula (I) is represented by the following compound (1); the compound of formula (Ib) is represented by the following compound (1b); and the compound of formula (Ic) is represented by the following compound (1c). Claim 16 A method according to claim 14 or 15, wherein the base comprises at least one selected from the group consisting of inorganic bases and organic bases. Claim 17 A method according to claim 16, wherein the inorganic base comprises at least one selected from the group consisting of alkali metal hydroxides, alkali metal hydrides, alkali metal alkoxides, alkali metal carboxylates, and alkali metal carbonates and bicarbonates. Claim 18 In paragraph 17, the method wherein the alkali metal carbonate is sodium bicarbonate. Claim 19 A method according to claim 16, wherein the organic base comprises at least one selected from the group consisting of primary amines, secondary amines, aromatic amines, and tertiary amines. Claim 20 A method according to claim 14 or 15, wherein the solvent comprises at least one selected from the group consisting of an alcoholic solvent, an ester solvent, an ether solvent, a hydrocarbon solvent, a polar aprotic solvent, a ketone solvent, a chloro solvent, a nitrile solvent, and a polar solvent. Claim 21 In paragraph 20, the method wherein the ester solvent is isopropyl acetate. Claim 22 A method according to claim 14 or 15, wherein the reaction of step (a) is performed at a temperature of 0 to 45°C. Claim 23 In paragraph 22, the method wherein the temperature range is 5 to 10℃. Claim 24 A method according to any one of claims 1 to 5, 14 and 15, wherein the chiral purity of the compound of formula (I), (Ib), (Ic) or (Id) is greater than 99%. Claim 25 In paragraph 24, the method wherein the chiral purity is greater than 99.5%. Claim 26 Compounds represented by the following structures: The above X is chloride, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, maleate, 2-hydroxyethanesulfonate, lactate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, It includes at least one selected from the group consisting of sulfonate, tartrate, thiocyanate, toluenesulfonate, and undecanoate salts. Claim 27 delete

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