RU2776802C2 - Method for production of 7h-pyrrolo[2,3-d]pyrimidine derivatives and intermediate compounds for their synthesis - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for the production of a compound having the formula [17] or its salt, using a compound having the formula [13] or its salt. The method includes following stages, at which: (1) a compound having the formula [10] or its salt with organic acid are introduced into a reaction with a compound having the formula [12] to obtain the compound having the formula [13] or its salt; (2) benzyl is removed from the compound having the formula [13] or its salt to obtain a compound having the formula [14] or its salt; and (3) cyanacetylation of the compound having the formula [14] or its salt is carried out to obtain the compound having the formula [17] or its salt. Intermediate compounds used in the synthesis are also proposed.

EFFECT: proposed method allows for obtaining a compound of the formula [17] for fewer stages, with high chemical and optical purity.

26 cl, 15 dwg, 12 tbl, 50 ex

Description

The field of technology to which the invention belongs

The present invention relates to a process for the preparation of 7H-pyrrolo[2,3-d]pyrimidine derivatives useful as Janus kinase (JAK) inhibitors, intermediates for their synthesis, and a method for the preparation of these intermediates.

State of the art

JAKs are members of the cytoplasmic protein tyrosine kinase family and include, for example, JAK1, JAK2, JAK3 and TYK2.

Patent Literature 1 describes Compound A (Compound [17]: 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6- diazaspiro[3,4]octan-1-yl]-3-oxopropanenitrile), which can be used as a JAK inhibitor.

List of cited literature

Patent Literature

[PTL 1] WO 2011/013785

Non-Patent Literature

[NPL 1] STACY, DM et al. Synthesis and biological evaluation of triazole-containing N-acyl homoserine lactones as quorum sensing modulators. Org Biomol Chem. Feb 14 2013, Vol. 11, No. 6, pp. 938-954.

Brief description of the essence of the invention

The present invention describes methods for preparing 7H-pyrrolo[2,3-d]pyrimidine derivatives that can be used as a JAK inhibitor, intermediates for the synthesis of these derivatives, and methods for preparing such intermediates.

The present invention includes the following embodiment:

Method for obtaining a compound having the formula [17]:

[Chem. one]

or its salt using a compound having the formula [13]:

[Chem. 2]

or a salt thereof, comprising the following steps:

(1) Benzyl is removed from a compound having the formula [13] or a salt thereof to obtain a compound having the formula [14]:

[Chem. 3]

or its salt, and

(2) a compound having the formula [14] or a salt thereof is reacted with a compound having the formula [18]:

[Chem. four]

to obtain a compound having the formula [17] or a salt thereof.

Brief description of the drawings

On FIG. 1 shows a BABL-HC X-ray powder diffraction pattern [3] with multiple recording. The diffraction intensity (imp/s: number of pulses per second) is shown on the vertical axis, and the diffraction angle 2θ (°) is plotted on the horizontal axis.

On FIG. Figure 2 shows the X-ray powder diffraction pattern of RR-MDDO [9] with multiple recording. The diffraction intensity (imp/s: number of pulses per second) is shown on the vertical axis, and the diffraction angle 2θ (°) is plotted on the horizontal axis.

On FIG. 3 shows analytical HPLC results for crude RR-MDDO [9] from Example 3. Absorbance (AU, absorbance units) is plotted on the vertical axis and retention time (min) is plotted on the horizontal axis.

On FIG. 4 shows analytical HPLC results for RR-MDDO [9] obtained after the crystallization step in Example 3. Absorbance (AU, absorbance units) is shown on the vertical axis and retention time (min) is plotted on the horizontal axis.

On FIG. 5 shows the X-ray powder diffraction pattern of SR-MDBN-DSU [11-1] with multiple recording. The diffraction intensity (imp/s: number of pulses per second) is shown on the vertical axis, and the diffraction angle 2θ (°) is plotted on the horizontal axis.

On FIG. 6 shows analytical HPLC results for compound [21] prepared from crude SR-MDBN [10] prepared in Example 8-Step 1. Absorbance (AU, absorbance units) is shown on the vertical axis and retention time (min) is plotted on the horizontal axis. axes.

On FIG. 7 shows analytical HPLC results for compound [21] obtained from SR-MDBN-DSU [11-1] obtained after the crystallization step in Example 8-Step 2. Absorbance (AU, absorbance units) is shown on the vertical axis and retention time (min) plotted on the horizontal axis.

On FIG. 8 is a differential scanning calorimetry (DSC) plot of SR-MDBN monosuccinate prepared in Example 8-2.

On FIG. 9 shows analytical HPLC results for crude SR-MDBN-DSU [11-1] prepared in Example 9. Absorbance (AU, absorbance units) is plotted on the vertical axis and retention time (min) is plotted on the horizontal axis.

On FIG. 10 shows analytical HPLC results for SR-MDBN-DSU [11-1] obtained after the purification step in Example 9. Absorbance (AU, absorbance units) is shown on the vertical axis and retention time (min) is plotted on the horizontal axis.

On FIG. 11 is an X-ray powder diffraction pattern of 1-ethanolate of Compound A (Compound [17]) with multiple recordings. The diffraction intensity (imp/s: number of pulses per second) is shown on the vertical axis, and the diffraction angle 2θ (°) is plotted on the horizontal axis.

On FIG. 12 is a differential scanning calorimetry (DSC) plot for a co-crystal (2:1, molar ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole as a seed crystal.

On FIG. 13 is a multiple write X-ray powder diffraction pattern of a co-crystal (2:1, mole ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole as a seed crystal. The diffraction intensity (imp/s: number of pulses per second) is shown on the vertical axis, and the diffraction angle 2θ (°) is plotted on the horizontal axis.

On FIG. 14 is a differential scanning calorimetry (DSC) plot of co-crystal (2:1, mole ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole.

On FIG. 15 is a multiple write X-ray powder diffraction pattern of a co-crystal (2:1, mole ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole. The diffraction intensity (imp/s: number of pulses per second) is shown on the vertical axis, and the diffraction angle 2θ (°) is plotted on the horizontal axis.

Description of Embodiments

The terms used in this text have the following meanings.

A compound having the formula [17] may be referred to herein, for example, as Compound [17].

Examples of halogen include fluorine, chlorine, bromine and iodine.

C _1-4 alkyl means linear or branched alkyl having 1 to 4 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

The salts of the compounds may be any salts, so long as such salts can be formed with the compound of the present invention, and include, for example, salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids.

Inorganic acids include, for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid. The preferred inorganic acid is hydrochloric acid.

Organic acids include, for example, oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, terephthalic acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorasulfonic acid. Preferred organic acids are oxalic acid, L-tartaric acid, D-tartaric acid, succinic acid, (+)-10-camphor sulfonic acid and (-)-10-camphor sulfonic acid. Preferred organic acids are oxalic acid, succinic acid, L-tartaric acid, D-tartaric acid, (+)-10-camphorsulfonic acid.

Salts with inorganic bases include, for example, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts.

Organic bases include, for example, methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine.

Amino acids include, for example, lysine, arginine, aspartic acid, glutamic acid.

According to known techniques, the compound of the present invention can be reacted with inorganic bases, organic bases, inorganic acids, organic acids, or amino acids to form salts of the compounds of the present invention.

The chlorinating agent includes, for example, thionyl chloride, oxalyl chloride, phosphoryl chloride. The preferred chlorinating agent is thionyl chloride.

The compound or salt thereof of the present invention may exist as a solvate.

A solvate is a compound in which a solvent molecule is coordinated with a compound or salt thereof of the present invention, and includes a hydrate. The preferred solvate is a pharmaceutically acceptable solvate and includes, for example, hydrate, ethanolate, DMSO solvate, 1-propanolate, 2-propanolate, chloroform solvate, dioxane solvate, anisole solvate, acetone solvate, ethylene glycol solvate or solvate with dimethylacetamide, compounds or salts thereof according to the present invention.

A solvate of a compound or salt thereof of the present invention can be prepared according to known procedures.

The compound of the present invention may exist as a tautomer. In this case, the compound of the present invention may exist as a single tautomer or as a mixture of individual tautomers.

The compound of the present invention may contain a carbon-carbon double bond. In this case, the compound of the present invention may exist as an E form, a Z form, or a mixture of an E form and a Z form.

The compound of the present invention may exist as a stereoisomer, which is the cis/trans isomer. In this case, the compound of the present invention may exist as a cis form, a trans form, or a mixture of a cis form and a trans form.

The compound of the present invention may contain one or more asymmetric carbon atoms. In this case, the compound of the present invention may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

The compound of the present invention may exist as an atropisomer. In this case, the compound of the present invention may exist as a single atropisomer or as a mixture of individual atropisomers.

The compound of the present invention may simultaneously contain several structural elements, leading to the possibility of the existence of these isomers. The compound of the present invention may contain such isomers in any ratio.

In the absence of other indications, such as signatures, etc., the formulas, chemical structures and names of compounds given in the present text, without indicating their stereochemistry, include all the isomers mentioned above that may exist.

A chemical bond depicted by a wavy line means that the compound is a mixture of stereoisomers or any of the stereoisomers. For example, a compound having the formula [6]:

[Chem. 5]

is a mixture of compounds having formulas [6-1] and [6-2]:

[Chem. 6]

or any of these compounds.

The diastereomeric mixture can be separated into the individual diastereomers by well-known methods such as chromatography or crystallization. Each diastereomer can also be obtained using a stereochemically pure starting compound or by a synthetic method using a stereoselective reaction.

Separation of a mixture of enantiomers into individual enantiomers can be carried out using methods well known in the art.

For example, in a standard method such as fractional crystallization or chromatography, a diastereomer with a higher ratio of isomers or a substantially pure diastereomer can be isolated from a mixture of diastereomers that results from the reaction of a mixture of enantiomers with a chiral excipient that is substantially pure enantiomer. The isolated diastereomer can be converted to the target enantiomer by removing the chiral auxiliary moiety by a cleavage reaction.

The target enantiomer can also be obtained by direct separation of a mixture of enantiomers by chromatography using a chiral solid phase, which is well known in the art.

Alternatively, the desired enantiomer can also be prepared using a substantially pure optically active starting material or by stereoselective synthesis using a chiral auxiliary or an asymmetric catalyst with a prochiral synthesis intermediate, i.e. using asymmetric induction.

The absolute configuration can be determined by X-ray diffraction analysis of the crystalline final product or intermediate in the synthesis. If necessary, the absolute configuration can be determined using the crystalline final product or an intermediate modified with a reagent having an asymmetric center with a known stereoconfiguration. In the present text, the configuration was determined by X-ray diffraction analysis of crystalline chloroformate Compound [17].

The compound of the present invention may be crystalline or amorphous.

The compound of the present invention may have an isotopic label including ³ H, ¹⁴ C, ³⁵ S.

Methods for preparing a compound of the present invention, or a salt or solvate thereof, are illustrated below.

At each stage, the reaction can be carried out in a solvent.

The compound obtained in each step may be isolated and purified, if necessary, by known methods such as distillation, recrystallization, column chromatography, or may optionally be used in a subsequent step without isolation or purification.

Room temperature in the present text means conditions where the temperature is not controlled, and in one embodiment, includes the range from 1°C to 40°C. The reaction temperature may include the specified temperature ± 5°C, preferably ±2°C.

An example of a method for preparing a compound of the present invention, or a salt or solvate thereof, is shown in Scheme 1 below. In particular, a synthesis scheme via the compound [8a] is shown.

In the above scheme, X ¹ represents chlorine or bromine; R ¹ is C _1-4 alkyl or benzyl; X ² is halogen; Y is an acid; n is any number from 0.5 to 2; and m is any number from 0.4 to 0.5.

Scheme 1

[Chem. 7]

[Chem. eight]

Another example of a method for preparing a compound of the present invention, or a salt or solvate thereof, is shown in Scheme 2 below. In particular, the synthesis scheme via compound [16a] is shown.

In the above scheme, X ¹ represents chlorine or bromine; R ¹ is C _1-4 alkyl or benzyl; X ² is halogen; Y is an acid; n is any number from 0.5 to 2; and m is any number from 0.4 to 0.5.

Scheme 2

[Chem. 9]

[Chem. ten]

Another example of a method for preparing a compound of the present invention, or a salt or solvate thereof, is shown in Scheme 3-1 and Scheme 3-2 below. In particular, the scheme of synthesis via compound [26a] is given.

In the above scheme, R ² represents methyl, ethyl or benzyl; R ³ is methyl, ethyl or benzyl; Y is an acid; and n is any number from 0.5 to 2.

Diagram 3-1

[Chem. eleven]

[Chem. 12]

Diagram 3-2

[Chem. 13]

[Chem. fourteen]

Other examples of the process for preparing a compound of the present invention, or a salt or solvate thereof, are shown in Schemes 4-1 to 6-2 below. In particular, the scheme of synthesis via compound [30a] is given.

In the diagrams, Y is an acid; and n is any number from 0.5 to 2.

Diagram 4-1

[Chem. fifteen]

Diagram 4-2

[Chem. 16]

Diagram 5-1

[Chem. 17]

Diagram 5-2

[Chem. eighteen]

Diagram 6-1

[Chem. 19]

Diagram 6-2

[Chem. twenty]

Below is a detailed description of the methods shown in the above Schemes 1 to 6-2.

[Production method 1] Preparation of a compound having the formula [2] or a salt thereof

[Chem. 21]

where X ¹ represents chlorine or bromine.

A compound having the formula [2] can be obtained by reacting a compound having the formula [1a] with benzylamine in the presence of a base. Optionally, instead of benzylamine, 4-chlorobenzylamine, 3-chlorobenzylamine, 4-methoxybenzylamine, 3-methoxybenzylamine, 4-methylbenzylamine, 3-methylbenzylamine, benzhydrylamine, triphenylmethylamine, and the like can be used.

Examples of compounds having formula [1a] include BBL and 3-chlorodihydrofuran-2-one. The preferred compound having the formula [1a] is BBL.

Examples of solvents include, for example, THF, acetonitrile, DMF, dimethylacetamide, N-methylpyrrolidone and DMSO. The preferred solvent is acetonitrile.

Examples of bases include, for example, tripotassium phosphate, potassium carbonate and cesium carbonate. The preferred base is tripotassium phosphate. The base can be used, for example, in an amount of 2.0 to 5.0 equivalents relative to the compound having the formula [1a], preferably 3.0 ± 0.5 equivalents.

The reaction temperature is in the range, for example, from room temperature to 60°C, preferably 45°C ± 5°C. Another preferred option is 50°C ± 5°C.

The reaction time is, for example, 5 hours to 48 hours, preferably 5 hours to 30 hours.

The compound having the formula [2] can form a salt with an acid.

The acid includes, for example, organic or inorganic salts.

Organic acids include, for example, oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, terephthalic acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

Inorganic acids include, for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like. The preferred inorganic acid is hydrochloric acid.

The salt of the compound having the formula [2] is preferably a monohydrochloride.

The compound having the formula [2] can be obtained in a crystalline form by forming a salt with an inorganic acid.

The salt of the compound having the formula [2] is, for example, a monohydrochloride, which is a crystalline substance having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle (2θ) = 8.5° ± 0.2°, 18.9° ± 0.2°, 21.0° ± 0.2°, 21.4° ± 0.2° or 24, 4° ± 0.2°, when analyzed using CuKα radiation.

Preferably, the salt of the compound having the formula [2] is a monohydrochloride, which is a crystalline substance having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a value diffraction angle (2θ) = 8.5° ± 0.1°, 18.9° ± 0.1°, 21.0° ± 0.1°, 21.4° ± 0.1° or 24.4° ± 0.1°, when analyzed using CuKα radiation.

More preferably, the salt of the compound having the formula [2] is a monohydrochloride, which is a crystalline substance having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) co peak diffraction angle (2θ) = 8.5° ± 0.06°, 18.9° ± 0.06°, 21.0° ± 0.06°, 21.4° ± 0.06° or 24.4 ° ± 0.06°, when analyzed using CuKα radiation.

[Production method 2] Preparation of a compound having the formula [2-2] or a salt thereof

[Chem. 22]

A compound having the formula [2-2] can be obtained by reacting a compound having the formula [15], which can be synthesized from L-methionine by the method described in Non-Patent Literature 1, with benzaldehyde under acidic conditions, followed by reduction of the resulting compound. Instead of benzaldehyde, 4-methoxybenzaldehyde and the like can optionally be used.

Examples of solvents include, for example, DMSO, DMF, dimethylacetamide, N-methylpyrrolidone, chloroform and THF. The preferred solvent is DMF.

Examples of acids include acetic acid.

Examples of reducing agents include, for example, sodium triacetoxyborohydride and sodium cyanoborohydride. The preferred reducing agent is sodium triacetoxyborohydride. The reducing agent can be used, for example, in an amount of 1.0 to 3.0 equivalents relative to the compound having the formula [15], preferably 1.2 ± 0.2 equivalents.

The reaction temperature is in the range, for example, 0°C to 60°C, room temperature is preferred.

The reaction time is, for example, 0.5 hours to 24 hours, preferably 1 hour to 5 hours.

[Production method 3] Preparation of a compound having the formula [6]

[Chem. 23]

Stage 1

[Chem. 24]

A compound having the formula [5] can be obtained by reacting a compound having the formula [4] with a chlorinating agent.

Examples of solvents include, for example, toluene, THF, DMF, acetonitrile, a mixture of acetonitrile and DMF, and a mixture of toluene and DMF. The preferred solvent is toluene, acetonitrile, a mixture of acetonitrile and DMF, or a mixture of toluene and DMF. The compound having the formula [5] can be obtained without the use of a solvent.

Examples of chlorinating agents include, for example, thionyl chloride, oxalyl chloride and phosphoryl chloride. The preferred chlorinating agent is thionyl chloride. The chlorinating agent can be used, for example, in an amount of 0.9 to 1.5 equivalents relative to the compound having the formula [4], preferably 0.95 to 1.15 equivalents.

The reaction temperature can be set based on general knowledge of chemistry. The reaction temperature in the case of using oxalyl chloride as the chlorinating agent is in the range, for example, from -20°C to 10°C, preferably from -10°C to 0°C. The reaction temperature in the case of using thionyl chloride as the chlorinating agent is in the range, for example, from 45°C to 75°C, preferably 65°C ± 5°C. Another preferred reaction temperature in the case of using thionyl chloride as the chlorinating agent is in the range -20°C to 10°C, preferably -20°C to 0°C.

The reaction time is, for example, 0.5 hours to 5 hours, preferably 0.5 hours to 3 hours, more preferably 1 hour to 2 hours.

The compound having the formula [5] can be purified by distillation, such as under reduced pressure or atmospheric pressure, preferably at atmospheric pressure.

Stage 2

[Chem. 25]

A compound having the formula [6] can be obtained by reacting a compound having the formula [2] or a salt thereof with a compound having the formula [5] in the presence of a base. At this stage, compound [2-2] or a salt thereof can be used in place of compound [2] or a salt thereof. In this case, you can get the connection [6-2]

[Chem. 26]

.

.

Examples of solvents include, for example, toluene, ethyl acetate, THF, and any mixture of these solvents. The preferred solvent is a mixture of toluene and ethyl acetate.

Examples of bases include, for example, 2,6-lutidine and N,N-diisopropylethylamine. The preferred base is 2,6-lutidine. The base can be used, for example, in an amount of 1.0 to 5.0 equivalents relative to the compound having the formula [2], preferably 3.0 ± 0.5 equivalents. It can be used, for example, in an amount of 2.0 to 5.0 equivalents relative to the salt of the compound having the formula [2], preferably 4.0 ± 0.5 equivalents.

The reaction temperature is in the range, for example, -20°C to 20°C, preferably -10°C to 10°C.

The reaction time is, for example, 1 hour to 5 hours, preferably 2 hours to 3 hours.

The compound having the formula [6] can be obtained in a crystalline form. Examples of solvents used for crystallization include, for example, toluene; 2-propanol; CPME; ethyl acetate; a mixture of two or more solvents selected from toluene, 2-propanol, CPME and ethyl acetate; a mixture of 2-propanol and water; and a mixture of toluene, 2-propanol, CPME or ethyl acetate and heptane. The preferred solvent is a mixture of toluene and heptane, or a mixture of 2-propanol and heptane.

[Production method 4] Preparation of a compound having the formula [7]

[Chem. 27]

A compound having the formula [7] can be obtained by a cyclization reaction of a compound having the formula [6] in the presence of a base. In this production method, compound [6-2] can be used instead of compound [6] to obtain compound [7].

Examples of solvents include, for example, THF, acetonitrile, toluene, DMSO, DMF, dimethylacetamide, N-methylpyrrolidone, and any mixture of these solvents. The preferred solvent is DMSO, THF or a mixture of toluene and THF.

Examples of bases include, for example, 1,8-diazabicyclo[5.4.0]-7-undecene, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, tripotassium phosphate, cesium carbonate, and t-butylimino-tri(pyrrolidino)phosphorane. The preferred base is lithium hexamethyldisilazide, cesium carbonate or tripotassium phosphate. A more preferred base is lithium hexamethyldisilazide.

When lithium hexamethyldisilazide is used as the base, this base can be used, for example, in an amount of 0.9 to 1.2 equivalents relative to the compound having the formula [6], preferably 1.0 ± 0.05 equivalents. The reaction temperature is in the range, for example, -20°C to 5°C, preferably -15°C to 0°C. The reaction time is, for example, 0.5 hours to 5 hours, preferably 1 hour to 3 hours.

When cesium carbonate or tripotassium phosphate is used as the base, this base can be used, for example, in an amount of 2.0 to 5.0 equivalents relative to the compound having the formula [6], preferably 3.0 ± 0.5 equivalents. The reaction temperature is in the range, for example, from room temperature to 60°C, room temperature is preferred. The reaction time is, for example, 10 hours to 30 hours, preferably 10 hours to 24 hours.

[Production method 5] Preparation of a compound having the formula [9]

[Chem. 28]

Stage 1

[Chem. 29]

where R ¹ represents C _1-4 alkyl or benzyl; and X ² is halogen.

The compound having the formula [8a] can be obtained by reacting the compound having the formula [7] with potassium phthalimide, followed by esterification of the obtained compound using the compound having the formula [19a]. Potassium phthalimide can be used, for example, in an amount of 1.0 to 2.0 equivalents relative to the compound having the formula [7], preferably 1.1 ± 0.05 equivalents.

Examples of compounds having the formula [19a] include, for example, methyl iodide, ethyl iodide and benzyl bromide. The preferred compound having the formula [19a] is ethyl iodide. The compound having the formula [19a] can be used, for example, in an amount of 1.0 to 2.0 equivalents relative to the compound having the formula [7], preferably 1.3 ± 0.05 equivalents.

Examples of solvents include, for example, DMF, dimethylacetamide, DMSO, N-methylpyrrolidone, toluene, and any mixture of these solvents. The preferred solvent is DMF, DMSO or a mixture of DMSO and toluene.

The reaction temperature for the reaction with potassium phthalimide is in the range, for example, 80°C to 150°C, preferably 90°C to 115°C. For carrying out the esterification, the temperature is in the range, for example, from room temperature to 80°C, preferably from room temperature to 60°C.

The reaction time for the reaction with potassium phthalimide is, for example, 10 hours to 30 hours, preferably 10 hours to 24 hours. For carrying out the esterification, the reaction time is, for example, 1 hour to 6 hours, preferably 4 hours to 5 hours. Another preferred reaction time for the esterification is 1 hour to 2 hours.

The compound having the formula [8a] can also be obtained by isolating the compound having the formula [22]

[Chem. thirty]

or its salts, followed by esterification. The esterification can be carried out according to known methods.

Stage 2

[Chem. 31]

where R ¹ represents C _1-4 alkyl or benzyl.

The compound having the formula [9] can be obtained by removing phthaloyl from the compound having the formula [8a]. Any known method for removing phthaloyl can be used, for example, a compound having the formula [9] can be prepared by reacting a compound having the formula [8a] with ethylenediamine or diethylenetriamine.

Ethylenediamine or diethylenetriamine can be used, for example, in an amount of 1.0 to 10 equivalents relative to the compound having the formula [8a], preferably 5.0 ± 0.5 equivalents.

Examples of solvents include, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and 2-methyl-2-propanol. The preferred solvent is 2-butanol.

The reaction temperature is in the range, for example, from 60°C to 105°C, preferably from 80°C to 95°C.

The reaction time is, for example, 1 hour to 6 hours, preferably 2 hours to 5 hours.

The compound having the formula [9] can be obtained in a crystalline form by crystallization. For example, a crystal of a compound having the formula [9] can be obtained by dissolving a compound having the formula [9] in CPME with heating and then adding diisopropyl ether to the solution, or by dissolving a compound having the formula [9] in toluene with heating and then adding heptane in solution.

The temperature for dissolving the compound [9] in the crystallization solvent is in the range of, for example, 40°C to 80°C. The preferred temperature is in the range of 50°C to 60°C in the case of CPME, and in the range of 65°C to 75°C in the case of toluene.

The crystallization time is, for example, 3 hours to 10 hours, preferably 3 hours to 5 hours.

The compound having the formula [9] is a crystal, for example, having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ) = 10.6° ± 0.2°, 16.0° ± 0.2°, 17.5° ± 0.2°, 18.3° ± 0.2° or 19.2° ± 0.2° , when analyzed using CuKα radiation.

Preferably, the compound having the formula [9] is a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ) = 10.6° ± 0.1°, 16.0° ± 0.1°, 17.5° ± 0.1°, 18.3° ± 0.1° or 19.2° ± 0.1°, when analyzed using CuKα radiation.

More preferably, the compound having the formula [9] is a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ ) = 10.6° ± 0.06°, 16.0° ± 0.06°, 17.5° ± 0.06°, 18.3° ± 0.06° or 19.2° ± 0.06 °, when analyzed using CuKα radiation.

[Production method 6] Alternative production method for a compound having the formula [9]

[Chem. 32]

Stage 1

[Chem. 33]

where R ¹ represents C _1-4 alkyl or benzyl; and X ² is halogen.

A compound having the formula [16a] can be obtained by reacting a compound having the formula [7] with sodium diformylamide and then esterifying the resulting compound using a compound having the formula [19a]. Sodium diformylamide can be used, for example, in an amount of 2.0 to 5.0 equivalents relative to the compound having the formula [7], preferably 3.0 ± 0.5 equivalents.

Examples of compounds having the formula [19a] include, for example, methyl iodide, ethyl iodide and benzyl bromide. The preferred compound having the formula [19a] is ethyl iodide. The compound having the formula [19a] can be used, for example, in an amount of 2.0 to 5.0 equivalents relative to the compound having the formula [7], preferably 3.0 ± 0.5 equivalents.

Examples of solvents include, for example, DMSO, dimethylacetamide and N-methylpyrrolidone. The preferred solvent is DMSO.

The reaction temperature for the reaction with sodium diformylamide is in the range of, for example, 80°C to 150°C, preferably 100°C±5°C. For the esterification reaction, the temperature is in the range, for example, from room temperature to 80°C, preferably from room temperature to 50°C.

The reaction time for the reaction with sodium diformylamide is, for example, 10 hours to 30 hours, preferably 10 hours to 24 hours. In the case of the esterification reaction, the reaction time is, for example, 3 hours to 6 hours, preferably 4 hours to 5 hours.

Stage 2

[Chem. 34]

where R ¹ represents C _1-4 alkyl or benzyl.

A compound having the formula [9] can be obtained by removing formyl from a compound having the formula [16a] in the presence of a base.

Examples of solvents include, for example, acetonitrile, THF, DMF, DMSO, dimethylacetamide, DMSO, and N-methylpyrrolidone. The preferred solvent is acetonitrile.

Examples of bases include, for example, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, cesium carbonate, tripotassium phosphate, and t-butylimino-tri(pyrrolidino)phosphorane. The preferred base is cesium carbonate. The base can be used, for example, in an amount of 1.0 to 2.0 equivalents relative to the compound having the formula [16a], preferably 1.5 ± 0.05 equivalents.

The reaction temperature is in the range, for example, from 0°C to 50°C, room temperature is preferred.

The reaction time is, for example, 3 hours to 6 hours, preferably 4 hours to 5 hours.

[Production method 7] Preparation of a compound having the formula [10]

[Chem. 35]

The compound having the formula [10] can be obtained by reducing the compound having the formula [9].

Examples of solvents include, for example, toluene, CPME, THF, and 2-methyl tetrahydrofuran. The preferred solvent is toluene, THF or a mixture thereof.

Examples of reducing agents include, for example, TMDS, which is used in the presence of a catalyst, triruthenium dodecacarbonyl or zinc trifluoromethanesulfonate, and lithium aluminum hydride, which is used in the presence of an acid. Examples of acids include, for example, sulfuric acid, aluminum chloride, zinc chloride, and chlorotrimethylsilane. A preferred reducing agent is TMDS which is used in the presence of a triruthenium dodecacarbonyl catalyst, or lithium aluminum hydride which is used in the presence of chlorotrimethylsilane or aluminum chloride.

[Production Method 7-1] Case where TMDS is used in the presence of a catalyst

The reducing agent can be used, for example, in an amount of 3.0 to 15.0 equivalents relative to the compound having the formula [9], preferably 10.0 ± 0.5 equivalents.

The catalyst can be used, for example, in an amount of 0.05 to 0.5 equivalents relative to the compound having the formula [9], preferably 0.1 to 0.3 equivalents.

An additive can also be added to the reaction mixture when a triruthenium dodecacarbonyl catalyst is used. Examples of additives include, for example, TMEDA and N,N,N',N'-tetramethyl-1,3-diaminopropane. The preferred additive is TMEDA. The additive can be used, for example, in an amount of 0.05 to 0.5 equivalents relative to the compound having the formula [9], preferably 0.1 to 0.3 equivalents.

The reaction temperature is in the range, for example, from 40°C to 100°C, preferably from 60°C to 80°C.

The reaction time is, for example, 10 hours to 50 hours, preferably 35 hours to 45 hours.

[Production Method 7-2] Case where lithium aluminum hydride is used in the presence of an acid

The reductant can be added in one dose or in two or more divided portions. Preferably, the reducing agent is added in two or more divided portions.

(1) When the reducing agent is added at one time, the reducing agent can be used in the presence of an acid, for example, in an amount of 1.0 to 5.0 equivalents relative to the compound having the formula [9], preferably 3.0 ± 0.5 equivalents. The preferred acid in this case is aluminum chloride or chlorotrimethylsilane. Aluminum chloride or chlorotrimethylsilane can be used, for example, in an amount of 1.0 to 5.0 equivalents relative to the compound having the formula [9], preferably 3.0 ± 0.5 equivalents.

The reaction temperature is in the range, for example, from room temperature to 60°C, preferably from 40°C to 50°C. The reaction time is, for example, 10 hours to 30 hours, preferably 15 hours to 24 hours.

(2) When the reducing agent is added in two or more divided portions, the reducing agent in the first portion can be used in the presence of an acid in an amount of, for example, 1.0 to 5.0 equivalents relative to the compound having the formula [9], preferably 2.5 ± 0.5 equivalents. The preferred acid in this case is chlorotrimethylsilane. Chlorotrimethylsilane can be used, for example, in an amount of 1.0 to 5.0 equivalents relative to the compound having the formula [9], preferably 2.5 ± 0.5 equivalents. The reducing agent in the second portion can be used, for example, in an amount of 0.3 to 3.0 equivalents relative to the compound having the formula [9], preferably 0.5 ± 0.1 equivalents.

The reaction temperature is in the range, for example, from -20°C to 10°C, preferably from -20°C to 5°C, for the first portion, and, for example, from room temperature to 60°C, preferably from 40°C up to 50°C, for the second portion. Another preferred reaction temperature for the second portion is the range from 45°C to 55°C.

The reaction time is, for example, from 0.5 hours to 3 hours, preferably from 1 hour to 2 hours, for the first portion, and for example, from 5 hours to 30 hours, preferably from 5 hours to 24 hours, for the second portion.

[Production method 8] Preparation of a salt of a compound having the formula [11a]

[Chem. 36]

where Y is an acid, n is any number from 0.5 to 2, such as 0.5, 1 or 2.

The compound having the formula [11a] can be obtained by salt formation of the compound having the formula [10] using an acid.

Examples of solvents include, for example, water, methanol, ethanol, 1-propanol, 2-propanol, THF, and any mixture of these solvents. The preferred solvent is 2-propanol.

The acid includes, for example, an organic or inorganic acid.

Examples of organic acids include, for example, oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, terephthalic acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid. , benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorosulfonic acid, and the like. Preferred organic acids are oxalic acid, L-tartaric acid, D-tartaric acid, succinic acid, (+)-10-camphorsulfonic acid or (-)-10-camphorsulfonic acid. More preferred organic acids are oxalic acid, succinic acid, L-tartaric acid, D-tartaric acid or (+)-10-camphorosulfonic acid.

Examples of inorganic acids include, for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like.

The reaction temperature is in the range, for example, from room temperature to 80°C, preferably from room temperature to 70°C.

The reaction time is, for example, 6 hours to 15 hours, preferably 8 hours to 12 hours.

An example of a compound having the formula [11a] is preferably the disuccinate salt of the compound having the formula [10].

The compound having the formula [11a] is, for example, the disuccinate salt of the compound having the formula [10], which is a crystalline substance having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with diffraction angle (2θ) = 4.8° ± 0.2°, 11.2° ± 0.2°, 16.2° ± 0.2°, 18.1° ± 0.2° or 20.1° ± 0.2° when analyzed using CuKα radiation.

Preferably, the compound having the formula [11a] is the disuccinate salt of the compound having the formula [10], which is a crystalline substance having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4 or 5) peak with diffraction angle (2θ) = 4.8° ± 0.1°, 11.2° ± 0.1°, 16.2° ± 0.1°, 18.1° ± 0 ,1° or 20.1° ± 0.1°, when analyzed using CuKα radiation.

More preferably, the compound having the formula [11a] is the disuccinate salt of the compound having the formula [10], which is a crystalline substance having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3 , 4, or 5) peak with diffraction angle (2θ) = 4.8° ± 0.06°, 11.2° ± 0.06°, 16.2° ± 0.06°, 18.1° ± 0.06° or 20.1° ± 0.06° when analyzed using CuKα radiation.

Another example of a compound having the formula [11a] is preferably a hemioxalate salt of a compound having the formula [10].

The compound having the formula [11a] can be purified by recrystallization or stirring of the mixed solution in which the compound having the formula [11a] is suspended in a solvent (hereinafter referred to as "stirring the suspension"). Alternatively, the compound having the formula [11a] can be purified by recrystallization and slurry stirring, and any of these operations can be carried out first. The preferred purification method is agitation of the slurry.

Examples of solvents used for recrystallization and stirring of the slurry include, for example, methanol, ethanol, 1-propanol, 2-propanol, THF, toluene, and a mixture of these solvents. The preferred recrystallization solvent is a mixture of methanol and toluene. The preferred solvent for stirring the suspension is 2-propanol.

The temperature while stirring the suspension is in the range, for example, from 0°C to 60°C, preferably from 30°C to 35°C. Another preferred temperature while stirring the suspension is from 35°C to 40°C.

The stirring time of the suspension is, for example, from 1 hour to 15 hours, preferably from 2 hours to 12 hours.

[Production method 9] Preparation of a compound having the formula [13]

[Chem. 37]

A compound having the formula [13] can be obtained by condensing a compound having the formula [11a] with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CPPY) [12] or a salt thereof in the presence of a base. The compound having the formula [10] can be used instead of the compound having the formula [11a]. The compound having the formula [13] may be in the form of a salt, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in this field.

Examples of solvents include, for example, tert-butanol, water, ethanol, methanol, 2-propanol, and any mixture of these solvents. The preferred solvent is a mixture of tert-butanol or 2-propanol and water.

Examples of bases include, for example, alkali metal phosphates such as tripotassium phosphate, alkali metal carbonates such as potassium carbonate, alkali metal hydroxides such as potassium hydroxide, or mixtures thereof. The preferred base is tripotassium phosphate or a mixture of tripotassium phosphate and potassium hydroxide. The base can be used, for example, in an amount of 4.0 to 10.0 equivalents relative to the compound having the formula [11a], preferably 5.0 to 8.0 equivalents.

CPPY [12] can be used, for example, in an amount of 0.95 to 1.10 equivalents relative to the compound having the formula [11a], preferably 1.02 ± 0.02 equivalents.

The reaction temperature is in the range, for example, from room temperature to 85°C, preferably 80°C ± 5°C. Another preferred reaction temperature is 75°C±5°C.

The reaction time is, for example, 1 hour to 10 hours, preferably 2 hours to 8 hours.

[Production method 10] Preparation of a compound having the formula [14]

[Chem. 38]

The compound having the formula [14] can be obtained by removing the protecting group (benzyl) from the compound having the formula [13]. Any of the known methods can be used to deprotect, for example, a compound having the formula [14] can be obtained by adding hydrogen to a compound having the formula [13] in the presence of a catalyst under acidic conditions. The compound having the formula [13] and the compound having the formula [14] may be in the form of their salts, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in the art.

Examples of solvents include, for example, tert-butanol, water, ethanol, 2-propanol, and any mixture of the listed solvents. The preferred solvent is a mixture of tert-butanol and water or a mixture of 2-propanol and water.

Examples of catalysts include, for example, 5% palladium on carbon (50% water content), 10% palladium on carbon (50% water content), palladium on carbon, palladium hydroxide on carbon, palladium black, and palladium on silica gel. The preferred catalyst is 5% palladium on carbon (50% water content) or 10% palladium on carbon (50% water content). The catalyst can be used, for example, in an amount of 0.01-fold to 0.5-fold of the weight of the compound having the formula [13], preferably 0.05-fold to 0.2-fold.

An example of an acid includes acetic acid.

Preferably, the hydrogen gas pressure is equal to atmospheric pressure. An increased pressure of about 0.1 MPa can be applied.

The reaction temperature is in the range, for example, from room temperature to 80°C, preferably 55°C ± 5°C. Another preferred option is 50°C ± 5°C.

The reaction time is, for example, 2 hours to 10 hours, preferably 3 hours to 8 hours.

[Production method 11] Preparation of a compound having the formula [17]

[Chem. 39]

A compound having the formula [17] can be prepared by condensing a compound having the formula [14] with 1-cyanoacetyl-3,5-dimethyl-1H-pyrazole (DPCN) [18] in the presence of a base. The compound having the formula [14] and the compound having the formula [17] may be in the form of their salts, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in the art.

Examples of solvents include, for example, acetonitrile and THF. The preferred solvent is acetonitrile.

Examples of bases include, for example, triethylamine and N,N-diisopropylethylamine. The preferred base is triethylamine.

DPCN [18] can be used, for example, in an amount of 0.95 to 1.2 equivalents relative to the compound having the formula [17], preferably 1.05 ± 0.10 equivalents.

The reaction temperature is in the range, for example, from room temperature to 80°C, preferably from 40°C to 50°C.

The reaction time is, for example, 1 hour to 12 hours, preferably 2 hours to 6 hours.

In this reaction, a compound having the formula [17] can also be obtained by condensing a compound having the formula [14] with 1-cyanoacetyl-3,5-dimethyl-1H-pyrazole (DPCN) [18] without using a base. Compounds having formula [14] and formula [17] can be replaced by their respective salts. Such salts can be obtained from their free forms according to known methods, and vice versa.

The solvent used in this technique includes, for example, acetonitrile and tetrahydrofuran. The preferred solvent is acetonitrile.

DPCN can be used, for example, in an amount of 0.95 to 1.2 equivalents relative to the compound having the formula [14], preferably 1.05 ± 0.05 equivalents.

The reaction temperature is in the range, for example, from room temperature to 80ºC, preferably from 70ºC to 80ºC.

The reaction time is, for example, 0.5 hours to 12 hours, preferably 0.5 hours to 6 hours.

A compound having the formula [17] can be obtained by reacting a compound having the formula [14] with a compound having the formula [35a]:

[Chem. 40]

where R ⁴ represents a hydrogen atom, methyl or ethyl

or its salt instead of 1-cyanoacetyl-3,5-dimethyl-1H-pyrazole (DPCN) [18]. The compound having the formula [14] and the compound having the formula [17] may be in the form of their salts, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in the art.

When R ⁴ is a hydrogen atom, a compound having the formula [17] can be obtained by reacting a compound having the formula [14] with a compound having the formula [35a] or a salt thereof in the presence of a base and a condensing agent.

Examples of condensing agents include, for example, the combination of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride ( ^WSC.HCl ) and 1-hydroxybenzotriazole (HOBt), and (benzotriazol-1-yloxy)tripyrrolidinephosphonium hexafluorophosphate (PyBOP). A preferred condensing agent is PyBOP.

When R ⁴ is methyl or ethyl, a compound having the formula [17] can be obtained by condensing a compound having the formula [14] with a compound having the formula [35a]. The reaction is preferably carried out in the presence of 3,5-dimethyl-1H-pyrazole and a catalytic amount of diazabicycloundecene (DBU).

[Production method 12] Preparation of a compound having the formula [20]

[Chem. 41]

The compound having the formula [20] can be obtained by crystallizing the compound having the formula [17] using a solvent. 1-Propanol, 2-propanol, chloroform, dioxane, anisole, acetone, ethylene glycol, dimethylacetamide or water can be used instead of ethanol in the case of the compound having the formula [20].

Examples of solvents include, for example, ethanol, 1-propanol, 2-propanol, chloroform, dioxane, anisole, acetone, ethylene glycol, dimethylacetamide and water. The preferred solvent is ethanol.

Although this step is not necessary to obtain the compound [17], it can be carried out to increase the purity of the compound [17].

The compound having the formula [20] is, for example, a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ ) = 8.3° ± 0.2°, 12.7° ± 0.2°, 13.0° ± 0.2°, 20.0° ± 0.2° or 24.1° ± 0.2 °, when analyzed using CuKα radiation.

Preferably, the compound having the formula [20] is a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ) = 8.3° ± 0.1°, 12.7° ± 0.1°, 13.0° ± 0.1°, 20.0° ± 0.1° or 24.1° ± 0.1°, when analyzed using CuKα radiation.

More preferably, the compound having the formula [20] is a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ) = 8.3° ± 0.06°, 12.7° ± 0.06°, 13.0° ± 0.06°, 20.0° ± 0.06° or 24.1° ± 0.06° , when analyzed using CuKα radiation.

[Production method 13] Purification of a compound having the formula [17]

[Chem. 42]

The compound having the formula [17] can be purified by crystallization after the compound having the formula [20] is dissolved.

Examples of crystallization solvents include, for example, 1-butanol, 1-propanol and 2-methyl-2-butanol. The preferred solvent is 1-butanol. The solvent can be used, for example, in an amount of 8.0 times to 20 times the weight of the compound having the formula [20], preferably 8.5 ± 0.5 times the amount.

The temperature for dissolving the compound [20] in the crystallization solvent is in the range, for example, from 100°C to 117°C, preferably 110°C ± 5°C.

The crystallization time is, for example, 15 hours to 48 hours, preferably 18 hours to 24 hours.

The compound having the formula [17] can also be purified by recrystallization of the compound having the formula [17].

The solvent used in this procedure includes, for example, 1-butanol, 1-propanol and 2-methyl-2-butanol. The preferred solvent is 1-butanol. The solvent can be used, for example, in an amount of 18 times to 22 times the weight of the compound having the formula [17], preferably 20 ± 0.5 times.

The dissolution temperature of the crystals is in the range, for example, from 85ºC to 100ºC, preferably from 90ºC to 100ºC.

The crystallization time is, for example, 10 hours to 48 hours, preferably 10 hours to 24 hours.

[Production method 14] Preparation of a compound having the formula [34a]

[Chem. 43]

where m is any number from 0.4 to 0.5.

A compound having the formula [34a] can be prepared by condensing a compound having the formula [14] with 1-cyanoacetyl-3,5-dimethyl-1H-pyrazole (DPCN) [18]. The compound having the formula [14] may be in the form of a salt, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in this field.

The preferred solvent is acetonitrile.

DPCN [18] can be used, for example, in an amount of 0.95 to 1.2 equivalents relative to the compound having the formula [14], preferably 1.1 ± 0.05 equivalents. Another preferred option is 1.05 ± 0.05 equivalents.

The reaction temperature is in the range, for example, from room temperature to 80ºC, preferably from 70ºC to 80ºC.

The reaction time is, for example, 0.5 hours to 12 hours, preferably 0.5 hours to 6 hours.

Although this step is not necessary to obtain the compound [17], it can be carried out to increase the purity of the compound [17].

The compound having the formula [34a] may be, for example, a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2 or 3) peak with a diffraction angle value (2θ) = 4, 6° ± 0.2°, 18.6° ± 0.2°, or 20.9° ± 0.2° when analyzed using CuKα radiation.

Preferably, the compound having the formula [34a] may be a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2 or 3) peak with a diffraction angle value (2θ) = 4.6° ± 0.1°, 18.6° ± 0.1°, or 20.9° ± 0.1° when analyzed using CuKα radiation.

More preferably, the compound having the formula [34a] may be a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2 or 3) peak with a diffraction angle value (2θ) = 4.6 ° ± 0.06°, 18.6° ± 0.06°, or 20.9° ± 0.06° when analyzed using CuKα radiation.

In addition, the compound having the formula [34a] may also be, for example, a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with diffraction angle (2θ) = 4.6° ± 0.2°, 12.6° ± 0.2°, 16.1° ± 0.2°, 18.6° ± 0.2° or 20.9 ° ± 0.2°, when analyzed using CuKα radiation.

Preferably, the compound having the formula [34a] may also be a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value (2θ ) = 4.6° ± 0.1°, 12.6° ± 0.1°, 16.1° ± 0.1°, 18.6° ± 0.1° or 20.9° ± 0.1 °, when analyzed using CuKα radiation.

More preferably, the compound having the formula [34a] may also be a crystal having an X-ray powder diffraction spectrum containing at least one (for example, at least 1, 2, 3, 4, or 5) peak with a diffraction angle value ( 2θ) = 4.6° ± 0.06°, 12.6° ± 0.06°, 16.1° ± 0.06°, 18.6° ± 0.06° or 20.9° ± 0, 06°, when analyzed using CuKα radiation.

[Production method 15] Purification of a compound having the formula [17]

[Chem. 44]

where m has the above meaning.

The compound having the formula [17] can be obtained by crystallization after dissolving the compound having the formula [34a]. Purification can be accomplished by adding 2,6-di-tert-butyl-4-methylphenol (BHT) during crystallization.

Examples of crystallization solvents include, for example, 1-butanol, 1-propanol and 2-methyl-2-butanol. The preferred solvent is 1-butanol. The solvent can be used, for example, in an amount of 8.0 times to 20 times the weight of the compound having the formula [34a], preferably 8.5 ± 0.5 times.

The temperature for dissolving the compound [34a] in the crystallization solvent is in the range, for example, from 100°C to 117°C, preferably 110°C ± 5°C.

The crystallization time is, for example, 15 hours to 48 hours, preferably 18 hours to 24 hours.

[Production method 16] Preparation of a compound having the formula [24a]

[Chem. 45]

where R ² represents methyl, ethyl or benzyl.

A compound having the formula [24a] can be obtained by reacting a compound having the formula [23] with methanol, ethanol, or benzyl alcohol; and an oxidizing agent. The compound having the formula [23] and the compound having the formula [24a] may be in the form of their salts, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in the art.

Examples of solvents include, for example, methanol, ethanol or benzyl alcohol; and a mixture of methanol and water, THF or toluene. The preferred solvent is methanol.

Examples of oxidizing agents include, for example, bromine, sodium hypochlorite, oxone, and (diacetoxyiodo)benzene. The preferred oxidizing agent is sodium hypochlorite or bromine. The oxidizing agent can be used, for example, in an amount of 0.9 to 2.0 equivalents relative to the compound having the formula [23], preferably 1.1 ± 0.05 equivalents.

The reaction temperature is in the range, for example, from 0°C to 60°C, preferably from 40°C to 50°C.

The reaction time is, for example, 1 hour to 5 hours, preferably 2 hours.

[Production method 17] Preparation of a compound having the formula [25a] or a salt thereof

[Chem. 46]

where R ² has the above meaning, and R ³ independently represents methyl, ethyl or benzyl.

A compound having the formula [25a] or a salt thereof can be obtained by reacting a compound having the formula [24a] with methanol, ethanol or benzyl alcohol; and acid. The compound having the formula [24a] may be in the form of a salt, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in the art.

Examples of solvents include, for example, methanol, ethanol or benzyl alcohol; and a mixture of methanol and water, THF or toluene. The preferred solvent is methanol.

Examples of acids or acid precursors include, for example, hydrochloric acid, acetyl chloride, thionyl chloride, phosphoryl chloride, oxalyl chloride. The preferred acid or acid precursor is hydrochloric acid or thionyl chloride, respectively. A more preferred acid or acid precursor is thionyl chloride. The acid or acid precursor can be used, for example, in an amount of 1.0 to 20.0 equivalents relative to the compound having the formula [24a], preferably 2.0 equivalents.

The reaction temperature is in the range, for example, from 0°C to 50°C, preferably from 15°C to 25°C.

The reaction time is, for example, 2 hours to 21 hours, preferably 2 hours.

[Production method 18] Preparation of a compound having the formula [26a] or a salt thereof

[Chem. 47]

where R ² and R ³ have the meanings given above.

A compound having the formula [26a] or a salt thereof can be obtained by reacting a compound having the formula [25a] or a salt thereof with benzaldehyde and a base, followed by reduction of the resulting compound. The compound having the formula [25a] and the compound having the formula [26a] may also be used or prepared in the form of their salt, and the preparation of such a salt from a free form or the preparation of a free form from such a salt may be carried out by any of the methods known in this areas.

Examples of solvents include, for example, methanol, ethanol, 2-propanol, acetonitrile and 1,2-dichloroethane. The preferred solvent is methanol.

Examples of bases include, for example, triethylamine and N,N-diisopropylethylamine. The preferred base is triethylamine.

Examples of reducing agents include, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and hydrogen gas. The preferred reducing agent is sodium borohydride. The reducing agent can be used, for example, in an amount of 0.95 to 1.2 equivalents relative to the compound having the formula [25a], preferably 1.1 ± 0.05 equivalents.

The benzaldehyde reagent can be used, for example, in an amount of 0.95 to 2.0 equivalents relative to the compound having the formula [25a], preferably 1.1 ± 0.05 equivalents.

The reaction temperature during the addition of sodium borohydride is in the range, for example, -30 to -5°C, preferably -20°C to -15°C. After adding sodium borohydride, the reaction temperature is 0°C to 25°C, preferably 20°C to 25°C.

The reaction time is, for example, 2 hours to 21 hours, preferably 3 hours to 6 hours.

An example of a salt of the compound having the formula [26a] is the hydrochloride salt.

Examples of solvents for forming the hydrochloride salt include, for example, methyl tert-butyl ether, 2-propanol, ethyl acetate, and 2-propyl acetate. The preferred solvent is ethyl acetate or 2-propyl acetate. A more preferred solvent is 2-propyl acetate.

The acid, hydrogen chloride, used to form the hydrochloride salt can be used, for example, in an amount of 0.95 to 5.0 equivalents relative to the compound having the formula [26a], preferably 1.5 to 2.5 equivalents.

The reaction temperature is in the range, for example, from -10°C to 50°C, preferably from 0°C to 10°C.

The reaction time is, for example, 30 minutes to 3 hours, preferably 1 hour to 2 hours.

The hydrochloride salt of the compound having the formula [26a] can be purified by stirring the suspension with heat.

Examples of cleaning solvents include, for example, methanol, ethanol, 2-propanol, 1-butanol and 2-propyl acetate. The preferred solvent is 2-propyl acetate.

The cleaning temperature is in the range, for example, from room temperature to 60°C, preferably from 40°C to 50°C.

The cleaning time is, for example, 2 hours to 12 hours, preferably 3 hours to 6 hours.

[Production method 19] Preparation of a compound having the formula [27a]

[Chem. 48]

where R ² and R ³ have the meanings given above.

Stage 1

[Chem. 49]

The compound having the formula [5] can be obtained similarly to Step 1 of Production Method 3.

Stage 2

[Chem. fifty]

where R ² and R ³ have the meanings given above.

A compound having the formula [27a] can be obtained by reacting a compound having the formula [26a] or a salt thereof with a compound having the formula [5] in the presence of a base. At this stage, compound [26b]

[Chem. 51]

or a salt thereof may be used in place of compound [26a] or a salt thereof. When compound [26b] is used in this step, compound [27b] can be obtained

[Chem. 52]

Examples of solvents include, for example, toluene, ethyl acetate, THF, methyl tert-butyl ether, acetonitrile, and any mixture of these solvents. The preferred solvent is acetonitrile, toluene or a mixture of toluene and water.

Examples of bases include, for example, 2,6-lutidine, N,N-diisopropylethylamine, triethylamine, pyridine, tripotassium phosphate and potassium carbonate. The preferred base is potassium carbonate or a combination of 2,6-lutidine and N,N-diisopropylethylamine. The base can be used, for example, in an amount of 1.0 to 5.0 equivalents relative to the compound having the formula [26a], preferably 3.0 to 4.0 equivalents.

The reaction temperature is in the range, for example, -20°C to 20°C, preferably -10°C to 5°C.

The reaction time is, for example, 1 hour to 5 hours, preferably 1 hour to 3 hours.

[Production method 20] Preparation of a compound having the formula [9]

[Chem. 53]

where R ² and R ³ have the meanings given above.

A compound having the formula [9] can be obtained by a double cyclization reaction of a compound having the formula [27a] in the presence of a base. Alternatively, a mixture of stereoisomers of compound [27a] can be used to obtain compound [9] as a mixture of enantiomers, which are then separated by chiral separation methods.

Examples of solvents include, for example, THF, acetonitrile, toluene, DMSO, DMF, dimethylacetamide, N-methylpyrrolidone, dimethyl carbonate, and any mixture of these solvents. The preferred solvent is acetonitrile or DMSO.

Examples of bases include, for example, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, tripotassium phosphate, cesium carbonate, t-butylimino-tri(pyrrolidino)phosphorane, potassium t-butoxide, and lithium 2-methyl-2-butoxide. The preferred base is lithium hexamethyldisilazide, cesium carbonate or lithium 2-methyl-2-butoxide. A more preferred base is lithium 2-methyl-2-butoxide.

When lithium 2-methyl-2-butoxide is used as the base, this base can be used, for example, in an amount of 1.0 to 3.0 equivalents relative to the compound having the formula [27a], preferably 3.0 equivalents. In this case, the reaction temperature is in the range of, for example, -20°C to 5°C, preferably -10°C to 0°C, and the reaction time is, for example, 1 hour to 5 hours.

When cesium carbonate is used as the base, this base can be used, for example, in an amount of 2.0 to 5.0 equivalents relative to the compound having the formula [27a], preferably 2.5 equivalents. In this case, the reaction temperature is in the range, for example, from 15°C to 50°C, preferably from 20°C to 25°C, and the reaction time is, for example, from 10 hours to 30 hours, preferably from 15 hours to 20 hours.

[Production method 21] Preparation of a compound having the formula [29a]

[Chem. 54]

where Y is an acid and n is any number from 0.5 to 1, such as 0.5 or 1.

The compound having the formula [29a] can be obtained by forming a salt of the compound having the formula [28] using an acid.

Examples of solvents include, but are not limited to, water, methanol, ethanol, 1-propanol, isopropanol, acetonitrile, acetone, toluene, methyl tert-butyl ether, tetrahydrofuran, and any mixture of these solvents. The preferred solvent is a mixture of tetrahydrofuran and toluene.

The acid includes, for example, an organic or inorganic acid.

Examples of organic acids include, for example, oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, terephthalic acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid , benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorosulfonic acid, and the like. The preferred organic acid is oxalic acid.

Examples of inorganic acids include, for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like.

The reaction temperature is in the range, for example, from 0°C to 80°C, preferably from 30°C to 60°C. The reaction time is, for example, 30 minutes to 24 hours, preferably 1 hour to 3 hours.

An example of a compound having the formula [29a] is preferably the oxalate salt of the compound having the formula [28].

[Production method 22] Preparation of a compound having the formula [30a]

[Chem. 55]

where Y is an acid and n is any number from 0.5 to 2, such as 0.5, 1 or 2.

The compound having the formula [30a] can be obtained by removing the protecting groups (ie, benzyloxycarbonyl and benzyl) from the compound having the formula [29a]. Any of the known methods can be used to deprotect, for example, a compound having the formula [30a] can be prepared by adding hydrogen to a compound having the formula [29a] in the presence of a catalyst under neutral, basic or acidic conditions. The compound having the formula [29a] and the compound having the formula [30a] may also be used or prepared in their free form, and the preparation of such a salt from the free form or the preparation of the free form from such a salt may be carried out by any of the methods known in this the field of technology.

Examples of solvents include, for example, tert-butanol, water, isopropanol, 1-propanol, ethanol, and any mixture of these solvents.

Examples of catalysts include, for example, 5% palladium on carbon (50% water content), 10% palladium on carbon (50% water content), palladium on carbon, palladium hydroxide on carbon, and palladium black. The preferred catalyst is 5% palladium on carbon (50% water content) or 10% palladium on carbon (50% water content). The catalyst can be used, for example, in an amount of 0.01-fold to 0.5-fold relative to the weight of the compound having the formula [29a], preferably 0.05-fold to 0.2-fold.

The hydrogen gas pressure is between 1 and 5 bar. The preferred hydrogen gas pressure is in the range of 2 to 4 bar.

The reaction temperature is in the range, for example, from room temperature to 80°C, preferably 40°C ± 20°C.

The reaction time is, for example, 2 hours to 24 hours, preferably 12 hours to 24 hours.

Examples of organic acids for salt formation include, for example, oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, terephthalic acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid. acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorosulfonic acid, and the like. Preferred organic acids are oxalic acid and succinic acid.

[Production method 23] Preparation of a compound having the formula [14] or a salt thereof

[Chem. 56]

where Y is an acid and n is any number from 0.5 to 2, such as 0.5, 1 or 2.

A compound having the formula [14] can be obtained by condensing a compound having the formula [30a] with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CPPY) [12] or a salt thereof in the presence of a base. The compound having the formula [30a] can also be used in free form. The compound having the formula [14] can also be obtained in the form of a salt, and obtaining such a salt from a free form or obtaining a free form from such a salt can be carried out by any of the methods known in this field.

Examples of solvents include, for example, ethanol, 2-propanol, 1-propanol, 2-propanol, t-butanol, acetonitrile, THF, and their mixture with water. The preferred solvent is a mixture of tert-butanol and water.

Examples of bases include, for example, potassium phosphate, potassium carbonate, potassium hydroxide, triethylamine and N,N-diisopropylethylamine. The preferred base is potassium phosphate alone or in combination with potassium hydroxide.

The CPPY reagent [12] can be used, for example, in an amount of 0.95 to 1.05 equivalents relative to the compound having the formula [30a], preferably 1.0 ± 0.02 equivalents.

The reaction temperature is in the range, for example, from room temperature to 80°C, preferably from 40°C to 50°C.

The reaction time is, for example, 2 hours to 48 hours, preferably 12 hours to 24 hours.

[Production method 24] Preparation of a compound having the formula [31]

[Chem. 57]

The compound having the formula [31] can be obtained in the same way as in Production Method 22.

[Production method 25] Preparation of a compound having the formula [30a]

[Chem. 58]

where Y is an acid and n is any number from 0.5 to 2, such as 0.5, 1 or 2.

The compound having the formula [31] can be obtained in the same manner as in Production Method 21.

The preferred organic acid used in this step is succinic acid.

The production method of a compound or a salt thereof or a solvate thereof of the present invention can have the following advantages compared to the Production method 6 in Patent Literature 1.

(1) By the method described herein, Compound A (Compound [17]) can be obtained in fewer steps.

(2) The method described in the present text is a production method without using an ozone oxidation reaction and a reaction under ultra-low temperature conditions, which are not suitable for large-scale synthesis.

(3) BABL [2] is produced as a major product by suppressing lactone ring cleavage in Production Method 1, which can increase the yield of Compound A (Compound [17]).

(4) Removal of bisbenzyl adduct and unreacted benzylamine and the like. in the isolation step using the BABL salt [2] can reduce side reactions in Production Method 3-Step 2, which can increase the yield of Compound A (Compound [17]).

(5) The method described herein, involving the formation of RR-AOBL [7], can stereoselectively form a β-lactam ring without the use of any special equipment or any special reagents.

(6) RR-AOPE [8a] and Compound [16a] can be produced by using potassium phthalimide or sodium diformylamide as a nitrogen source in the method for producing RR-MDDO [9], followed by cleavage at position 7 in RR-AOBL [7] , which can reduce the number of synthetic steps and increase the yield of Compound A (Compound [17]).

(7) Preparation of Compound A (Compound [17]) with high chemical purity and optical purity can be carried out during the isolation step using RR-MDDO [9].

(8) Preparation of Compound A (Compound [17]) with high optical purity can be carried out during the isolation step using SR-MDBN salt [10].

(9) Isolation and purification operations by extraction and silica gel column chromatography may be unnecessary due to the high stability of Compound [34a], which can be directly isolated from the reaction mixture. Compound A (Compound [17]) can be obtained in high chemical purity.

Embodiments of the present invention include the following embodiments:

Item 1: Method for obtaining a compound having the formula [17]:

[Chem. 59]

or its salt using a compound having the formula [13]:

[Chem. 60]

or a salt thereof, comprising the following steps:

(1) removing benzyl from a compound having the formula [13] or a salt thereof to obtain a compound having the formula [14]:

[Chem. 61]

or its salt, and

(2) cyanoacetylation of a compound having the formula [14] or a salt thereof to obtain a compound having the formula [17] or a salt thereof.

Item 2: The method according to item 1, additionally including the step of reacting a compound having the formula [10]:

[Chem. 62]

or its salts with an organic acid with a compound having the formula [12]:

[Chem. 63]

or its salt to obtain a compound having the formula [13], or its salt.

Item 3: The method according to item 2, further comprising the step of adding an organic acid to a compound having the formula [10] to obtain a salt of the compound having the formula [10] with an organic acid.

Item 4: The method according to item 2 or 3, wherein the organic acid salt of the compound having the formula [10] is a disuccinate, an oxalate, or a hemioxalate.

Item 5: The method according to item 2 or 3, wherein the organic acid salt of the compound having the formula [10] is hemioxalate.

Item 6: The method according to any one of paragraphs. 2-5, additionally including the step of reducing the compound having the formula [9]:

[Chem. 64]

to obtain a compound having the formula [10], or its salt with an organic acid.

Item 7: The method according to item 6, where the reduction is carried out in the presence of an acid and lithium aluminum hydride.

Item 8: The method according to item 6 or 7, further comprising the step of removing phthaloyl from the compound having the formula [8a]:

[Chem. 65]

where R ¹ represents C _1-4 alkyl or benzyl;

to obtain a compound having the formula [9].

Item 9: The method according to item 6 or 7, further comprising the step of removing formyl from the compound having the formula [16a]:

[Chem. 66]

where R ¹ represents C _1-4 alkyl or benzyl;

to obtain a compound having the formula [9].

Item 10: The method according to item 8, further comprising the step of reacting a compound having the formula [7]:

[Chem. 67]

with potassium phthalimide, followed by esterification to give a compound having the formula [8a].

Item 11: The method according to item 9, further comprising the step of reacting a compound having the formula [7]:

[Chem. 68]

with sodium diformylamide, followed by esterification to obtain a compound having the formula [16a].

Item 12: The method according to item 10 or 11, further comprising the step of reacting a compound having the formula [6]:

[Chem. 69]

with a base to obtain a compound having the formula [7].

Item 13: The method of item 12, wherein the base is lithium hexamethyldisilazide.

Item 14: Method for producing a salt of a compound having the formula [10]:

[Chem. 70]

with an organic acid, comprising the step of adding an organic acid to a compound having the formula [10] to obtain a salt of the compound having the formula [10] with an organic acid.

Item 15: The method of claim 14 wherein the organic acid salt is a disuccinate, oxalate or hemioxalate.

Item 16: The method of claim 14 wherein the organic acid salt is hemioxalate.

Item 17: The method according to claims. 14-16, additionally including the step of reducing the compound having the formula [9]:

[Chem. 71]

to obtain a compound having the formula [10], or its salt with an organic acid.

Item 18: The method according to item 17, wherein the reduction is carried out in the presence of an acid and lithium aluminum hydride.

Item 19: The method according to item 17 or 18, further comprising the step of removing phthaloyl from the compound having the formula [8a]:

[Chem. 72]

where R ¹ represents C _1-4 alkyl or benzyl;

to obtain a compound having the formula [9].

Item 20: The method according to item 17 or 18, further comprising the step of removing formyl from the compound having the formula [16a]:

[Chem. 73]

where R ¹ represents C _1-4 alkyl or benzyl;

to obtain a compound having the formula [9].

Item 21: The method according to item 19, further comprising the reaction of a compound having the formula [7]:

[Chem. 74]

with potassium phthalimide, followed by esterification to give a compound having the formula [8a].

Item 22: The method according to item 19, further comprising the step of reacting a compound having the formula [7]:

[Chem. 75]

with sodium diformylamide, followed by esterification to obtain a compound having the formula [16a].

Item 23: The method according to item 21 or 22, further comprising the step of reacting a compound having the formula [6]:

[Chem. 76]

with a base to obtain a compound having the formula [7].

Item 24: The method of item 23, wherein the base is lithium hexamethyldisilazide.

Item 25: The method according to item 23 or 24, further comprising the reaction of a compound having the formula [2]:

[Chem. 77]

or its salts with a compound having the formula [5]:

[Chem. 78]

in the presence of a base to obtain a compound having the formula [6].

Item 26: The method of item 25, wherein the base is 2,6-lutidine.

Item 27: The method according to item 25 or 26, further comprising the step of adding an inorganic acid to a compound having the formula [2] to obtain a salt of the compound having the formula [2] with an inorganic acid.

Item 28: The method according to any one of paragraphs. 25, 26 and 27, further comprising the step of reacting a compound having the formula [4]:

[Chem. 79]

with a chlorinating agent to obtain a compound having the formula [5].

Item 29: The method according to item 28, further comprising the step of reacting a compound having the formula [1a]:

[Chem. 80]

where X ¹ represents chlorine or bromine;

with benzylamine in the presence of a base to obtain a compound having the formula [2] or a salt thereof.

Item 30: The method of item 29, wherein the base is tripotassium phosphate.

Item 31: Method for producing a compound having the formula [9]:

[Chem. 81]

,

,

including the step of removing phthaloyl from the compound having the formula [8a]:

[Chem. 82]

where R ¹ represents C _1-4 alkyl or benzyl;

to obtain a compound having the formula [9].

Item 32: Method for producing a compound having the formula [9]:

[Chem. 83]

comprising the step of removing formyl from a compound having the formula [16a]:

[Chem. 84]

where R ¹ represents C _1-4 alkyl or benzyl;

to obtain a compound having the formula [9].

Item 33: The method according to item 31, further comprising the step of reacting a compound having the formula [7]:

[Chem. 85]

with potassium phthalimide, followed by esterification to give a compound having the formula [8a].

Item 34: The method according to item 32, further comprising the step of reacting a compound having the formula [7]:

[Chem. 86]

with sodium diformylamide, followed by esterification to obtain a compound having the formula [16a].

Item 35: The method according to item 33 or 34, further comprising the step of reacting a compound having the formula [6]:

[Chem. 87]

with a base to obtain a compound having the formula [7].

Item 36: The method of item 35, wherein the base is lithium hexamethyldisilazide.

Item 37: The method according to item 35 or 36, further comprising the step of reacting a compound having the formula [2]:

[Chem. 88]

or its salts with a compound having the formula [5]:

[Chem. 89]

in the presence of a base to obtain a compound having the formula [6].

Item 38: The method of item 37, wherein the base is 2,6-lutidine.

Item 39: The method according to item 37 or 38, further comprising the step of adding an inorganic acid to a compound having the formula [2] to obtain a salt of the compound having the formula [2] with an inorganic acid.

Item 40: The method according to any one of paragraphs. 37, 38 and 39, further comprising the step of reacting a compound having the formula [4]:

[Chem. 90]

with a chlorinating agent to obtain a compound having the formula [5].

Item 41: The method according to item 40, further comprising the step of reacting a compound having the formula [1a]:

[Chem. 91]

where X ¹ represents chlorine or bromine;

with benzylamine in the presence of a base to obtain a compound having the formula [2] or a salt thereof.

Item 42: The method of item 41, wherein the base is tripotassium phosphate.

Item 43: Method for producing a compound having the formula [7]:

[Chem. 92]

,

,

including the stage of the reaction of the compound having the formula [6]:

[Chem. 93]

with a base to obtain a compound having the formula [7].

Item 44: The method of item 43, wherein the base is lithium hexamethyldisilazide.

Item 45: The method according to item 43 or 44, further comprising the step of reacting a compound having the formula [2]:

[Chem. 94]

or its salts with a compound having the formula [5]:

[Chem. 95]

in the presence of a base to obtain a compound having the formula [6].

Item 46: The method of item 45, wherein the base is 2,6-lutidine.

Item 47: The method according to item 45 or 46, further comprising the step of adding an inorganic acid to a compound having the formula [2] to obtain a salt of the compound having the formula [2] with an inorganic acid.

Item 48: The method according to any one of paragraphs. 45, 46 and 47, further comprising the step of reacting a compound having the formula [4]:

[Chem. 96]

with a chlorinating agent to obtain a compound having the formula [5].

Item 49: The method according to item 48, further comprising the step of reacting a compound having the formula [1a]:

[Chem. 97]

where X ¹ represents chlorine or bromine;

with benzylamine in the presence of a base to obtain a compound having the formula [2] or a salt thereof.

Item 50: The method of item 49, wherein the base is tripotassium phosphate.

Item 51: The method according to item 6 or 17, further comprising the step of cyclizing a compound having the formula [27a]:

[Chem. 98]

where R ² and R ³ each independently represent methyl, ethyl or benzyl;

to obtain a compound having the formula [9].

Item 52: The method according to item 51, further comprising the step of reacting a compound having the formula [26a]:

[Chem. 99]

where R ² and R ³ have the above meanings;

or its salts with a compound having the formula [5]:

[Chem. 100]

in the presence of a base to give a compound having the formula [27a].

Item 53: The method according to item 52, further comprising the step of reacting a compound having the formula [4]:

[Chem. 101]

with a chlorinating agent to obtain a compound having the formula [5].

Item 54: The method according to item 52 or 53, further comprising the step of reacting a compound having the formula [25a]:

[Chem. 102]

where R ² and R ³ have the above meanings;

or its salt with benzaldehyde to obtain a compound having the formula [26a], or its salt.

Item 55: The method of item 54, further comprising the step of esterifying a compound having the formula [24a]:

[Chem. 103]

where R ² has the above meaning;

or a salt thereof to obtain a compound having the formula [25a], or a salt thereof.

Item 56: The method according to item 55, further comprising the step of obtaining a compound having the formula [24a] or a salt thereof from a compound having the formula [23]:

[Chem. 104]

or its salt.

Item 57: Method for producing a compound having the formula [9]:

[Chem. 105]

,

,

including the stage of cyclization of the compound having the formula [27a]:

[Chem. 106]

where R ² and R ³ each independently represent methyl, ethyl or benzyl;

to obtain a compound having the formula [9].

Item 58: The method of item 57, further comprising the step of reacting a compound having the formula [26a]:

[Chem. 107]

where R ² and R ³ have the above meanings;

or its salts with a compound having the formula [5]:

[Chem. 108]

in the presence of a base to give a compound having the formula [27a].

Item 59: The method according to item 58, further comprising the step of reacting a compound having the formula [4]:

[Chem. 109]

with a chlorinating agent to obtain a compound having the formula [5].

Item 60: The method according to item 59, further comprising the step of reacting a compound having the formula [25a]:

[Chem. 110]

where R ² and R ³ have the above meanings;

or its salt with benzaldehyde to obtain a compound having the formula [26a], or its salt.

Item 61: The method of item 60, further comprising the step of esterifying a compound having the formula [24a]:

[Chem. 111]

where R ² has the above meaning;

or a salt thereof to obtain a compound having the formula [25a], or a salt thereof.

Item 62: The method according to item 61, further comprising the step of obtaining a compound having the formula [24a] or a salt thereof from a compound having the formula [23]:

[Chem. 112]

or its salt.

Item 63: Method for producing a compound having the formula [26a]:

[Chem. 113]

where R ² and R ³ have the above meanings;

or a salt thereof, comprising the step of reacting a compound having the formula [25a]:

[Chem. 114]

where R ² and R ³ have the above meanings;

or its salt with benzaldehyde to obtain a compound having the formula [26a], or its salt.

Item 64: The method of item 63, further comprising the step of esterifying a compound having the formula [24a]:

[Chem. 115]

where R ² has the above meaning;

or a salt thereof to obtain a compound having the formula [25a], or a salt thereof.

Item 65: The method according to item 64, further comprising the step of obtaining a compound having the formula [24a] or a salt thereof from a compound having the formula [23]:

[Chem. 116]

or its salt.

Item 66: Method for producing a compound having the formula [17]:

[Chem. 117]

or its salt using a compound having the formula [31]:

[Chem. 118]

or its salt with an organic acid, comprising the following steps:

(1) the reaction of a compound having the formula [31] or an organic acid salt thereof with a compound having the formula [12]:

[Chem. 119]

or its salt to obtain a compound having the formula [14]:

[Chem. 120]

or its salts; and

(2) cyanoacetylation of a compound having the formula [14] or a salt thereof to obtain a compound having the formula [17] or a salt thereof.

Item 67: The method according to item 66, further comprising the step of adding an organic acid to a compound having the formula [31] to obtain a salt of the compound having the formula [31] with an organic acid.

Item 68: The method of item 66 or 67 wherein the organic acid salt is a disuccinate or oxalate.

Item 69: The method according to any one of paragraphs. 66, 67 and 68, further comprising the step of obtaining a compound having the formula [31] or its salt with an organic acid from a compound having the formula [28]:

[Chem. 121]

or its salts with an organic acid.

Item 70: The method of item 69, further comprising the step of adding an organic acid to a compound having the formula [28] to obtain a salt of the compound having the formula [28] with an organic acid.

Item 71: The method according to item 69 or 70, wherein the organic acid salt of the compound having the formula [28] is an oxalate.

Item 72: Method for producing a salt of a compound having the formula [31]:

[Chem. 122]

with an organic acid, comprising the step of adding an organic acid to a compound having the formula [31] to obtain a salt of the compound having the formula [31] with an organic acid.

Item 73: The method of item 72, wherein the organic acid salt of the compound having the formula [31] is a disuccinate or an oxalate.

Item 74: The method according to item 72 or 73, further comprising the step of obtaining a compound having the formula [31] or an organic acid salt thereof from a compound having the formula [28]:

[Chem. 123]

or its salts with an organic acid.

Item 75: The method of item 74, further comprising the step of adding an organic acid to a compound having the formula [28] to obtain a salt of the compound having the formula [28] with an organic acid.

Item 76: The method according to item 74 or 75, wherein the organic acid salt of the compound having the formula [28] is an oxalate.

Item 77: A compound having the formula [13]:

[Chem. 124]

or its salt.

Item 78: A compound having the formula [10]:

[Chem. 125]

or its salt with an organic acid.

Item 79: The salt of item 78, wherein the organic acid salt is a disuccinate, oxalate, or hemioxalate.

Item 80: The salt of item 78, wherein the organic acid salt is hemioxalate.

Item 81: Disuccinate crystal of a compound having the formula [10]:

[Chem. 126]

having an X-ray powder diffraction spectrum containing at least one peak with a diffraction angle value (2θ) = 4.8° ± 0.2°, 11.2° ± 0.2°, 16.2° ± 0.2°, 18.1° ± 0.2° or 20.1° ± 0.2° when analyzed using CuKα radiation.

Item 82: A compound having the formula [9]:

[Chem. 127]

.

.

Item 83: The crystalline form of the compound having the formula [9]:

[Chem. 128]

having an X-ray powder diffraction spectrum containing at least one peak with a diffraction angle value (2θ) = 10.6° ± 0.2°, 16.0° ± 0.2°, 17.5° ± 0.2°, 18.3° ± 0.2° or 19.2° ± 0.2° when analyzed using CuKα radiation.

Item 84: A compound having the formula [8a]:

[Chem. 129]

where R ¹ represents C _1-4 alkyl or benzyl.

Item 85: A compound having the formula [16a]:

[Chem. 130]

where R ¹ represents C _1-4 alkyl or benzyl.

Item 86: A compound having the formula [7]:

[Chem. 131]

.

.

Item 87: A compound having the formula [6]:

[Chem. 132]

.

.

Item 88: A compound having the formula [27a]:

[Chem. 133]

where R ² and R ³ have the above meanings.

Item 89: A compound having the formula [26a]:

[Chem. 134]

where R ² and R ³ have the above meanings;

or its salt.

Item 90: A compound having the formula [25a]:

[Chem. 135]

where R ² and R ³ have the above meanings;

or its salt.

Item 91: A compound having the formula [24a]:

[Chem. 136]

where R ² has the above meaning;

or its salt.

Item 92: A compound having the formula [31]:

[Chem. 137]

or its salt with an organic acid.

Item 93: The salt of item 92, wherein the organic acid salt is a disuccinate or an oxalate.

Item 94: Salt of a compound having the formula [28]:

[Chem. 138]

with organic acid.

Item 95: The salt of item 94, wherein the organic acid salt is an oxalate.

Examples

Particular methods for preparing the compounds of the present invention, or their salts or solvates thereof, are illustrated in the Examples below. However, the present invention is not limited to these Examples.

At the stages of crystallization in obtaining Compound [9] (Example 4), Compound [20] (Example 13), Compound [29] (Example 36), Compound [30-2] (Example 39) and Compound A (Compound [17] ) (Examples 15 and 41), and in the purification of Compound A (Compound [17]) (Examples 14, 16 and 20) seed crystals were used to promote crystallization. Crystals of these compounds can be obtained by the same methods as described in the Examples, and without the use of seed crystals.

Below are the transcripts of the abbreviations used in this text.

BBL: 3-bromodihydrofuran-2-one

BABL: 3-benzylaminodihydrofuran-2-one

BABL-HC: 3-benzylaminodihydrofuran-2-one monohydrochloride

BHT: 2,6-di-tert-butyl-4-methylphenol

R-CPRA: (R)-2-chloropropionic acid

R-CPRC: (R)-2-chloropropionyl chloride

R-CPBL: (R)-N-benzyl-2-chloro-N-(2-oxotetrahydrofuran-3-yl)-propionylamide

RR-AOBL: (3R,4R)-1-benzyl-3-methyl-6-oxa-1-azaspiro[3.4]octane-2,5-dione

RR-AOPE: (2R,3R)-1-benzyl-2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-ethyl]3-methyl-4-oxoazetidine-2 ethyl ester -carboxylic acid

RR-AOPA: (2R,3R)-1-benzyl-2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-ethyl]3-methyl-4-oxoazetidine-2-carboxylic acid

RR-MDDO: (3R,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane-2,5-dione)

SR-MDBN: (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane

SR-MDBN-DSU: (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane disuccinate

SR-MDBP: 4-[(3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]oct-6-yl]-7H-pyrrolo[2,3-d]pyrimidine

SR-MDOP: 4-[(3S,4R)-3-methyl-1,6-diazaspiro[3.4]-octan-6-yl]-7H-pyrrolo[2,3-d]pyrimidine

Compound A (Compound [17]): 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4] octan-1-yl]-3-oxopropanenitrile

CPPY: 4-chloro-7H-pyrrolo[2,3-d]pyrimidine

DPCN: 1-cyanoacetyl-3,5-dimethyl-1H-pyrazole

THF: tetrahydrofuran

CPME: cyclopentyl methyl ether

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

TMDS: 1,1,3,3-tetramethyldisiloxane

TMEDA: N,N,N',N'-tetramethylethylenediamine

TMSCl: chlorotrimethylsilane

LHMDS: lithium hexamethyldisilazide

TBBA: Bromoacetic acid tert-butyl ester

Boc-Gln-OH: (tert-butoxycarbonyl)-L-glutamine

Boc-Dab(MeOCO)-OH: (S)-2-((tert-butoxycarbonyl)amino)-4-((methoxycarbonyl)amino)butanoic acid

SR-ZMDB: benzyl (3S,4R)-6-benzyl-3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylate

SR-ZMDB-OX: benzyl (3S,4R)-6-benzyl-3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylate oxalate

S-BAPO: (S)-2-(benzylamino)propan-1-ol

S-BBMO: tert-butyl (S)-N-benzyl-N-(1-hydroxypropan-2-yl)glycinate

R-BCAB: tert-butyl (R)-N-benzyl-N-(2-chloropropyl)glycinate

S-MABB: tert-butyl (3S)-1-benzyl-3-methylazetidine-2-carboxylate

S-MABB-HC: tert-butyl (3S)-1-benzyl-3-methylazetidine-2-carboxylate hydrochloride

S-MACB-HC: tert-butyl (3S)-3-methylazetidine-2-carboxylate hydrochloride

S-ZMAB: 1-benzyl 2-(tert-butyl) (3S)-3-methylazetidine-1,2-dicarboxylate

RS-ZMBB: 1-benzyl 2-(tert-butyl) (2R,3S)-2-(2-(tert-butoxy)-2-oxoethyl)-3-methylazetidine-1,2-dicarboxylate

RS-ZMAA: (2R,3S)-1-((benzyloxy)carbonyl)-2-(carboxymethyl)-3-methylazetidine-2-carboxylic acid

RS-ZMAA-DN 2H ₂ O: disodium (2R,3S)-1-((benzyloxy)carbonyl)-2-(carboxymethyl)-3-methylazetidine-2-carboxylate dihydrate

RS-ZMOO: benzyl (2R,3S)-2-(2-hydroxyethyl)-2-(hydroxymethyl)-3-methylazetidine-1-carboxylate

RS-ZMSS: benzyl (2R,3S)-3-methyl-2-(2-((methylsulfonyl)oxy)ethyl)-2-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate

The instruments used in the Examples and the conditions for taking the spectra are described below.

¹ H-NMR spectra were recorded in CDCl ₃ , DMSO-d ₆ or deuterium oxide using trimethylsilane as an internal standard, and all δ values are in parts per million (ppm). The spectra were recorded on an NMR instrument with a frequency of 400 MHz, unless otherwise indicated.

The symbols in the Examples have the following meanings.

c: singlet

e: doublet

t: triplet

square: quartet

dd: doublet of doublets

d.kv: doublet of quartets

ddd: doublet of doublets of doublets

brs: widened singlet

m: multiplet

J: spin-spin coupling constant

Powder x-ray diffraction patterns of the samples were obtained by powder x-ray diffraction.

Device: X'Pert Pro (SPECTRIS)

Analysis conditions:

Anticathode: Cu

Current and voltage in X-ray tube: 45 kV, 40 mA

Sample rotation speed: every 1 sec.

Soller slit for the incident beam: 0.02 rad

Vertical divergence slot for incident beam: 15mm

Spreading slit for incident beam: automatic, beam width 15 mm

Incident beam slit: 1°

Reflected beam filter: Nickel filter

Soller slit for reflected beam: 0.02 rad

Divergence slit for reflected beam: automatic, beam width 15 mm

Detector: X'Celerator

Detector Mode: Scan

Effective detector width: 2.122°

Scan axis: Gonio.

Scan Mode: Continuous

Scan range: 3°-60°

Single step time: 10 sec.

The weight % of carbon, hydrogen and nitrogen in the samples was determined by elemental analysis.

The content of ions in the sample was determined as the average of three measurements for the sample.

Instrument: LC-20 Ion Exchange Chromatograph (Shimadzu Corporation)

Analysis Conditions: SHIMADZU CDD-10A VP Conductivity Detector

Column for the analysis of anions SHIMADZU SHIM-PAC IC-A3

Cation analysis column SHIMADZU SHIM-PAC IC-C1

The water content in the sample was determined by the Karl Fischer titration method.

Instrument: CA-06 Coulometric Water Titrator (Mitsubishi Chemical Corporation)

Analysis conditions: Sample quantity: about 20 mg

Reagent: Aquamicron AX anode solution (API Corporation)

Aquamicron CXU Cathode Solution (API Corporation)

[Example 1] Preparation of BABL-HC (Compound [3])

[Chem. 139]

Stage 1

[Chem. 140]

Tripotassium phosphate (1466.7 g, 6.9 mol), acetonitrile (3.8 L), benzylamine (246.8 g, 2.30 mol) and BBL [1] (380 g, 2, 30 mol) into a reaction flask at room temperature. The reaction mixture was stirred at 40°C - 45°C for 21 hours and then cooled to room temperature. Any insoluble matter in the reaction mixture was filtered off and washed with acetonitrile (760 ml). The filtrate was combined with the washings and evaporated under reduced pressure. Toluene (3.8 L), 20% sodium chloride solution (1.14 L) and acetic acid (20.75 g) were added to the evaporation residue, and after stirring the mixture, the organic layer was separated. The resulting organic layer was washed with a mixture of 20% sodium chloride solution (760 ml) and 5% sodium bicarbonate aqueous solution (380 ml), and the solvent was distilled off from the organic layer under reduced pressure. Toluene (380 ml) was added to the evaporation residue. All insoluble matter was filtered off and washed with toluene (380 ml). The filtrate was combined with the wash solution and evaporated under reduced pressure. The procedure for adding ethyl acetate (1.52 L) to the evaporation residue followed by evaporation was repeated twice and ethyl acetate (760 ml) was added to give a solution of BABL [2] in ethyl acetate (440 g, equivalent to 2.30 mol). The resulting solution of BABL [2] in ethyl acetate was used in the next step, assuming a yield of 100%.

Crude BABL [2], obtained by the same method, was evaporated to dryness to record the mass spectrum (MS).

MS: m/z = 192 [M+H] ⁺

Stage 2

[Chem. 141]

Under nitrogen atmosphere, methanol (380 ml) was added to a solution of BABL [2] in ethyl acetate (440 g, equivalent to 2.30 mol) at room temperature. In the resulting mixture was added 4n. a solution of hydrogen chloride in ethyl acetate (575 ml, 2.30 mol) at 0°C, and the reaction mixture was stirred at 0°C for 1.5 hours. The precipitated solid was collected on the filter and washed twice with ethyl acetate (760 ml). The resulting wet solid was dried under reduced pressure to give BABL-HC [3] (385.1 g, 1.69 mol) in 73.4% yield.

Using BABL-HC [3], obtained by the same method, the NMR spectrum was recorded and the melting point was determined, and elemental analysis was performed.

¹ H-NMR (DMSO-d ₆ ) δ: 10.11 (1H, br s), 7.55-7.41 (5H, m), 4.47 (1H, t, J = 8.8 Hz ), 4.36-4.22(4H, m), 3.31(1H, brs), 2.61-2.54(1H, m), 2.49-2.41(1H, m ).

Melting point: 206°C - 208°C

Elemental analysis: C 58.1 wt.%, H 6.2 wt.% and N 6.1 wt.% (Theoretical value: C 58.0 wt.%, H 6.2 wt.% and N 6.2 the weight.%).

Using BABL-HC [3], obtained by the same method, the diffraction angle 2θ and the diffraction intensity were determined by powder X-ray diffraction. The resulting spectrum is shown in Fig. one.

The corresponding peaks in Fig. 1 have the characteristics shown in the table below.

Table 1

Diffraction angle
[2θ (°)] Relative intensity
[%] Diffraction intensity
[imp/s] 8.4720 65.46 4970.48 11.8659 14.93 1133.49 14.8286 14.45 1096.96 16.6274 4.93 374.50 17.0114 2.78 211.08 17.7705 16.90 1283.55 18.8793 100.00 7593.69 19.7206 25.67 1949.02 20.7055 11.10 842.77 20.9531 36.78 2792.92 21.4266 47.81 3630.51 23.8737 10.23 777.18 24.4323 27.55 2091.80 24.7131 6.23 473.16

[Example 2] Getting BABL (Compound [2-2])

Stage 1

[Chem. 142]

Aminolactone bromate [15] (1.0 g, 5.49 mmol) synthesized by the method described in Non-Patent Literature 1, DMF (15 ml), acetic acid (0.1 ml) and benzaldehyde (0.62 ml, 6, 04 mmol) were sequentially added to the reaction flask, and the mixture was cooled to 0°C. Sodium triacetoxyborohydride (1.39 g, 6.59 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. 1M hydrochloric acid was added to the reaction mixture, and the mixture was washed with toluene. A saturated sodium bicarbonate aqueous solution was added to the resulting aqueous layer, and the product was extracted with ethyl acetate three times. The combined organic layer was washed with saturated sodium chloride solution and evaporated under reduced pressure to give BABL [2-2] (976 mg, equivalent to 5.11 mmol).

Crude BABL [2-2], obtained by the same method, was evaporated to dryness to record the mass spectrum (MS).

MS: m/z = 192 [M+H] ⁺

[Example 3] Receiving RR-MDDO (Connection [9])

[Chem. 143]

Stage 1

[Chem. 144]

Thionyl chloride (107.8 ml, 1.48 mol) was added under nitrogen in DMF (260 ml) at 0° C. and the mixture was stirred at the same temperature for 30 minutes. To the resulting solution was added dropwise a solution of R-CPRA [4] (148.7 g, 1.37 mol) in toluene (260 ml) at 0°C, and the mixture was stirred at the same temperature for 1 hour, obtaining a solution of R -CPRC [5] (equivalent to 1.37 mol) in toluene.

Under a nitrogen atmosphere, BABL-HC [3] (260 g, 1.14 mol), ethyl acetate (2 L) and 2,6-lutidine (489.4 g, 4.57 mol) were added successively to the reaction flask and the mixture was stirred at room temperature for 20 min. The mixture was cooled to 0°C, then the previously obtained solution of R-CPRC [5] (equivalent to 1.37 mol) in toluene was added dropwise at a temperature below 5°C, and the mixture was stirred at the same temperature for 2 hours. 1M hydrochloric acid (1.3 L) was added to the reaction mixture, and after stirring, the organic layer was separated and washed successively twice with 5% aqueous sodium bicarbonate solution (1.3 L) and then with water (1.3 L). The resulting organic layer was evaporated under reduced pressure, then toluene (780 ml) was added to the evaporation residue and the mixture was again evaporated under reduced pressure. This procedure was repeated once more. DMSO (750 ml) was added to the evaporation residue, obtaining a solution of crude R-CPBL [6] in DMSO (1187.94 g, equivalent to 1.14 mol). The resulting R-CPBL [6] was used in the next step, assuming a yield of 100%.

An aliquot of a solution of crude R-CPBL [6] in toluene, obtained by the same procedure, was evaporated to dryness to record the NMR spectrum, mass spectrum (MS) and melting point, and to perform elemental analysis.

¹ H-NMR (DMSO-d ₆ ) δ: (3:2 mixture of diastereomers) 5.03 and 4.99 (1H, q, J = 6.5 Hz, proton at chlorine addition site), 1.51 and 1 .47 (3H, d, J = 6.5 Hz, methyl proton).

MS: m/z = 282 [M+H] ⁺

Melting point: 101°C - 104°C

Elemental analysis: C 59.8 wt.%, H 5.7 wt.% and N 4.9 wt.% (Theoretical value: C 59.7 wt.%, H 5.7 wt.% and N 5.0 the weight.%).

Stage 2

[Chem. 145]

In a nitrogen atmosphere, to the previously obtained solution of crude R-CPBL [6] in DMSO (1161.8 g, equivalent to 1.12 mol), DMSO (250 ml) and cesium carbonate (728.1 g, 2.23 mol) were added successively at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was added dropwise to 2M hydrochloric acid (1.78 L) cooled to below 20° C. and the product was extracted with ethyl acetate (2.5 L). The resulting organic layer was washed successively with 5% sodium bicarbonate aqueous solution (1.3 L) and twice with 20% sodium chloride solution (1.3 L) and evaporated under reduced pressure to give crude RR-AOBL [7] ( 353.9 g, equivalent to 1.12 mol, diastereomer ratio 97:3). The resulting crude RR-AOBL [7] was used in the next step, assuming a yield of 100%.

Crude RR-AOBL [7], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 4.86 (1H, d, J = 15.3 Hz), 4.21 (1H, ddd, J = 9 .9, 5.2, 4.0 Hz), 4.13-4.06 (1H, m), 4.02 (1H, d, J = 15.3 Hz), 3.36 (1H, q, J = 7.5 Hz), 2.13-2.10 (2H, m), 1.31 (3H, d, J = 7.3 Hz).

MS: m/z = 246 [M+H] ⁺

Stage 3

[Chem. 146]

Crude RR-AOBL [7] (220.15 g, equivalent to 0.97 mol), DMF (1.5 L) and potassium phthalimide (232.81 g, 1.26 mol) were successively added to the reaction flask under nitrogen atmosphere at room temperature and the mixture was stirred at 80°C - 100°C overnight. The reaction mixture was then cooled to about 50°C, ethyl iodide (226.21 g, 1.45 mol) was added dropwise to the mixture and stirred at 40°C - 50°C for 4 hours. The reaction mixture was cooled to about 0° C., 20% sodium chloride solution (1.1 L) was added to the mixture and the product was extracted with toluene (1.1 L). The resulting organic layer was washed successively with 20% sodium chloride solution (1.1 L) and water (1.1 L) and then evaporated under reduced pressure. 2-Butanol (1.1 L) was added to the evaporation residue and the mixture was evaporated under reduced pressure. This procedure was repeated once more to obtain a solution of crude RR-AOPE [8] in 2-butanol (809.67 g, equivalent to 0.97 mol). The resulting solution of RR-AOPE [8] in 2-butanol was used in the next step, considering the yield to be 100%.

Crude RR-AOPE [8], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (CDCl ₃ ) δ: 7.83-7.80 (2H, m), 7.73-7.69 (2H, m), 7.37-7.32 (4H, m), 7 .29-7.25 (1H, m), 4.79 (1H, d, J = 15.7 Hz), 4.40 (1H, d, J = 15.7 Hz), 4.15-4, 06 (2H, m), 3.68-3.61 (1H, m), 3.52-3.44 (1H, m), 3.37 (1H, q, J = 7.5 Hz), 2 .27-2.12 (2H, m), 1.26-1.22 (6H, m).

MS: m/z = 421 [M+H] ⁺

Stage 4

[Chem. 147]

Ethylenediamine (10.56 g, 175.6 mmol) was added under nitrogen atmosphere to a solution of RR-AOPE [8] in 2-butanol (36.78 g, equivalent to 43.9 mmol) at room temperature, and the mixture was stirred at 80° C-90°C for 4 hours. The reaction mixture was cooled to about 50°C, added THF (120 ml), the mixture was stirred at 40°C-50°C for 1 hour and then at room temperature overnight. Any insoluble matter was filtered off, then a 25% aqueous potassium hydrogen sulfate solution (170 ml) was added to the filtrate, and the layers were separated. The resulting organic layer was washed with a mixture of 7.5% sodium bicarbonate aqueous solution and saturated sodium chloride solution (1/4, 50 ml) and evaporated under reduced pressure. Ethyl acetate (200 ml) and CARBORAFFIN 20 (0.5 g, Japan EnviroChemicals, Ltd.) were added to the evaporation residue and the mixture was stirred at room temperature for 30 minutes. All undissolved substances from the mixture were filtered off, the filtrate was evaporated, CPME (50 ml) was added to the evaporation residue, and then the mixture was evaporated (crude RR-MDDO [9]). CPME (40 ml) was added to the evaporation residue and the mixture was heated at 50°C to 60°C. Diisopropyl ether (40 ml) was added dropwise to the resulting mixture, and the mixture was stirred at the same temperature for 1 hour and then 2 hours after cooling to room temperature. The precipitated solid was collected on a filter, washed with CPME/diisopropyl ether (1:1, 20 mL) and dried at 50°C under reduced pressure to give RR-MDDO [9] (6.70 g, 27.4 mmol) with 62.5% yield from BABL-HC [3].

Using RR-MDDO [9] obtained by the same procedure, the NMR spectrum, mass spectrum (MS) and melting point were recorded, and elemental analysis was performed.

¹ H-NMR (CDCl ₃ ) δ: 7.33-7.26 (5H, m), 5.92 (1H, brs), 4.85 (1H, d, J = 15.5 Hz), 3.99 (1H, d, J = 15.5 Hz), 3.27-3.18 (2H, m), 3.16-3.10 (1H, m), 2.07-1.99 ( 2H, m), 1.28 (3H, d, J = 7.6 Hz).

MS: m/z = 245 [M+H] ⁺

Melting point: 125°C - 127°C.

Elemental analysis: C 68.9 wt.%, H 6.6 wt.% and N 11.4 wt.% (Theoretical value: C 68.8 wt.%, H 6.6 wt.% and N 11.5 the weight.%).

Using RR-MDDO [9] obtained by the same procedure, the diffraction angle 2θ and the diffraction intensity were determined by powder X-ray diffraction. The resulting spectrum is shown in Fig. 2.

The corresponding peaks in Fig. 2 have the characteristics shown in the table below.

table 2

Diffraction angle
[2θ (°)] Relative intensity
[%] Diffraction intensity
[imp/s] 9.0979 21.90 4009.37 10.1864 21.77 3984.95 10.5858 100.00 18308.77 11.1145 21.00 3844.56 11.7820 7.79 1426.10 12.0289 14.60 2672.35 13.4150 6.21 1136.91 13.7219 6.74 1234.41 14.1371 4.12 754.46 14.8721 16.29 2983.07 15.1409 0.92 169.18 16.0216 53.20 9740.15 17.1231 7.20 1319.00 17.4922 23.90 4376.64 17.6960 7.72 1412.88 18.2720 41.92 7675.44 19.2469 28.89 5289.35 20.4687 3.92 718.21 20.7692 13.66 2501.28 21.2746 18.60 3405.92 21.6985 3.31 605.42 22.0927 3.97 726.82 22.3675 1.53 279.23 23.0181 8.09 1480.46 23.2134 10.64 1947.43 23.5762 3.74 684.16 24.0124 6.62 1212.01 24.2166 5.08 930.76 24.7758 6.22 1138.51

The crude RR-MDDO [9] obtained in Example 3 and the RR-MDDO [9] obtained after the crystallization step were analyzed by HPLC.

The HPLC analysis apparatus and conditions are described below.

Device: Nexera system (Shimadzu)

Terms:

Column: CHIRAL PAK IF-3: 3 µm, 250 mm x 4.6 mm (Daicel)

Column temperature: 40°C

Flow rate: 1.0 ml/min

Analysis time: 35 min

Detector wavelength: UV (220nm)

Mobile phase: Hexane/2-propanol = 80/20

The retention time of RR-MDDO [9] under the HPLC analysis conditions described above was about 14.6 min. The retention time for each stereoisomer was about 10.9 minutes for the SS form, about 16.5 minutes for the RS form, and about 18.6 minutes for the SR form.

The result of HPLC analysis of crude RR-MDDO [9] obtained in Example 3 is shown in FIG. 3 and in the table below.

Table 3

Retention time (min) Square Height % area Configuration one 6.598 41404 3008 1.704 2 7.039 108861 10591 4.481 3 10.871 23189 1775 0.955 SS four 11.094 31718 1945 1.306 5 11.729 30699 1923 1.264 6 14,580 2143972 95372 88.251 RR 7 16.504 35162 1479 1.447 RS eight 18.566 14399 314 0.593 SR

The result of the HPLC analysis of RR-MDDO [9] obtained after the crystallization step is shown in FIG. 4 and in the table below.

Table 4

Retention time (min) Square Height % area Configuration one 10.910 1761 114 0.041 SS 2 11.764 3750 257 0.087 3 14.516 4302521 189506 99.832 RR four 16.244 1714 5 0.040 RS

The crystallization step of RR-MDDO [9] is useful for removing its diastereomer, RS-MDDO. The ratio of diastereomers in crude RR-MDDO [9] was [RR-MDDO/RS-MDDO = 88.25%/1.45% (Percentage of areas by HPLC)], while the ratio of diastereomers in RR-MDDO [9] obtained after the crystallization step was [RR-MDDO/RS-MDDO = 99.83%/0.04% (HPLC area percentage)].

[Example 4] Receiving RR-MDDO (Connection [9])

[Chem. 148]

Diethylenetriamine (91.72 g, 889.0 mmol) was added under nitrogen atmosphere to a solution of RR-AOPE [8] in 2-butanol (equivalent to 177.5 mmol) at room temperature and the mixture was stirred at 85°C - 95°C within 2 hours. The reaction mixture was cooled to 10°C or below, and then added dropwise concentrated hydrochloric acid (160 ml) and 25% sodium chloride solution (150 ml). The product was extracted after adding ethyl acetate (500 ml). The resulting organic layer was washed with a mixture of 7.5% sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution (1/3, 200 ml) and evaporated under reduced pressure. Toluene was added to the evaporation residue, bringing the total volume to 200 ml, and ethyl acetate (400 ml) and CARBORAFFIN 20 (3.0 g, Japan EnviroChemicals, Ltd.) were added. The mixture was stirred at room temperature overnight. All undissolved substances were removed from the solution and the filtrate was evaporated. Toluene (250 ml) was added to the evaporation residue and the mixture was evaporated, repeating this procedure twice. Toluene was added to the evaporation residue, bringing the total volume to 250 ml, and the mixture was dissolved by heating to a temperature of from 55°C to 65°C. A seed crystal of RR-MDDO [9] (51 mg) was added to the resulting solution, and the mixture was stirred at the same temperature for 1 hour. Then, n-heptane (125 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour, then cooled to room temperature and stirred overnight. The precipitated solid was collected on a filter and washed with toluene/n-heptane (2/1, 150 mL), then dried at 50°C under reduced pressure to give RR-MDDO [9] (31.07 g, 127.2 mmol ) with a yield of 71.6% from R-CPBL [6].

The NMR spectrum and mass spectrum (MS) were recorded for the obtained RR-MDDO [9].

¹ H-NMR (DMSO-d ₆ ) δ: 8.10 (1H, br s), 7.35-7.24 (5H, m), 4.55 (1H, d, J = 16.0 Hz ), 3.95 (1H, d, J = 16.0 Hz), 3.35 (1H, q, J = 7.6 Hz), 3.15-3.05 (2H, m), 2.17 -2.12 (1H, m), 2.07-1.99 (1H, m), 1.07 (3H, d, J = 7.4 Hz).

MS: m/z = 245 [M+H] ⁺

[Example 5] Isolation of R-CPBL (Compound [6]) by Crystallization

[Chem. 149]

Thionyl chloride (0.57 ml, 7.88 mmol) was added under nitrogen in DMF (1.4 ml) at 0° C. and the mixture was stirred at the same temperature for 30 minutes. To the resulting solution was added dropwise a solution of R-CPRA [4] (789 mg, 7.27 mmol) in toluene (1.4 ml) at 0°C, and the mixture was stirred at the same temperature for 1 hour, obtaining a solution of R -CPRC [5] (923 mg, equivalent to 7.88 mmol) in toluene.

Under nitrogen atmosphere, BABL [2] (1.16 g, 6.06 mmol), ethyl acetate (9 ml) and 2,6-lutidine (1.95 g, 18.18 mmol) were successively added to the reaction flask and the mixture was stirred at room temperature for 20 min. The mixture was cooled to 0°C and the previously obtained solution of R-CPRC [5] (923 mg, equivalent to 7.88 mmol) in toluene at a temperature below 5°C was added dropwise, then the mixture was stirred at the same temperature for 2 hours. 1M hydrochloric acid (5 ml) was added to the reaction mixture, after stirring, the organic layer was separated and washed successively twice with 7.5% aqueous sodium bicarbonate solution (6 ml) and water (6 ml). CARBORAFFIN 20 (0.2 g, Japan EnviroChemicals, Ltd.) was added to the resulting organic layer, and the mixture was stirred at room temperature overnight. All insoluble matters were filtered off and washed with ethyl acetate. The filtrate was combined with the washings and evaporated under reduced pressure. The resulting residue was crystallized using toluene (6 ml) and heptane (6 ml) to give R-CPBL [6] (1.19 g, 4.22 mmol) in 98.2% yield.

Using R-CPBL [6], obtained by the same method, the NMR spectrum, mass spectrum (MS) and melting point were recorded, and elemental analysis was performed.

¹ H-NMR (DMSO-d ₆ ) δ: (3:2 mixture of diastereomers) 5.03 and 4.99 (1H, q, J = 6.5 Hz, proton at chlorine addition site), 1.51 and 1 .47 (3H, d, J = 6.5 Hz, methyl proton).

MS: m/z = 282 [M+H] ⁺

Melting point: 101°C-104°C

Elemental analysis: C 59.8 wt.%, H 5.7 wt.% and N 4.9 wt.% (Theoretical value: C 59.7 wt.%, H 5.7 wt.% and N 5.0 the weight.%).

[Example 6] Obtaining RR-AOBL (Compound [7])

[Chem. 150]

R-CPBL [6] (5.58 g, equivalent to 24.5 mmol), DMSO (22 ml) and tripotassium phosphate (15.6 g, 73.5 mmol) were added successively to the reaction flask under nitrogen atmosphere at room temperature, and the mixture was stirred at 30°C - 40°C for 24 hours. The reaction mixture, cooled to room temperature, was added dropwise to 3M hydrochloric acid (33.5 ml) and the product was extracted with ethyl acetate. The resulting organic layer was washed once with 7.5% sodium bicarbonate aqueous solution and twice with 20% sodium chloride solution successively, and then evaporated under reduced pressure. Toluene (400 ml) was added to the evaporation residue and the mixture was evaporated to give a solution of RR-AOBL [7] in toluene (6.44 g, equivalent to 24.5 mmol). The resulting solution of RR-AOBL [7] in toluene was used in the next step, considering the yield to be 100%.

Crude RR-AOBL [7], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 4.86 (1H, d, J = 15.3 Hz), 4.21 (1H, ddd, J = 9 .9, 5.2, 4.0 Hz), 4.13-4.06 (1H, m), 4.02 (1H, d, J = 15.3 Hz), 3.36 (1H, q, J = 7.5 Hz), 2.13-2.10 (2H, m), 1.31 (3H, d, J = 7.3 Hz).

MS: m/z = 246 [M+H] ⁺

[Example 7] Receiving RR-MDDO (Connection [9])

[Chem. 151]

Stage 1

[Chem. 152]

Under nitrogen atmosphere, RR-AOBL [7] (3.0 g, 12.2 mmol), DMSO (20 ml) and sodium diformylamide (3.48 g, 36.6 mmol) were successively added to the reaction flask at room temperature, and the mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to about 45°C, ethyl iodide (3.0 ml, 37.8 mmol) was added dropwise and the mixture was stirred at 45°C for 5 hours. After the reaction mixture was cooled to room temperature, a 5% potassium carbonate aqueous solution was added and the product was extracted with toluene. The resulting organic layer was washed successively with a 5% potassium carbonate aqueous solution and a 20% sodium chloride solution, and then evaporated under reduced pressure. The resulting crude compound [16] was used in the next step, assuming a yield of 100%.

The crude compound [16], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (CDCl ₃ ) δ: 8.82 (1H, s), 7.98 (1H, s), 7.37-7.14 (5H, m), 4.85 (1H, d, J = 15.7 Hz), 4.23 (2H, q, J = 7.1 Hz), 4.20 (1H, d, J = 15.7 Hz), 3.71 (1H, q, J = 7 .1 Hz), 3.27-3.17 (1H, m), 3.11-3.02 (1H, m), 2.06-1.98 (1H, m), 1.95-1, 85 (1H, m), 1.30 (3H, t, J = 7.1 Hz), 1.21 (3H, d, J = 7.1 Hz).

MS: m/z = 319 [M+H] ⁺

Stage 2

[Chem. 153]

Under nitrogen atmosphere, crude compound [16] (equivalent to 3.05 mmol), acetonitrile (5 ml) and cesium carbonate (1.49 g, 4.58 mmol) were successively added to the reaction flask at room temperature, and the mixture was stirred at room temperature within 4 hours. A 25% aqueous potassium hydrogen sulfate solution (5 ml) was added to the reaction mixture, and the product was extracted three times with chloroform (5 ml). The resulting organic layers were combined, washed with saturated aqueous sodium bicarbonate (5 ml) and evaporated under reduced pressure. The evaporation residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to give RR-MDDO [9] (638 mg, 2.61 mmol) in 85.6% yield.

Using RR-MDDO [9], obtained by the same method, the NMR spectrum and mass spectrum (MS) were recorded.

¹ H-NMR (CDCl ₃ ) δ: 7.33-7.26 (5H, m), 5.92 (1H, brs), 4.85 (1H, d, J = 15.5 Hz), 3.99 (1H, d, J = 15.5 Hz), 3.27-3.18 (2H, m), 3.16-3.10 (1H, m), 2.07-1.99 ( 2H, m), 1.28 (3H, d, J = 7.6 Hz).

MS: m/z = 245 [M+H] ⁺

[Example 8] Obtaining SR-MDBN-DSU (Connection [11-1])

[Chem. 154]

Stage 1

[Chem. 155]

RR-MDDO [9] (1.0 g, 4.09 mmol), toluene (10 mL), triruthenium dodecacarbonyl (261 mg, 0.41 mmol), TMDS (5.49 g , 40.9 mmol) and TMEDA (0.061 ml, 0.41 mmol) and the mixture was stirred at 70° C. for 40 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure, 2M hydrochloric acid (10 ml) and THF (10 ml) were added to the resulting residue, and the layers were separated. CPME (10 ml) and 25% aqueous sodium hydroxide solution (5 ml) were added to the resulting aqueous layer, and the layers were separated. The resulting organic layer was washed with saturated sodium chloride solution (5 ml) and evaporated under reduced pressure. 2-propanol (10 ml) was added to the evaporation residue to give a solution of crude SR-MDBN [10] in 2-propanol (equivalent to 4.09 mmol). The resulting solution of SR-MDBN [10] in 2-propanol was used in the next step, assuming the yield to be 100%.

Crude SR-MDBN [10], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.20 (5H, m), 3.62 (1H, d, J = 12.9 Hz), 3.59 (1H, d, J = 12 .9 Hz), 3.21 (1H, dd, J = 7.5, 6.6 Hz), 2.99 (1H, d, J = 12.1 Hz), 2.95 (1H, d, J = 12.1 Hz), 2.84 (2H, t, J = 7.3 Hz), 2.68 (1H, t, J = 5.8 Hz), 2.43-2.35 (1H, m ), 2.22-2.15(1H, m), 1.81-1.74(2H, m), 1.13(3H, d, J = 6.9 Hz).

MS: m/z = 217 [M+H] ⁺

Stage 2

[Chem. 156]

Under a nitrogen atmosphere, succinic acid (966 mg, 8.18 mmol) and 2-propanol (5 ml) were added to the reaction flask, and the mixture was heated to 70°C. A solution of crude SR-MDBN [10] in 2-propanol (equivalent to 4.09 mmol) was added dropwise to the resulting suspension at 70°C, the mixture was cooled to room temperature and then stirred for 8 hours. The precipitated solid was collected on a filter, washed twice with 2-propanol (3 ml) and dried at 40° C. under reduced pressure to give SR-MDBN-DSU [11-1] (1.25 g, 2.77 mmol) with yield 67.7%.

Using SR-MDBN-DSU [11-1], obtained by the same method, the NMR spectrum was recorded and the melting point was determined, and elemental analysis was performed.

¹ H-NMR (D ₂ O) δ: 7.43-7.38 (5H, m), 4.30 (1H, d, J = 12.1 Hz), 4.24 (1H, d, J = 12.1 Hz), 3.96 (1H, dd, J = 10.1, 8.9 Hz), 3.85 (1H, d, J = 14.5 Hz), 3.77 (1H, d, J = 14.5 Hz), 3.45-3.33(3H, m), 2.99-2.91(1H, m), 2.89-2.81(1H, m), 2.53 -2.47 (1H, m), 1.17 (3H, d, J = 7.3 Hz).

Melting point: 126°C - 128°C.

Elemental analysis: C 58.4 wt.%, H 7.1 wt.% and N 6.1 wt.% (Theoretical value: C 58.4 wt.%, H 7.1 wt.% and N 6.2 the weight.%).

Using SR-MDBN-DSU [11-1] obtained by the same procedure, the diffraction angle 2θ and diffraction intensity were determined by powder X-ray diffraction. The resulting spectrum is shown in Fig. 5.

The corresponding peaks in Fig. 5 have the characteristics shown in the table below.

Table 5

Diffraction angle
[2θ (°)] Relative intensity
[%] Diffraction intensity
[imp/s] 4.8029 84.94 8145.72 9.6302 15.96 1530.79 10.8332 19.99 1917.06 11.1933 100.00 9590.10 11.8635 46.66 4474.68 13.0866 28.70 2752.50 14.4786 21.34 2046.30 15.6090 20.59 1974.60 16.1689 51.86 4973.37 17.0568 9.32 893.48 18.1269 74.24 7119.23 19.6147 9.35 896.81 20.1328 57.36 5501.07 21.1796 2.35 224.89 21.9108 36.80 3528.73 22.2909 16.57 1589.02 22.5258 8.99 861.74 22.9718 25.26 2421.98 23.8514 20.16 1933.47 24.2442 45.40 4354.10

Each dibenzyl derivative (Compound [21]) of SR-MDBN [10] and SR-MDBN-DSU [11-1] was prepared as described below and analyzed by HPLC.

[Chem. 157]

Under nitrogen atmosphere into a solution of SR-MDBN-DSU [11-1] (72 mg, 0.16 mmol) or crude SR-MDBN [10] (34 mg, equivalent to 0.16 mmol) and benzaldehyde (0.024 ml, 0.16 mmol) 24 mmol) in DMF (1 ml) was added sodium triacetoxyborohydride (67 mg, 0.32 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added 2M hydrochloric acid (1 ml) and washed with toluene (2 ml). A 2M aqueous sodium hydroxide solution (2 ml) was added to the resulting aqueous layer, and the product was extracted three times with ethyl acetate (2 ml). The combined organic layer was washed with saturated sodium chloride solution (3 ml), dried over anhydrous sodium sulfate and evaporated under reduced pressure. An aliquot of the resulting residue was analyzed by HPLC.

The HPLC analysis apparatus and conditions are described below.

Device: Nexera system (Shimadzu)

Terms:

Column: CHIRALCEL OJ-RH: 3 µm, 4.6 mm x 150 m (Daicel)

Column temperature: 25°C

Flow rate: 0.8 ml/min

Analysis time: 15 min

Detector wavelength: UV (210nm)

Mobile phase: Methanol/diethylamine = 100/0.1 (v/v)

The retention time of compound [21] under the HPLC analysis conditions described above was about 5.2 min. The retention time for each stereoisomer was about 4.4 minutes for the RR form, about 7.2 minutes for the SS form, and 8.6 minutes for the RS form.

The result of HPLC analysis of compound [21] obtained from crude SR-MDBN [10] in Example 8-Step 1 is shown in FIG. 6 and in the table below.

Table 6

Retention time (min) Square Height % area Configuration one 4,394 10041 1534 0.144 RR 2 5.209 6683427 559633 95.812 SR 3 7.209 101904 6111 1.461 SS four 8.637 180223 8900 2.584 RS

The result of HPLC analysis of compound [21] obtained from SR-MDBN-DSU [11-1] obtained after the crystallization step in Example 8-Step 2 is shown in FIG. 7 and in the table below.

Table 7

Retention time (min) Square Height % area Configuration one 4.403 14724 1644 0.171 RR 2 5.207 8475065 677373 98.481 SR 3 7.208 42110 2810 0.489 SS four 8.644 73894 3732 0.859 RS

The SR-MDBN-DSU [11-1] crystallization step is useful for removing its RS-MDBN enantiomer. The ratio of enantiomers in crude SR-MDBN [10] was [SR-MDBN/RS-MDBN = 95.81%/2.59% (Percentage of area by HPLC)], and the ratio of enantiomers in SR-MDBN obtained after the crystallization step, was [SR-MDBN/RS-MDBN = 98.48%/0.86% (HPLC area percentage)].

[Example 8-2] Preparation of SR-MDBN Monosuccinate

To a solution of SR-MDBN (446 mg, 2.06 mmol) in 2-propanol (2.9 ml) was added succinic acid (243 mg, 2.06 mmol) at room temperature. The mixture was stirred at room temperature and then sonicated to precipitate crystals. The precipitated crystals were filtered off, washed with 2-propanol (2 ml) and then dried under reduced pressure at room temperature. SR-MDBN monosuccinate (467 mg, 1.39 mmol) was obtained in 67.8% yield.

The resulting SR-MDBN monosuccinate was analyzed by differential scanning calorimetry and elemental analysis.

Differential Scanning Calorimetry

The analysis was performed on a DSC-60A differential scanning calorimeter (manufactured by Shimadzu Corporation) at a temperature rise rate of 5°C/min (hermetically sealed aluminum cell). The DSC curve obtained in the experiment is shown in Fig. 8. The enthalpy of the endothermic peaks in the DSC curve was 97.56 J/g, the endothermic onset temperature was 118.53ºC, and the extrapolated transition onset temperature was 117.25ºC.

Elemental analysis: C 64.69 wt%, H 7.78 wt%, N 8.34 wt% (Theoretical value: C 64.65 wt%, H 7.84 wt%, N 8.38 the weight.%)/

[Example 9] Clearing SR-MDBN-DSU (Connection [11-1])

[Chem. 158]

Under nitrogen atmosphere, crude SR-MDBN-DSU [11-1] (3.00 g, 6.63 mmol) and 2-propanol (18 ml) were placed in a reaction flask and the mixture was stirred at room temperature for 2.5 hours . The solid was collected on a filter and washed with 2-propanol (9 ml), then dried under reduced pressure at 50°C to give SR-MDBN-DSU [11-1] (2.74 g, 6.06 mmol) in 91 .3%.

The NMR spectrum for the resulting SR-MDBN-DSU was recorded [11-1].

¹ H-NMR (DMSO-D ₆ ) δ: 11.99 (4H, br s), 7.33-7.21 (5H, m), 3.69 (1H, d, J = 12.9 Hz ), 3.48 (1H, d, J = 12.9 Hz), 3.24 (1H, d, J = 12.7 Hz), 3.23-3.17 (1H, m), 3.11 -3.05 (2H, m), 2.93 (1H, d, J = 12.7 Hz), 2.64 (1H, dd, J = 6.9, 3.7 Hz), 2.33 ( 8H, s), 2.31-2.23 (2H, m), 2.02-1.95 (1H, m), 1.15 (3H, d, J = 6.9 Hz).

HPLC analysis of SR-MDBN-DSU [11-1] obtained in Example 9 was carried out.

The HPLC analysis apparatus and conditions are described below.

Instrument: LC-10 system (Shimadzu Corporation)

Terms:

Column: CHIRALPAK IE-3: 3 µm, 4.6 mm x 250 mm (Daicel Corporation)

Column temperature: 40°C

Flow rate: 1.0 ml/min.

Analysis time: 30 min.

Detector wavelength: UV (220nm)

Mobile phase: n-hexane/ethanol/isopropylamine = 95/5/0.1 (v/v ratio)

The retention time for compound [11-1] under the above HPLC conditions was about 16.4 minutes. The retention time for the enantiomer, RS-MDBN-DSU, was about 21.9 minutes.

The purification step of SR-MDBN-DSU [11-1] has been shown to be effective in removing its enantiomer, RS-MDBN-DSU. The enantiomeric ratio in crude SR-MDBN-DSU [11-1] was [SR-MDBN-DSU/RS-MDBN-DSU = 98.2%/1.8% (HPLC area percentage)] and the enantiomeric ratio in SR -MDBN [11-1] after the purification step was [SR-MDBN-DSU/RS-MDBN-DSU = >99.9%/<0.1% (Area Percentage by HPLC)].

The HPLC analysis results for crude SR-MDBN-DSU [11-1] in Example 9 are shown in FIG. 9 and in the table below.

Table 8

Retention time (min) Square Height % area Configuration one 16.354 15790968 438277 98.167 SR 2 18.507 4568 0 0.028 3 21.854 290240 11127 1.804 RS

The HPLC analysis results for SR-MDBN-DSU [11-1] after the purification step in Example 9 are shown in FIG. 10 and in the table below.

Table 9

Retention time (min) Square Height % area Configuration one 16.680 15541643 278621 99.938 SR 2 21.884 6429 441 0.041 RS 3 22.443 3236 231 0.021

[Example 10] Obtaining SR-MDBN (Compound [10])

[Chem. 159]

Under a nitrogen atmosphere, aluminum chloride (820 mg, 6.15 mmol) and THF (1 ml) were placed in a reaction flask at 0°C. A 1M solution of lithium aluminum hydride in THF (6.1 ml, 6.15 mmol) was added dropwise to the mixture at a temperature below 10° C., and the mixture was stirred at room temperature for 1 hour. A solution of RR-MDDO [9] (500 mg, 2.05 mmol) in THF (2 mL) was added dropwise to the reaction mixture at -15°C to -10°C, and the mixture was stirred at -10°C for for 1 hour, then at 40°C overnight. The reaction mixture was cooled to 0°C, a saturated aqueous solution of potassium-sodium tartrate (10 ml) was added dropwise to the reaction mixture. Then 25% aqueous sodium hydroxide solution (5 ml) was added and the product was extracted twice with CPME (5 ml). The resulting organic layers were combined, washed with saturated sodium chloride solution (5 ml) and evaporated under reduced pressure. 2-propanol (5 ml) was added to the evaporation residue to give a solution of crude SR-MDBN [10] in 2-propanol (equivalent to 2.05 mmol).

Crude SR-MDBN [10], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.20 (5H, m), 3.62 (1H, d, J = 12.9 Hz), 3.59 (1H, d, J = 12 .9 Hz), 3.21 (1H, dd, J = 7.5, 6.6 Hz), 2.99 (1H, d, J = 12.1 Hz), 2.95 (1H, d, J = 12.1 Hz), 2.84 (2H, t, J = 7.3 Hz), 2.68 (1H, t, J = 5.8 Hz), 2.43-2.35 (1H, m ), 2.22-2.15(1H, m), 1.81-1.74(2H, m), 1.13(3H, d, J = 6.9 Hz).

MS: m/z = 217 [M+H] ⁺

[Example 11]

(A) Preparation of SR-MDBN (Compound [10])

[Chem. 160]

Under a nitrogen atmosphere, chlorotrimethylsilane (22.2 g, 205 mmol) and toluene (60 ml) were added to the reaction flask at room temperature, and then a 10% solution of lithium aluminum hydride in THF (83.0 ml, 205 mmol) was added dropwise at temperatures from -10°C to 0°C. The mixture was stirred at the same temperature for 0.5 hours. A solution of RR-MDDO [9] (20.0 g, 81.9 mmol) in THF (100 mL) was added dropwise to the reaction mixture at -10°C to 0°C, and the mixture was stirred at the same temperature for within 1 hour. A 10% solution of lithium aluminum hydride in THF (19.9 ml, 49.1 mmol) was added dropwise to the reaction mixture at -5°C to 0°C, and then the mixture was stirred at 50°C for 20 hours . The reaction mixture was cooled to 0°C, then 2-propanol (40 ml) was added dropwise. The mixture was stirred for 2.5 hours. The resulting mixture was added dropwise to a mixture of 50% aqueous potassium sodium tartrate (300 ml) and 8N. aqueous potassium hydroxide solution (40 ml) and stirred at room temperature overnight. The organic layer was separated, washed with 50% aqueous potassium sodium tartrate (100 ml) and evaporated under reduced pressure. 2-Propanol (60 ml) was added to the evaporation residue and the mixture was evaporated, repeating this procedure twice, obtaining a solution of crude SR-MDBN [10] in 2-propanol (equivalent to 81.9 mmol).

Part of the solution of crude SR-MDBN [10] in 2-propanol, synthesized in the same way, was evaporated and dried, then the NMR spectrum and mass spectrum (MS) were recorded.

¹ H-NMR (DMSO-D ₆ ) δ: 7.28-7.17 (5H, m), 3.56 (1H, d, J = 13.9 Hz), 3.52 (1H, d, J = 13.2 Hz), 3.20 (1H, br s), 3.09-3.05 (1H, m), 2.80 (1H, d, J = 11.3 Hz), 2.73 -2.67(3H, m), 2.56-2.53(1H, m), 2.28-2.20(1H, m), 2.09-2.02(1H, m), 1 .69-1.63 (1H, m), 1.06 (3H, d, J = 6.9 Hz).

MS: m/z = 217 [M+H] ⁺

(B) Preparation of SR-MDBN (Compound [10])

[Chem. 161]

SR-MDBN [10] was obtained by the alternative method described below. THF (535 ml) was cooled to 0-5° C. under nitrogen, then a 15% solution of lithium aluminum hydride in toluene/THF (374 ml, 1.314 mol) was added dropwise. The mixture was stirred for 10 minutes at 0-5°C, then chlorotrimethylsilane (142.8 g, 1.314 mol) was added dropwise and the mixture was stirred for 10 minutes at 0-5°C. A solution of RR-MDDO [9] (107.0 g, 0.438 mol) in THF (535 ml) was added dropwise. After 30 minutes the cooling was stopped and the mixture was heated to 40-50°C. The mixture was stirred at the same temperature for 1 hour. The mixture was then heated to boiling and stirred at this temperature for 14 hours. The reaction mixture was cooled to 0-5° C. and tert-butyl methyl ether (2140 ml, first 400 ml added dropwise) was added. Then, a saturated aqueous solution of Rochelle's salt (1740 ml, the first 150 ml were added keeping the temperature in the range of 0–5°C) and water (670 ml) were added dropwise. Upon completion of the addition, the reaction mixture was left to warm to 15-20°C and then stirred at 20°C for 1 hour. The organic layer was separated, evaporated under reduced pressure. 2-Propanol was added to the evaporation residue and the mixture was evaporated by repeating this procedure twice to give a solution of crude SR-MDBN [10] in 2-Propanol (equivalent to 0.417 mmol).

[Example 12] Obtaining SR-MDOP (Compound [14])

[Chem. 162]

Stage 1

[Chem. 163]

Purified water (30 ml) was added to tripotassium phosphate (14.1 g, 66.3 mmol) under nitrogen atmosphere. SR-MDBN-DSU [11-1] (5.0 g, 11.0 mmol), CPPY [12] (1.73 g, 11.3 mmol) and tert-butanol (15 ml) were successively added to the resulting solution. at temperatures between 30°C and 40°C. The reaction mixture was stirred at 75°C to 85°C for 2.5 hours and cooled to room temperature. The layers of the reaction mixture were separated to give a solution of crude SR-MDBP [13] in aqueous tert-butanol (43.16 g, equivalent to 11.0 mmol). The resulting solution of crude SR-MDBP [13] in aqueous tert-butanol was used in the next step, assuming a yield of 100%.

Crude SR-MDBP [13], obtained by the same procedure, was evaporated to dryness to record the NMR spectrum and mass spectrum (MS).

¹ H-NMR (DMSO-d ₆ ) δ: 11.57 (1H, s), 8.09 (1H, s), 7.29-7.15 (5H, m), 7.10 (1H, t , J = 2.8 Hz), 6.57 (1H, br. s), 3.75-3.53 (6H, m), 3.23 (1H, dd, J = 7.4, 6.5 Hz), 2.70 (1H, t, J = 5.8 Hz), 2.36 (1H, dt, J = 19.5, 7.2 Hz), 2.29-2.22 (1H, m ), 2.14-2.07 (1H, m), 1.07 (3H, d, J = 7.2 Hz).

MS: m/z = 344 [M+H] ⁺

Stage 2

[Chem. 164]

To a solution of crude SR-MDBP [13] in aqueous tert-butanol (43.16 g, equivalent to 11.0 mmol) was added successively purified water (3.7 ml), acetic acid (1.32 g, 22.0 mmol) and 10% palladium on carbon (Kawaken Fine Chemicals Co., Ltd. Type M, 52.6% water content, 370 mg). The reaction vessel was filled with hydrogen, and the mixture was stirred at 55°C for 7 hours at atmospheric pressure. The reaction solution was cooled to room temperature, and then the reaction flask was filled with nitrogen. Toluene (17 ml) and 8M aqueous sodium hydroxide solution (15.5 ml, 44.0 mmol) were added to the solution, and the mixture was stirred at 45° C. for 6 hours. After the reaction mixture was cooled to room temperature, 10% palladium-carbon was filtered off. The reaction vessel and 10% palladium on carbon were washed with a mixture of tert-butanol and toluene (1:1, 7 ml). The filtrate was combined with the washings and the layers were separated. The resulting organic layer was washed with 10% sodium chloride solution (7 ml) and evaporated under reduced pressure. The procedure for adding toluene (17 ml) to the evaporation residue followed by evaporation was repeated three times. Then toluene (20 ml) was again added to the evaporation residue, and the mixture was stirred at a temperature of from 15°C to 30°C for 1 hour, then at a temperature of from 0°C to 10°C for 1 hour. The precipitated solid was collected on a filter and washed with toluene (5 ml). The resulting wet solid was dried under reduced pressure to give SR-MDOP [14] (2.45 g, 10.07 mmol) in 91.5% yield.

Using SR-MDOP [14], obtained by the same method, the NMR spectrum and mass spectrum (MS) were recorded.

¹ H-NMR (DMSO-d ₆ ) δ: 11.57 (br s, 1H), 8.07 (s, 1H), 7.10 (d, 1H, J = 3.2 Hz), 6, 58 (d, 1H, J = 3.2 Hz), 3.92-3.59 (m, 4H), 3.49 (dd, 1H, J = 8.3, 7.2 Hz), 2.93 (dd, 1H, J = 7.2, 6.1 Hz), 2.61-2.53 (m, 2H), 2.12-2.01 (m, 2H), 1.10 (d, 3H , J = 6.9 Hz).

MS: m/z = 244 [M+H] ⁺

[Example 13] Preparation of Compound A (Compound [17]) 1-ethanolate (Compound [20])

[Chem. 165]

Acetonitrile (60 mL) and triethylamine (416 mg, 4.11 mmol) were added under nitrogen atmosphere to SR-MDOP [14] (5.00 g, 20.5 mmol), followed by dropwise addition of DPCN solution [18] (3 .69 g, 22.6 mmol) in acetonitrile (35 ml) at 45°C. The used addition funnel was washed with acetonitrile (5.0 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at 45°C for 3 hours, then cooled to room temperature. 5% sodium bicarbonate aqueous solution (25 ml), 10% sodium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture, and the mixture was stirred. Then the organic layer was separated. The solvent from the organic layer was removed under reduced pressure. The procedure for adding THF (50 ml) to the evaporation residue followed by evaporation was repeated four times. THF (50 ml) was added to the evaporation residue, then water was added to the mixture so that the water content was 5.5 wt%. The precipitated insoluble matter was filtered off. The reaction vessel and the filter cake were washed with THF (15 ml). The filtrate was combined with the washings and the solvent was removed from the filtrate under reduced pressure. Ethanol (50 ml) and a crystal (5.1 mg) of Compound A (Compound [17]) previously obtained according to the method described below from Example 11 were added to the evaporation residue, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, ethanol (50 ml) was added to the residue and the mixture was evaporated again. Ethanol (15 ml) was added to the evaporation residue and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected on a filter and washed with ethanol (20 ml). The resulting wet solid was dried under reduced pressure to give Compound A (Compound [17]) 1-ethanolate [20] (6.26 g, 17.6 mmol) in 85.5% yield.

Using Compound A (Compound [17]) 1-ethanolate obtained by the same method, NMR spectrum and mass spectrum (MS) were recorded.

¹ H-NMR (DMSO-d ₆ ) δ: 11.59 (broad s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.3 Hz ), 6.58 (dd, 1H, J = 3.5, 1.8 Hz), 4.34 (t, 1H, J = 5.1 Hz), 4.16 (t, 1H, J = 8, 3 Hz), 4.09-3.92 (m, 3H), 3.84-3.73 (m, 1H), 3.71 (d, 1H, J = 19.0 Hz), 3.65 ( d, 1H, J = 19.0 Hz), 3.58 (dd, 1H, J = 8.2, 5.9 Hz), 3.44 (dkv, 2H, J = 6.7, 5.1 Hz ), 2.69-2.60 (m, 2H), 2.23-2.13 (m, 1H), 1.12 (d, 3H, J = 7.1 Hz), 1.06 (t, 3H, J = 6.7 Hz).

MS: m/z = 311 [M+H] ⁺

Using Compound A (Compound [17]) 1-ethanolate prepared by the same procedure, the 2θ diffraction angle and diffraction intensity were determined by powder X-ray diffraction. The resulting spectrum is shown in Fig. eleven.

The corresponding peaks in Fig. 11 have the characteristics shown in the table below.

Table 10

Diffraction angle
[2θ (°)] Relative intensity
[%] Diffraction intensity
[imp/s] 8.2697 100.00 5765.29 10.0967 7.73 445.63 11.0161 4.77 275.16 11.9986 19.17 1105.32 12.6933 63.30 3649.39 12.9629 58.64 3380.72 13.8549 25.71 1482.08 14.8506 4.53 261.35 16.5910 10.63 613.11 17.0458 10.84 624.86 18.1156 6.92 399.14 20.0496 64.61 3724.97 22.1288 6.60 380.77 23.1059 13.68 788.68 24.0968 38.33 2209.75

[Example 14] Cleaning Compound A (Compound [17])

[Chem. 166]

Compounds A (Compound [17]) 1-ethanolate [20] (4.00 g, 11.2 mmol) and 1-butanol (32 ml) were mixed under nitrogen atmosphere and the mixture was dissolved at 110°C. Then, the solution was cooled to 85°C, a crystal (4.0 mg) of Compound A (Compound [17]), which was previously obtained by the same procedure, was added, and the mixture was stirred at 85°C for 2 hours, 75°C in for 1 hour and then at room temperature for 16 hours. The precipitated solid was collected on a filter and washed successively with 1-butanol (8.0 ml) and ethyl acetate (8.0 ml). The resulting wet solid was dried under reduced pressure to give Compound A (Compound [17]) (3.18 g, 10.2 mmol) in 91.3% yield.

Using Compound A (Compound [17]) prepared by the same procedure, an NMR spectrum and a mass spectrum (MS) were recorded.

¹ H-NMR (DMSO-d ₆ ) δ: 11.59 (broad s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.5 Hz ), 6.58 (dd, 1H, J = 3.5, 1.8 Hz), 4.16 (t, 1H, J = 8.3 Hz), 4.09-3.93 (m, 3H) , 3.84-3.73 (m, 1H), 3.71 (d, 1H, J = 19.0 Hz), 3.65 (d, 1H, J = 19.0 Hz), 3.58 ( dd, 1H, J = 8.2, 5.9 Hz), 2.69-2.59 (m, 2H), 2.23-2.13 (m, 1H), 1.12 (d, 3H, J = 7.2 Hz).

MS: m/z = 311 [M+H] ⁺

Conducted X-ray diffraction analysis of a single crystal of Compound A (Compound [17]), obtained by the same method.

(1) Single crystal production method

To 10 mg of Compound A (Compound [17]) in a 2.0 ml LaPha Robovial wide mouth vial was added 0.5 ml of chloroform and the vial was capped. Compound A (Compound [17]) was completely dissolved. For slow evaporation of the solvent in the septum mounted in the lid, a hole was made with a needle from a TERUMO syringe, and the vial was left to stand at room temperature. The resulting single crystal was used for X-ray diffraction analysis.

(2) Instrument

Radiation source: SPring-8 BL32B2

Detector: Rigaku R-AXIS V diffractometer

(3) Measurement method

The single crystal was subjected to radiation of 0.71068 Å, recording X-ray diffraction.

(4) Analysis

Using the effect of anomalous X-ray scattering on the chlorine atom in the obtained chloroform solvate of Compound A (Compound [17]), the absolute configuration of Compound A (Compound [17]) was determined as (3S,4R). Based on the established absolute configuration of Compound A (Compound [17]), the absolute configuration of each intermediate in the synthesis was identified.

[Example 15] Preparation of Compound A (Compound [17])

[Chem. 167]

Under nitrogen atmosphere, acetonitrile (900 ml) was added to SR-MDOP [14] (90.0 g, 370 mmol), then a solution of DPCN [18] (63.5 g, 389 mmol) in acetonitrile (540 ml) at temperatures between 70ºC and 80ºC. The used addition funnel was washed with acetonitrile (90 ml) and the washing solution was added to the reaction mixture. The reaction mixture was stirred at 70° C. to 80° C. for 1.5 hours and 1-butanol (900 ml) was added to the mixture. The solvent was removed under reduced pressure. 1-Butanol (900 ml) was added to the evaporation residue and the mixture was evaporated again. 1-Butanol was added to the evaporation residue to a total volume of the mixture of 2.1 l, and the mixture was dissolved by heating to 90ºC - 100ºC. The resulting solution was cooled to a temperature of 60°C to 70°C, and a crystal of compound A (90 mg) obtained in advance by the same method was added. The mixture was stirred at 60°C to 70°C for 2 hours and cooled to 30°C for 4 hours. The mixture was stirred at 20°C to 30°C for 1 hour, then stirred at 0°C to 5°C for 4 hours. The precipitated solid was collected on a filter and washed successively with 1-butanol (180 ml) and ethyl acetate (180 ml). The resulting wet solid was dried under reduced pressure to give Compound A [17] (104 g, 335 mmol) in 90.5% yield.

Registered NMR spectrum and mass spectrum (MS) for compound A, which was synthesized according to the method described above.

¹ H-NMR (DMSO-d ₆ ) δ: 11.60 (s, 1H), 8.09 (s, 1H), 7.12 (dd, 1H, J = 3.0, 2.7 Hz), 6.58 (brs, 1H), 4.16 (t, 1H, J = 8.4 Hz), 4.11-3.91 (m, 3H), 3.88-3.72 (m, 1H), 3.68 (d, 2H, J = 2.1 Hz), 3.57 (dd, 1H, J = 8.4, 6.0 Hz), 2.70-2.56 (m, 2H ), 2.24-2.10 (m, 1H), 1.12 (d, 3H, J = 7.2 Hz).

MS: m/z = 311 [M+H] ⁺

[Example 16] Cleaning Compound A (Compound [17])

Under nitrogen atmosphere, Compound A (Compound [17]) (100 g, 322 mmol) obtained in Example 15 was mixed with 1-butanol (1.8 L) and dissolved at 90°C to 100°C. The solution was filtered at 85° C. to 100° C. and the flask and filter cake were washed with 1-butanol (200 ml). The washing solution was added to the filtrate. The filtrate was cooled to 60ºC - 70ºC and crystals of Compound A (100 mg) obtained in advance by the same method were added. The mixture was stirred at 60°C to 70°C for 2 hours and then cooled to 30°C for 3 hours. The mixture was stirred at 20°C to 30°C for 1 hour, then at 0°C to 5°C for 4 hours. The precipitated solid was collected on a filter and washed successively with 1-butanol (200 ml) and ethyl acetate (200 ml). The resulting wet solid was dried under reduced pressure to give Compound A (Compound [17]) (91.7 g, 295 mmol) in 91.7% yield. The resulting compound was analyzed by powder X-ray diffraction, etc., confirming the identity of Compound A.

Registered NMR spectrum and mass spectrum (MS) for compound A, which was synthesized according to the method described above.

¹ H-NMR (DMSO-d ₆ ) δ: 11.60 (s, 1H), 8.09 (s, 1H), 7.12 (dd, 1H, J = 2.7, 2.4 Hz), 6.59 (brs, 1H), 4.16 (t, 1H, J = 8.2 Hz), 4.11-3.91 (m, 3H), 3.86-3.72 (m, 1H), 3.68 (d, 2H, J = 2.1 Hz), 3.58 (dd, 1H, J = 8.1, 6.0 Hz), 2.71-2.56 (m, 2H ), 2.27-2.09 (m, 1H), 1.12 (d, 3H, J = 6.9 Hz).

MS: m/z = 311 [M+H] ⁺

[Example 17] Obtaining RR-AOPA (Compound [22])

[Chem. 168]

Stage 1

[Chem. 169]

In a nitrogen atmosphere, a solution of R-CPBL [6] (25.0 g, 88.7 mmol) in THF (100 ml) was added dropwise with a 24% solution of lithium hexamethyldisilazide in THF (66.3 g, 93.2 mmol ) at -10ºC to 0ºC, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added dropwise to 2M hydrochloric acid (100 ml) and the product was extracted with toluene (200 ml). The resulting organic layer was washed successively with 5% aqueous sodium bicarbonate (125 ml) and water (125 ml), then evaporated under reduced pressure. Toluene (125 ml) was added to the evaporation residue, the mixture was evaporated, and this procedure was repeated twice, obtaining a solution of RR-AOBL [7] in toluene (69.1 g, equivalent to 88.7 mol). The final solution of RR-AOBL [7] in toluene was obtained with an estimated yield of 100% and used in the next step.

Part of the resulting solution of crude RR-AOBL [7] in toluene, synthesized as described above, was evaporated and dried, and then the NMR spectrum and mass spectrum (MS) were recorded.

¹ H-NMR (DMSO-D ₆ ) δ: 7.36-7.25 (5H, m), 4.54 (1H, d, J = 15.7 Hz), 4.35-4.30 (1H , m), 4.24-4.18 (1H, m), 4.13 (1H, d, J = 15.7 Hz), 3.60 (1H, q, J = 7.4 Hz), 2 .46-2.35 (2H, m), 1.10 (3H, d, J = 7.4 Hz).

MS: m/z = 246 [M+H] ⁺

Stage 2

[Chem. 170]

Under nitrogen, a solution of crude RR-AOBL [7] in toluene (69.1 g, equivalent to 88.7 mmol), DMSO (100 ml), and potassium phthalimide (18.1 g, 97.6 mmol) was successively added to the reaction flask. at room temperature, and the mixture was stirred while heating to 90ºC - 110ºC overnight. The reaction mixture was cooled to room temperature and the product was extracted after addition of water (100 ml) and toluene (100 ml). A 5% aqueous potassium hydrogen sulfate solution (500 ml) was added to the aqueous layer, the mixture was extracted with ethyl acetate (150 ml) twice and then evaporated under reduced pressure. The evaporation residue was purified by silica gel column chromatography (chloroform:methanol = 9:1) to give RR-AOPA [22] (25.5 g, 65.0 mol) in 63.7% yield from R-CPBL [6] .

The NMR spectrum and mass spectrum (MS) were recorded for the obtained RR-AOPA [22].

¹ H-NMR (DMSO-D ₆ ) δ: 13.45 (1H, brs), 7.84-7.81 (4H, m), 7.39-7.31 (4H, m), 7 .24 (1H, t, J = 7.2 Hz), 4.63 (1H, d, J = 16.1 Hz), 4.33 (1H, d, J = 16.1 Hz), 3.64 -3.57(1H, m), 3.52-3.44(1H, m), 3.36(1H, q, J=7.5Hz), 2.30-2.15(2H, m ), 1.09 (3H, d, J = 7.5 Hz).

MS: m/z = 393 [M+H] ⁺

[Example 18] Preparation of co-crystal (2:1, mole ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole (Seed crystal)

[Chem. 171]

To Compound A (Compound [17]) (70.0 g, 226 mmol) and 3,5-dimethylpyrazole [32] (21.7 g, 226 mmol) was added acetonitrile (490 ml) under nitrogen atmosphere and the mixture was dissolved at heating up to 80ºC. The mixture was stirred at 65°C for 2 hours. After precipitation of a crystalline precipitate, the mixture was slowly cooled to room temperature. The mixture was stirred with cooling in an ice bath for 2 hours, the precipitate was collected on a filter and washed with ice-cold acetonitrile (140 ml). The resulting wet solid was dried under reduced pressure to give a co-crystal (2:1, mole ratio) of (Compound [33]) Compound A (Compound [17]) with 3,5-dimethylpyrazole (75.3 g, 210 mmol) with a yield of 93.1%.

An NMR spectrum was recorded, elemental analysis and differential scanning calorimetry were performed for the synthesized co-crystal (2:1, mole ratio) of Compound A (Compound [17]) with 3,5-dimethylpyrazole.

¹ H-NMR (DMSO-d ₆ ) δ: 11.98 (br s, 0.5H), 11.59 (br s, 1H), 8.08 (s, 1H), 7.11 (dd , 1H, J = 3.5, 2.2 Hz), 6.58 (dd, 1H, J = 3.5, 1.4 Hz), 5.73 (s, 0.5H), 4.16 ( t, 1H, J = 8.3 Hz), 4.09-3.93 (m, 3H), 3.84-3.74 (m, 1H), 3.70 (d, 1H, J = 19, 0 Hz), 3.65 (d, 1H, J = 19.0 Hz), 3.58 (dd, 1H, J = 8.2, 5.9 Hz), 2.70-2.58 (m, 2H), 2.22-2.12 (m, 1H), 2.12 (s, 3H), 1.12 (d, 3H, J = 7.2 Hz).

Elemental analysis: C 61.9 wt.%, H 6.1 wt.%, N 27.2 wt.% (Theoretical value: C 62.0 wt.%, H 6.2 wt.%, N 27.4 the weight.%).

Differential Scanning Calorimetry

The analysis was performed on a DSC-60A differential scanning calorimeter (manufactured by Shimadzu Corporation) at a temperature rise rate of 5°C/min (hermetically sealed aluminum cell). The DSC curve obtained in the experiment is shown in Fig. 12. The enthalpy of the endothermic peaks in the DSC curve was 100.26 J/g, the endothermic onset temperature was 173.66ºC, and the extrapolated transition onset temperature was 172.36ºC. The resulting spectrum is shown in Fig. 12.

The 2θ diffraction angle and diffraction intensity were determined by powder X-ray diffraction for a co-crystal (2:1, mole ratio) of Compound A (Compound [17]) with 3,5-dimethylpyrazole. The resulting spectrum is shown in Fig. 13.

The corresponding peaks in Fig. 13 have the characteristics shown in the table below.

Table 11

Diffraction angle
[2θ (°)] Relative intensity
[%] Diffraction intensity
[imp/s] 4.5995 22.59 1219.62 6.5864 6.80 367.17 7.7159 12.60 680.20 9.2996 3.43 185.09 11.1525 4.05 218.54 12.6288 100.00 5398.64 13.2491 52.15 2815.46 13.8436 1.87 101.04 14.2405 18.90 1020.43 14.6304 8.80 475.04 15.1842 15.26 823.69 16.0529 68.62 3704.73 17.0279 6.45 348.43 17.4374 6.06 327.35 18.0485 3.67 197.88 18.6535 39.95 2156.57 19.1303 45.91 2478.47 19.3693 26.84 1449.11 19.6389 6.22 335.68 20.3423 28.14 1519.44 20.9117 45.96 2481.20 21.8334 5.48 295.84 22.8850 40.22 2171.23 23.3477 6.21 335.04 23.9286 18.49 998.22 24.4043 16.04 866.13 24.7252 29.15 1573.95

[Example 19] Preparation of co-crystal (2:1, molar ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole

[Chem. 172]

To SR-MDOP [14] (800 g, 3.29 mol) was added acetonitrile (8.0 L) under nitrogen atmosphere, then a solution of DPCN [18] (563 g, 3.45 mol) in acetonitrile was added dropwise to the mixture (4.8 L) at 75ºC. The used addition funnel was washed with acetonitrile (0.8 L) and the washings were added to the reaction mixture. After stirring the reaction mixture at 75° C. for 1.5 hours, the reaction solution was evaporated under reduced pressure to 8.0 L. Co-crystal (2:1, mole ratio) (Compound [33]) of Compound A (Compound [17]) with 3,5-dimethylpyrazole (80 mg) synthesized in Example 18 was added to the residue at 65°C. After stirring at 65°C for 2 hours, the mixture was stirred for 2 hours while cooling in an ice bath. The precipitated solid was collected on a filter and washed with ice-cold acetonitrile (2.4 L). The resulting wet solid was dried under reduced pressure to give a co-crystal (2:1, mole ratio) of (Compound [33]) Compound A (Compound [17]) with 3,5-dimethylpyrazole (1070 g, 2.99 mol) with a yield of 90.8%.

An NMR spectrum was recorded, elemental analysis and differential scanning calorimetry were performed for the synthesized co-crystal (2:1, mole ratio) of Compound A (Compound [17]) with 3,5-dimethylpyrazole.

¹ H-NMR (DMSO-d ₆ ) δ: 11.99 (br s, 0.5H), 11.59 (br s, 1H), 8.11 (s, 1H), 7.11 (s , 1H), 6.58 (d, 1H, J = 3.0 Hz), 5.73 (s, 0.5H), 4.16 (t, 1H, J = 8.4 Hz), 4.10 -3.92 (m, 3H), 3.85-3.74 (m, 1H), 3.70 (d, 1H, J = 19.1 Hz), 3.65 (d, 1H, J = 19 .1 Hz), 3.57 (dd, 1H, J = 7.9, 6.1 Hz), 2.70-2.58 (m, 2H), 2.22-2.14 (m, 1H) , 2.12 (s, 3H), 1.12 (d, 3H, J = 6.9 Hz).

Elemental analysis: C 62.0 wt.%, H 6.2 wt.%, N 27.2 wt.% (Theoretical value: C 62.0 wt.%, H 6.2 wt.%, N 27.4 the weight.%).

Differential Scanning Calorimetry:

The analysis was performed on a DSC-60A differential scanning calorimeter (manufactured by Shimadzu Corporation) at a temperature rise rate of 5°C/min (hermetically sealed aluminum cell). The DSC curve obtained in the experiment is shown in Fig. 14. The enthalpy of the endothermic peaks in the DSC curve was 78.02 J/g, the endothermic onset temperature was 173.81ºC, and the extrapolated transition onset temperature was 172.02ºC. The resulting spectrum is shown in Fig. fourteen.

The 2θ diffraction angle and diffraction intensity were determined by X-ray powder diffraction for the synthesized co-crystal (2:1, mole ratio) of Compound A (Compound [17]) with 3,5-dimethylpyrazole. The resulting spectrum is shown in Fig. fifteen.

The corresponding peaks in Fig. 15 have the characteristics shown in the table below.

Table 12

Diffraction angle
[2θ (°)] Relative intensity
[%] Diffraction intensity
[imp/s] 4.6074 12.69 341.47 6.5985 6.20 166.76 7.7215 9.57 257.49 9.3039 2.93 78.86 11.1582 2.08 56.00 12.6252 100.00 2690.94 13.2478 72.85 1960.46 13.8405 4.03 108.35 14.2414 16.75 450.87 14.6317 18.63 501.35 15.1837 27.93 751.46 16.0555 97.64 2627.45 17.0293 4.96 133.42 17.4558 4.29 115.36 18.0432 4.82 129.78 18.6385 45.15 1214.91 19.1352 29.44 792.08 19.3755 30.43 818.96 19.6628 4.02 108.11 20.3391 29.67 798.38 20.9048 35.47 954.60 21.8601 3.95 106.37 22.8816 36.84 991.38 23.3272 7.46 200.72 23.9114 23.73 638.46 24.4128 13.76 370.22 24.7091 29.29 788.13

[Example 20]

(A) Cleaning Compound A (Compound [17])

[Chem. 173]

Co-crystal (2:1, mole ratio) (Compound [33]) Compound A (Compound [17]) with 3,5-dimethylpyrazole (5.00 g, 14.0 mmol), BHT (0.15 g) and 1-butanol (40 ml) were mixed under nitrogen and dissolved at 110°C. After the mixture was cooled to 85°C, a pre-prepared crystal (5 mg) of Compound A (Compound [17]) was added to the mixture. After stirring at 85°C for 2 hours, the mixture was slowly cooled to room temperature and stirred at room temperature for 3 hours. The precipitated solid was collected on a filter and washed successively with 1-butanol (10 ml) and ethyl acetate (10 ml). The resulting wet solid was dried under reduced pressure to give Compound A (Compound [17]) (3.96 g, 12.8 mmol) in 91.5% yield.

NMR and MS spectra were recorded for Compound A (Compound [17]), which was synthesized as described above.

¹ H-NMR (DMSO-d ₆ ) δ: 11.58 (broad s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.3 Hz ), 6.58 (dd, 1H, J = 3.5, 1.6 Hz), 4.16 (t, 1H, J = 8.4 Hz), 4.10-3.94 (m, 3H) , 3.84-3.74 (m, 1H), 3.70 (d, 1H, J = 19.0 Hz), 3.65 (d, 1H, J = 18.7 Hz), 3.58 ( dd, 1H, J = 8.2, 5.9 Hz), 2.70-2.59 (m, 2H), 2.23-2.12 (m, 1H), 1.12 (d, 3H, J = 7.2 Hz).

MS: m/z = 311 [M+H] ⁺

(B) Cleaning Compound A (Compound [17])

[Chem. 174]

Compound A (Compound [17]) was purified by the alternative method described below. Under a nitrogen atmosphere, the compound having the formula [33] (10.0 g, 27.9 mmol) was dissolved in 2-methyl-2-butanol (150 ml) at 110°C. At 75°C, a seed crystal of Compound [17] was added to the solution. The solution was cooled to 0-5°C. The precipitate was washed with 2-methyl-2-butanol (20 ml) and then with ethyl acetate (20 ml). The precipitated solid was collected on a filter and washed with 2-methyl-2-butanol (20 ml) and then with ethyl acetate (20 ml). The resulting wet solid was dried under reduced pressure to give compound [17] (7.6 g, 24 mmol).

[Example 21] Preparation of Boc-Dab(MeOCO)-OH (Compound [24])

[Chem. 175]

Sodium hydroxide (60.0 g, 1.5 mmol) was added to methanol (600 ml). The mixture was heated to 40° C. for 45 minutes until all solids were completely dissolved. Boc-Gln-OH (Compound [23]) (62.82 g, 250 mmol) was added portionwise to the resulting solution with methanol (30 ml). The resulting solution was stirred at 40°C for 30 minutes. Bromine (15.4 ml, 300 mmol) was added dropwise. After 90 minutes of stirring, an additional portion of bromine (10.2 ml, 200 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and then left to cool to room temperature.

The solvent was evaporated to give a solid residue which was dissolved in water (250 ml) and ethyl acetate (315 ml) was added. The mixture was vigorously stirred and an aqueous solution of hydrogen chloride (2M, 290 ml) was added dropwise until pH = 2 in the aqueous phase. The phases were separated and the aqueous phase was extracted with ethyl acetate (315 ml). The combined organic phases were evaporated to give the crude product [24] (71.31 g) up to 95% pure.

The resulting compound was used in the next step without further purification.

[Example 22] Preparation of Boc-Dab(MeOCO)-OH (Compound [24])

[Chem. 176]

Solid sodium hydroxide (194.9 g, 4.87 mol) was added portionwise at 10-20° C. to methanol (6 L). Boc-Gln-OH [23] (600 g, 2.44 mol) was added to the solution at 20-25°C. The reaction mixture was heated to 40-45°C. An aqueous solution of sodium hypochlorite (158.4 g/L, 1.26 L, 199.6 g, 2.68 mol) was added to the reaction mixture at 40-45°C for 1 hour. The mixture was stirred at 40-45°C for 1-3 hours.

The reaction mixture was cooled to 20-25° C. and a solution of sodium sulfite (61.4 g, 0.49 mol) in water (300 ml) was added. The mixture was stirred for 10 minutes, then evaporated. 2-propyl acetate (1.8 L) was added portionwise to the evaporation residue and the mixture was evaporated to dryness. Water (300 ml) and 2-propyl acetate (3 L) were added to the evaporation residue. The pH was adjusted to 2-3 with dilute hydrochloric acid (2M, 2.75 L; pH 2.56) at 20-25°C. The phases were separated and the aqueous phase was extracted with 2-propyl acetate (2 x 1.5 L). The organic phases were combined and washed with water (1.2 L). The phases were separated and the organic phase was evaporated to give Boc-Dab(MeOCO)-OH [24] (669.4 g, 2.42 mol) with an HPLC purity of 96.3%.

The resulting compound was used in the next step without further purification.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.47 (br s, 1H), 7.15-7.05 (m, 2H), 3.88 (td, J = 9.1, 4 .7 Hz, 1H), 3.50 (s, 3H), 3.06-2.96 (m, 2H), 1.87-1.78 (m, 1H), 1.70-1.60 ( m, 1H), 1.38 (s, 9H). The compound contained the minor rotamer form: 6.81-6.68 (m), 3.82-3.75 (m), 1.34 (s).

LC-MS: m/z = 275 [MH] ^-

[Example 23] Preparation of methyl (S)-2-amino-4-((methoxycarbonyl)amino)butanoate hydrochloride (Compound [25])

[Chem. 177]

Methanol (3.5 L) was added to Compound [24] (669 g, 2.42 mol) at 10-20°C. The resulting mixture was cooled to 15-20°C. A methanolic solution of hydrogen chloride (42.19 wt.%, 864 g, 9.99 mol) was added while maintaining the temperature at 15-20°C. The reaction mixture was stirred at 15-20°C.

Nitrogen was bubbled through the reaction mixture for 30 minutes to remove hydrogen chloride. The mixture was evaporated to dryness. Methanol (1 L) was added to the residue and evaporated to dryness to give Compound [25] (555.9 g, 2.42 mol) with an HPLC purity of 89.7%.

[Example 24] Preparation of methyl (S)-2-amino-4-((methoxycarbonyl)amino)butanoate hydrochloride (Compound [25])

[Chem. 178]

Methanol (285 ml) was cooled to -10° C. and acetyl chloride (174 ml) was added dropwise over 30 minutes. The resulting methanolic hydrogen chloride solution was stirred at 0°C and Compound [24] (purity to 95%, 71.31 g, 245 mmol) dissolved in methanol (143 ml) was added. After 1 hour stirring, the mixture was allowed to warm to 20°C. The mixture was stirred for 2 hours, after which LC-MS analysis showed complete disappearance of the Compound [24].

The reaction mixture was evaporated. Toluene (200 ml) was added and the resulting solution was evaporated. This procedure was repeated with another portion of toluene (200 ml) to give Compound [25]. This compound was used in the next step without further purification.

[Example 25] Preparation of methyl (S)-2-amino-4-((methoxycarbonyl)amino)butanoate hydrochloride (Compound [25])

[Chem. 179]

Compound [24] (12.4 g, 40.6 mmol) was dissolved in MeOH (60 ml). Thionyl chloride (5.9 ml, 81 mmol) was added to the mixture while maintaining the temperature between 15°C and 20°C. The reaction mixture was stirred at 15-20° C. for 21 hours, after which nitrogen was bubbled through the reaction mixture for 30 minutes. The resulting mixture was evaporated to dryness. Methanol (40 ml) was added and the solution was evaporated to dryness. The residue was evaporated with toluene (2 x 50 ml) to give Compound [25], which was used in the next step without further purification.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.62 (broad s, 3H), 7.26 (t, J = 5.8 Hz, 1H), 4.02 (t, J = 6, 6 Hz, 1H), 3.74 (s, 3H), 3.52 (s, 3H), 3.17-3.08 (m, 2H), 2.01-1.88 (m, 2H).

[Example 26] Preparation of methyl (S)-2-(benzylamino)-4-((methoxycarbonyl)amino)butanoate hydrochloride (Compound [26-2])

[Chem. 180]

Stage 1

[Chem. 181]

Methanol (1.853 L) was added to Compound [25] (185.3 g, 817.5 mmol) followed by triethylamine (136.7 ml, 981.0 mmol) and benzaldehyde (91.4 ml, 899 mmol). The mixture was stirred at 20-25°C for 90 minutes and cooled to -20°C to -15°C. Sodium borohydride (46.35 g, 122.6 mmol) was added portionwise to the resulting mixture. The mixture was heated to 20-25°C and continued the reaction for 21 hours.

The reaction was quenched with water (1.85 L) and stirred for 15 minutes. Methanol was distilled off at 40° C. and 2-propyl acetate (1.85 L) was added to the residue. The phases were separated, the emulsion aqueous layer was extracted with 2-propyl acetate (1.85 L). The emulsion was filtered. The combined organic layers were washed with aqueous sodium hydrogen carbonate solution (20%, 1.85 L) and saturated sodium chloride solution (1.85 L). The organic solution was evaporated to give crude amine (methyl (S)-2-(benzylamino)-4-((methoxycarbonyl)amino)butanoate) (197.3 g, 703.8 mmol) with a purity of 92.7%.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.35-7.29 (m, 4H), 7.28-7.25 (m, 1H), 5.49 (br s, 1H), 3, 82 (d, J = 12.9 Hz, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.61 (d, J = 12.9 Hz, 1H), 3, 43–3.36 (m, 1H), 3.30 (dd, J = 9.0, 4.5 Hz, 1H), 3.28–3.23 (m, 1H), 1.95–1, 87 (m, 1H), 1.75–1.65 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ 175.4, 157.1, 139.6, 128.6, 128.5, 127.4, 59.4, 52.4, 52.1 (2C), 39.1, 32.8.

Stage 2

[Chem. 182]

To crude amine (590.4 g, 2.11 mol) was added 2-propyl acetate (5.9 L). The resulting mixture was heated to 50°C was added dropwise and a solution of hydrogen chloride in 2-propyl acetate (17.3 wt.%, 1.066 g, 184.5 g, 5.06 mol). The resulting suspension was stirred at 50°C for 15 minutes, cooled to 0-5°C and stirred for 1 hour.

The suspension was filtered, the filter cake was washed with cold 2-propyl acetate (2 x 500 ml) and dried at 45-50° C. in vacuo to give the crude Compound (520.6 g, 1.64 mol) with a purity of 97.5%.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.37 (br s, 1H), 9.85 (br s, 1H), 7.63-7.53 (m, 2H), 7, 46–7.37 (m, 3H), 7.26 (t, J = 5.9 Hz, 1H), 4.20 (d, J = 13.0 Hz, 1H), 4.13 (d, J = 13.1 Hz, 1H), 4.06–4.00 (m, 1H), 3.72 (s, 3H), 3.52 (s, 3H), 3.16 (dKV, J = 13, 6, 5.9 Hz, 1H), 3.07 (dKV, J = 13.7, 6.9 Hz, 1H), 2.18 (dKV, J = 13.5, 7.3 Hz, 1H), 2.05 (dkv, J = 14.0, 7.8 Hz, 1H).

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 168.9, 156.7, 131.5, 130.5 (2C), 129.1, 128.6 (2C), 56.4, 52.9 , 51.4, 49.1, 36.5, 29.0.

LC-MS: m/z = 281 [M+H] ⁺

Stage 3

[Chem. 183]

The resulting crude hydrochloride salt [26-2] (1.100 kg) was added to 2-propanol (14 L). The resulting mixture was boiled and stirred for 15 minutes, then cooled to 0-5°C and stirred for 1 hour.

The solid was filtered off and washed with cold 2-propyl acetate (2 x 500 ml), then dried at 45-50° C. in vacuo to give Compound [26-2] (1.063 kg) with HPLC purity 99.5%.

[Example 27] Preparation of methyl (S)-2-((R)-N-benzyl-2-chloropropanamido)-4-((methoxycarbonyl)amino)butanoate (Compound [27])

[Chem. 184]

Stage 1

[Chem. 185]

To (2R)-2-chloropropionic acid [4] (162 g, 1.49 mol) was added thionyl chloride (119.2 ml, 195.3 g, 1.642 mol) over 45 minutes at 60-65°C. The resulting mixture was heated to 85°C and stirred for 2 hours, then heated at 100°C for 3 hours.

The reaction mixture was distilled at atmospheric pressure in a stream of nitrogen. Major fractions were collected at 105-110° C. to give Compound [5] (118.24 g, 931.3 mmol) as a liquid with 99% HPLC purity and 96.5% enantiomeric purity according to chiral HPLC.

¹ H NMR (600 MHz, CDCl ₃ ) δ 4.66 (q, J = 7.0 Hz, 1H), 1.82 (d, J = 7.1 Hz, 3H).

Stage 2

[Chem. 186]

To a suspension of Compound [26-2] (250.0 g, 789.2 mmol) in toluene (1.25 L) was added a solution of potassium carbonate (327.1 g, 2.367 mol) in water (300 mL). The mixture was stirred at 20-25ºC until complete dissolution of the solid phase. The resulting mixture was cooled to a temperature between -5 and 0°C and a solution of Compound [5] (110 g, 868 mmol) in toluene (220 ml) was added dropwise while maintaining the temperature of the reaction mixture below 0°C. The reaction mixture was stirred at a temperature between -5°C and 0°C for 3 hours, then more Compound [5] (20.04 g, 157.8 mmol) in toluene (40 ml) was added, maintaining the temperature of the reaction mixture below 0 °C

Water (1.25 L) was added to the reaction mixture. After 15 minutes of stirring, the phases were separated and the aqueous phase was extracted with toluene (2 x 500 ml). The combined organic phases were filtered and the solvent was evaporated under reduced pressure to give Compound [27] (312.79 g, 843.46 mmol) with an HPLC purity of 97.90%.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.59-7.13 (m, 5H), 4.92-4.26* [m, 5H; 4.86 (d, J = 17.0 Hz), 4.80–4.62 (m), 4.58–4.53 (d, J = 16.9 Hz), 4.52 (q, J = 6.6 Hz), 4.49–4.44 (m), 4.30 (t, J = 6.8 Hz)], 3.70* (s, 2.3H), 3.64 (s , 3H), 3.55* (s, 0.7H), 3.28–3.01 (m, 2H), 2.28 (dQ, J = 13.9, 6.8 Hz, 1H), 2 .01–1.84 (m, 1H), 1.76* (d, J = 6.4 Hz, 0.7H), 1.64* (d, J = 6.5 Hz, 2.3H). *Denotes rotamer peaks.

LC-MS: m/z = 371 [M+H] ⁺

[Example 28] Preparation of methyl (S)-2-((R)-N-benzyl-2-chloropropanamido)-4-((methoxycarbonyl)amino)butanoate (Compound [27])

[Chem. 187]

Stage 1

[Chem. 188]

Oxalyl chloride (13.0 ml, 150 mmol) was added dropwise over 15 minutes to a solution of N,N-dimethylformamide (23.2 ml, 300 mmol) in acetonitrile (300 ml), maintaining the temperature between -10°C and 0° C. After 45 minutes of stirring at 0°C, (2R)-2-chloropropionic acid [4] (11.0 ml, 125 mmol) was added dropwise. The mixture was stirred for 30 minutes and cooled to -10°C.

Stage 2

[Chem. 189]

N,N-Diisopropylethylamine (17.4 ml, 100 mmol) and 2,6-lutidine (34.8 ml, 300 mmol) were added to a suspension of Compound (33.35 g, 100 mmol) in acetonitrile (85 ml) at 0 °C The resulting solution was added dropwise over 10-15 minutes to the reaction mixture obtained in Step 1, which contained acyl chloride [5], maintaining the temperature of the mixture below 0°C. The mixture was stirred for 30 minutes.

The reaction was quenched by adding dropwise aqueous hydrochloric acid (2M, 200 ml) and then toluene (165 ml) and ethyl acetate (165 ml). The biphasic mixture was intensively stirred for 10 minutes. The organic phase was separated from the acidic aqueous phase, dried over sodium sulfate, filtered and evaporated to give a crude product (39.5 g). Acetonitrile (100 ml) was added and the mixture was evaporated. HPLC analysis showed that the product [27] was formed with a ratio of diastereomers of 97:3.

[Example 29] Receiving RR-MDDO (Connection [9])

[Chem. 190]

Acetonitrile (240 ml) was added to Compound [27] (24.07 g, 63.1 mmol, calculated as 100% theoretical yield from the acylation step). Cesium carbonate (61.7 g, 189.3 mmol) was added. The resulting suspension was intensively stirred at 20-25°C for 15 hours. MeOH (48 ml) was added.

The suspension was evaporated to half the volume. The cesium salts were filtered off and washed with toluene (3 x 40 ml) and the filtrate was evaporated to a volume of 25 ml. The solution was clarified by the addition of Tonsil® filtration aid (3 g), which was then filtered off. The resulting solution was subjected to crystallization at a temperature between 2°C and 6°C during the night. The precipitate was filtered off and washed with toluene (3 x 4 ml). The resulting product was dried under reduced pressure at 30°C to give Compound [9] (9.31 g, 38.1 mmol) with HPLC purity of 98.85% and enantiomeric purity of 99.55% by chiral HPLC.

[Example 30] Receiving RR-MDDO (Connection [9])

[Chem. 191]

Lithium 2-methyl-2-butoxide in heptane (40 wt.%, 401.33 ml, 1.245 mol) was added over 20 minutes to acetonitrile (535 ml), maintaining the temperature between -10°C and -5°C. A solution of Compound [27] (167.5 g, 415.2 mmol) in acetonitrile (230 ml) was added dropwise over 60 minutes. The mixture was stirred at 0-5°C for 5 hours.

The mixture was cooled to below 0° C. and an aqueous sodium chloride solution (saturated, 330 ml) and 2-propyl acetate (790 ml) was added to the mixture. Then an aqueous solution of citric acid (50 wt.%, 159 g) was added, bringing to a pH value of 5-6. After 20 minutes of stirring, the phases were separated and the aqueous phase was extracted with 2-propyl acetate (2 x 263 ml). The combined organic phases were evaporated to half volume under reduced pressure and washed with aqueous sodium chloride solution (saturated, 263 ml). The organic phase was evaporated and toluene (800 ml) was added. The solution was evaporated to a volume of 6 ml per gram of product, based on 100% theoretical yield.

The resulting solution was heated to 60°C, then left to cool. Seeded at 40°C and cooled to 20-25°C. Heptane (304 ml, 3 ml per gram) was then added dropwise to the stirred mixture. Upon completion of the addition, the mixture was stirred for 1 hour at 20°C. The solid precipitate that formed was filtered off. The precipitate was washed with a mixture of toluene and heptane (1:2) (202 ml) and dried under reduced pressure at 40°C to give Compound [9] (70.39 g, 288.1 mmol) with an HPLC purity of 98.53% and 97.93% enantiomeric purity by chiral HPLC.

The product was stirred in toluene (1.5 ml per gram of product) at 50°C for 1 hour. The precipitate was filtered off at 20°C, washed with toluene (2 x 15 ml) and dried under reduced pressure at 40°C. The product [9] (64.79 g, 265.2 mmol) was obtained with an HPLC purity of 99.78% and an enantiomeric purity of 99.56% by chiral HPLC.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.34-7.26 (m, 5H), 6.51 (broad s, 1H), 4.86 (d, J = 15.5 Hz, 1H) , 3.99 (d, J = 15.5 Hz, 1H), 3.27 (q, J = 7.5 Hz, 1H), 3.24–3.20 (m, 1H), 3.15 ( ddt, J = 10.0, 8.1, 2.3 Hz, 1H), 2.05 (ddd, J = 13.3, 6.8, 2.5 Hz, 1H), 2.01 (dt, J = 13.3, 8.6 Hz, 1H), 1.29 (d, J = 7.5 Hz, 3H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ 174.2, 169.8, 136.4, 128.8 (2C), 128.3 (2C), 127.8, 65.8, 55.8, 44 .5, 38.3, 30.7, 9.8.

LC-MS: m/z = 245 [M+H] ⁺

[Example 31] Obtaining SR-MDBN (Compound [10])

[Chem. 192]

A solution of lithium aluminum hydride in a mixture of tetrahydrofuran/toluene (2.4:1) (15 wt.%, 217.5 ml, 193.55 g, 765 mmol) was added dropwise to dry tetrahydrofuran (374 ml) at a temperature between -5° C and 0°C. After 10 minutes of stirring, trimethylsilyl chloride (83.11 g, 97.1 ml, 765 mmol) was added dropwise and the mixture was stirred for 10 minutes maintaining the temperature between -5°C and 0°C. A solution of Compound [9] (74.8 g, 306.2 mmol) in dry tetrahydrofuran (748 ml) was then added dropwise. After 30 minutes, the cooling was stopped and the reaction mixture was heated to 45-50°C. The reaction mixture was stirred for 2 hours, then more lithium aluminum hydride in tetrahydrofuran/toluene (2.4:1) (15 wt.%, 87 ml, 77.4 g, 306.2 mmol) was added dropwise at 45-50 °C After 18 hours of stirring, more lithium aluminum hydride in tetrahydrofuran/toluene (2.4:1) (15 wt.%, 43.5 ml, 38.7 g, 153 mmol) was added dropwise at 45-50°C, and the resulting the mixture was stirred at the same temperature for 19 hours.

The reaction mixture was cooled to 0° C., then water (46.5 ml) was added dropwise. Tetrahydrofuran (500 ml) was added to the resulting suspension. An aqueous solution of sodium hydroxide (15 wt%, 46.5 ml, 6.98 g, 174 mmol) and water (139.5 ml) were then added to the suspension. The resulting mixture was allowed to warm to room temperature, then Celite (registered trademark) and sodium sulfate (60 g) were added. Stirring was continued for another 15 minutes. The precipitate was filtered through a pad of Celite (registered trademark). The filter cake was washed with tetrahydrofuran (4 x 250 ml) and the filtrate was evaporated under reduced pressure to give the product [10] (64.71 g, 299.1 mmol) with HPLC purity 92.37% and enantiomeric purity 99.45% according to chiral GC data.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.33–7.27 (m, 4H), 7.23–7.19 (m, 1H), 3.62 (d, J = 13.1 Hz, 1H), 3.58 (d, J = 13.0 Hz, 1H), 3.20 (dd, J = 7.5, 6.5 Hz, 1H), 2.95 (s, 2H), 2, 82 (dd, J = 7.7, 6.7 Hz, 2H), 2.66 (dd, J = 6.5, 5.5 Hz, 1H), 2.39 (pd, J = 7.1, 5.4 Hz, 1H), 2.17 (dt, J = 13.1, 7.5 Hz, 1H), 1.76 (dt, J = 13.4, 6.8 Hz, 1H), 1, 12 (d, J = 7.0 Hz, 3H), 1.68 (broad s, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ 139.2, 128.7, 128.4, 126.9, 75.7, 57.8, 55.7, 48.9, 45.6, 35.9 , 35.8, 15.6.

LC-MS: m/z = 217 [M+H] ⁺

[Example 32] Preparation of (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane oxalate (Compound)

[Chem. 193]

A solution of oxalic acid (0.082 g) in tetrahydrofuran (1.5 ml) was added dropwise to a solution of Compound [10] (0.180 g) in tetrahydrofuran (2.0 ml).

The precipitate that formed was filtered off and dried under reduced pressure to give Compound (0.204 g).

¹ H NMR (600 MHz, DMSO-d ₆ ) δ 7.33-7.27 (m, 4H), 7.26-7.21 (m, 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 3.29 (d, J = 12.7 Hz, 1H), 3.24 (ddd, J = 11.4, 7 .8, 5.5 Hz, 1H), 3.16–3.09 (m, 2H), 3.02 (d, J = 12.7 Hz, 1H), 2.68 (dd, J = 6, 7, 3.8 Hz, 1H), 2.36–2.27 (m, 1H), 2.03 (ddd, J = 12.9, 7.2, 5.5 Hz, 1H), 1.16 (d, J = 7.1 Hz, 3H).

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 164.2, 137.8, 128.4, 128.2, 126.9, 73.6, 56.2, 53.7, 46.1, 43 .5, 34.6, 30.2, 15.9.

[Example 33] Preparation of (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane hemioxalate (Compound [11-3])

[Chem. 194]

Stage 1

Compound [10] (52.47 g, 218.3 mmol) was dissolved in 2-propanol (367 ml) and the resulting mixture was heated to 60°C. A solution of oxalic acid (9.83 g, 109.1 mmol) in 2-propanol (157 ml) was added dropwise over 2 hours while maintaining the temperature at 60°C. Upon completion of the addition, the mixture was stirred at 60°C for 25 minutes, then seed crystals of Compound [11-3] were added.

After an additional 35 minutes of stirring at 60°C, the resulting suspension was filtered at the same temperature and the precipitate was washed with 2-propanol (2 x 25 ml) at 20-25°C. The product was dried under reduced pressure at 40° C. to give Compound (48.65 g, 186.14 mmol) with 99.12% purity by HPLC and 99.6% enantiomeric purity by chiral HPLC.

¹ H NMR (600 MHz, D ₂ O) δ 7.45–7.36 (m, 5H), 3.76 (d, J = 12.2 Hz, 1H), 3.71 (d, J = 12 .2 Hz, 1H), 3.52 (d, J = 13.2 Hz, 1H), 3.42 (t, J = 7.9 Hz, 1H), 3.33 (ddd, J = 12.5 , 7.8, 5.0 Hz, 1H), 3.27–3.20 (m, 2H), 2.86 (dd, J = 7.7, 4.9 Hz, 1H), 2.48 ( ddt, J = 11.7, 9.4, 7.9 Hz, 2H), 2.24 (ddd, J = 13.5, 6.9, 5.0 Hz, 1H), 1.17 (d, J = 7.2 Hz, 3H).

¹³ C NMR (151 MHz, D ₂ O) δ 176.25, 138.73, 132.28 (2C), 131.62 (2C), 130.73, 76.91, 58.99, 57.34, 48.48, 46.69, 37.54, 34.33, 17.38.

Stage 2A

Stirring a suspension of (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane hemioxalate (Compound [11-3])

[Chem. 195]

The resulting hemioxalate (48.5 g, 185.6 mmol) was stirred in a mixture of water and 2-propanol (1:24, 303 ml) for 5 hours at 20-25°C. The resulting mixture was cooled to a temperature between -5°C and 0°C and stirred for 1 hour.

The suspension was filtered at 0°C and washed with cold 2-propanol (2 x 8 ml). The solid was dried under reduced pressure at 40° C. to give a product (45.95 g, 175.8 mmol) of 99.50% HPLC purity and 99.93% enantiomeric purity by chiral GC.

Stage 2B

Recrystallization of (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane hemioxalate (Compound [11-3])

[Chem. 196]

The resulting hemioxalate (5 g, 19.1 mmol) was dissolved in a mixture of 2-propanol (34 ml) and water (0.75 ml) at the boil. After complete dissolution, the mixture was evaporated to half the volume. 2-propanol (20 ml) was added, then evaporated. This operation was repeated twice and the mixture was stirred in 2-propanol (15 ml) for 1 hour at 0–5°C. The product was filtered off and washed twice with 2-propanol (1.5 ml). The resulting solid was dried under reduced pressure at 40° C. to give a recrystallized product (4.755 g, 18.2 mmol).

[Example 34]

(A) Preparation of SR-MDBP (Compound [13])

[Chem. 197]

Potassium phosphate (8.12 g, 38.3 mmol) was added to the mixture Compounds [11-3], (5.00 g, 19.1 mmol), CPPY [12] (2.95 g, 19.2 mmol) , water (20 ml) and 2-propanol (25 ml). The reaction mixture was stirred at 75°C for 4.5 hours and cooled to 30°C.

The aqueous layer was separated and the resulting solution of crude SR-MDBP [13] in aqueous 2-propanol was used in the next step, assuming a yield of 100%.

(B) Preparation of SR-MDBP (Compound [13])

[Chem. 198]

Compound [13] was obtained by the alternative method described below. Potassium phosphate (8.12 g, 38.3 mmol) and 45% aqueous potassium hydroxide solution (5.01 g, 40.2 mmol) were added to a mixture of Compounds [11-3] (10.0 g, 38. 3 mmol), CPPY [12] (5.91 g, 38.5 mmol), water (40 ml) and 2-propanol (50 ml). The reaction mixture was stirred at 75°C for 18 hours and cooled to 40°C.

The aqueous layer was separated and the resulting solution of crude SR-MDBP [13] in aqueous 2-propanol was used in the next step, assuming a yield of 100%.

[Example 35]

(A) Preparation of SR-MDOP (Compound [14])

[Chem. 199]

To a solution of crude SR-MDBP [13] (19.1 mmol) in aqueous 2-propanol, purified water (15 ml), formic acid (3.61 ml, 95.7 mmol) and 5% palladium on carbon (0 .67 g, water content 53% by weight. The reaction mixture was stirred at 55°C for 15 hours.

The reaction mixture was cooled to room temperature, the palladium on carbon was filtered off and washed with a mixture of 2-propanol and water (9:1, 12 ml). Aqueous sodium hydroxide solution (8M, 15 ml), sodium chloride (7.5 g), 2-propanol (15 ml) and toluene (55 ml) were added to the combined filtrate. The layers were separated, the organic layer was washed with sodium chloride solution (20 wt.%, 10 ml) and evaporated. The residue (25 g) was diluted with a mixture of toluene and 2-propanol (1:1, 35 ml) and filtered. The resulting solution was evaporated at 50°C to obtain a residue (~25 g). Spent two cycles of adding toluene (35 ml) and evaporation at 50°C to obtain a residue (~25 g), while formed a solid residue.

Toluene (~25 g) was added to the concentrated suspension, bringing the total weight of the suspension to 48 g. The suspension was kept at 4°C for 16 hours, then stirred at 0°C for 30 minutes. The suspension was filtered and the filter cake was washed with toluene (14 ml). The solid product was dried at 50° C. under reduced pressure to give SR-MDOP [14] (4.21 g, 17.3 mmol).

(B) Preparation of SR-MDOP (Compound [14])

[Chem. 200]

Compound [14] was obtained by the alternative method described below. To a solution of crude SR-MDBP [13] (76.5 mmol) in aqueous 2-propanol was added purified water (77 ml), formic acid (11.5 ml, 306 mmol) and then palladium on silica gel (Pd content 0.20 mmol/g, 3.8 g, 0.765 mmol). The reaction mixture was stirred at 55°C for 22 hours.

The reaction mixture was cooled to room temperature, the palladium on silica gel was filtered off and washed with a mixture of 2-propanol and water (9:1, 60 ml). Aqueous sodium hydroxide solution (8M, 57 ml), sodium chloride (29.1 g) and toluene (199 ml) were added to the combined filtrate. The layers were separated, the organic layer was washed with sodium chloride solution (20 wt.%, 38 ml) and evaporated. The residue (70 g) was diluted with a mixture of toluene and 2-propanol (1:1, 140 ml) and evaporated. The residue (100 g) was diluted with a mixture of toluene and 2-propanol (1:1, 140 ml) and filtered. The resulting solution was evaporated. The residue (80 g) was diluted with toluene (140 ml) and evaporated to a precipitate. The mixture was stirred at 50°C for 1 hour and evaporated to a weight of 120 g. The residue was diluted with toluene (140 ml), evaporated to a weight of 120 g and diluted with toluene (92 ml). The resulting suspension was kept at 4°C for 4 days, then stirred at 0°C for 90 minutes. The resulting suspension was filtered and the filter cake was washed with toluene (50 ml). The solid product was dried at 50° C. under reduced pressure to give SR-MDOP [14] (17.3 g, 71.1 mmol).

[Example 36] Preparation of SR-ZMDB-OX (Compound [29])

[Chem. 201]

A solution of SR-ZMDB [28] (10.0 g, 28.5 mmol), Compound [28], which was synthesized according to the methods described in Examples 42 - 50, in tetrahydrofuran (40 ml) and toluene (10 ml) dropwise was added to a stirred solution of oxalic acid (2.84 g, 31.4 mmol) in tetrahydrofuran (50 ml) at 50° C. under nitrogen atmosphere. When approximately 50% SR-ZMDB [28] was added, the reaction mixture was seeded with Compound [29] (5 mg) and continued to finish. The resulting mixture was kept for 30 minutes at 50°C, diluted with tetrahydrofuran (20 ml) and cooled to 20°C. Added additional amount of tetrahydrofuran (20 ml). Stirring was continued at 20°C for 11 hours.

The crystallization mixture was kept at 0° C. for 1 hour and the precipitated solid was filtered off. The precipitate was washed with cold tetrahydrofuran (40 ml). The solid was dried under reduced pressure at 30° C. to give Compound [29] (11.1 g, 25.2 mmol).

¹ H-NMR (D ₂ O, internal standard d ₄ -TMSP) δ 7.71-7.05 (m, 10H), 5.30-4.98 (m, 2H), 4.56-1.98 (m, 11H), 1.28-0.98 (m, 3H).

¹³ C NMR (151 MHz, DMSO-d ₆ ) δ 164.2, 154.2, 153.9, 136.6, 136.5, 133.2, 132.7, 130.0, 129.8, 128 .8, 128.7, 128.5, 128.4, 128.2, 127.9, 127.6, 73.6, 73.4, 66.1, 65.6, 57.6, 55.5 , 55.1, 52.6, 52.4, 51.7, 51.2, 37.3, 36.5, 35.5, 34.6, 15.2, 15.0.

Elemental analysis: C 65.5 wt.%, H 6.3 wt.% and N 6.3 wt.%.

Theoretical value: C 65.4 wt.%, H 6.4 wt.% and N 6.4 wt.%.

[Example 37] Preparation of (3S,4R)-3-methyl-1,6-diazaspiro[3.4]octane oxalate (Compound)

[Chem. 202]

Suspension of SR-ZMDB-OX [29] (50 mg, 0.11 mmol) and 10% palladium on carbon (5 mg, moisture content 53.4 wt%) in water (1 ml) and 2-methylpropane-2- ole (1 ml) was treated with hydrogen (3 bar) at 30°C for 2 hours.

The hydrogen atmosphere was changed to argon and the mixture was filtered through Celite (registered trademark) with water (0.5 ml). The combined filtrates were evaporated to dryness under reduced pressure to give Compound (24 mg, 0.11 mmol).

¹ H NMR (600 MHz, D ₂ O, internal standard d ₄ -TMSP) δ 4.17 (dd, J = 10.7, 8.8 Hz, 1H), 3.99 (dd, J = 14.2 , 1.4 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.65 (dd, J = 10.7, 6.9 Hz, 1H), 3.58 (ddd , J = 12.7, 8.7, 4.2 Hz, 1H), 3.48 (ddd, J = 12.2, 9.8, 7.1 Hz, 1H), 3.17 (d.sq. .d, J = 8.8, 7.3 Hz, 6.9 Hz, 1H), 2.84 (dddd, J = 15.1, 7.2, 4.2, 1.4 Hz, 1H), 2.50 (dt, J = 15.0, 9.3 Hz, 1H), 1.29 (d, J = 7.3 Hz, 3H).

¹³ C NMR (151 MHz, D ₂ O) δ 175.9, 78.0, 51.6, 51.1, 46.7, 37.8, 37.4, 16.6.

[Example 38] Preparation of (3S,4R)-3-methyl-1,6-diazaspiro[3.4]octane oxalate (Compound [30-1])

[Chem. 203]

Stage 1

[Chem. 204]

A mixture of SR-ZMDB [28] (350 mg, 1.00 mmol) and 10% palladium-carbon (35 mg, moisture content 53.4 wt%) in ethanol (3 ml) was treated with hydrogen (3 bar) at 50° C within 2 hours.

Stage 2

[Chem. 205]

The hydrogen atmosphere was replaced with argon. The reaction mixture from Step 1 was filtered through a 0.2 μm PTFE filter with ethanol (0.75 ml) and added dropwise to a stirred solution of oxalic acid (100 mg, 1.10 mmol) in ethanol (0.75 ml). The resulting mixture was heated to 50-60°C for 5 minutes, then kept at 20°C for 20 hours.

The mixture was filtered, the filter cake was washed with ethanol (0.30 ml) and dried under reduced pressure at 50°C to give Compound [30-1] (205 mg, 0.947 mmol).

¹ H NMR (600 MHz, D ₂ O, internal standard d ₄ -TMSP) δ 4.17 (dd, J = 10.7, 8.8 Hz, 1H), 3.99 (dd, J = 14.2 , 1.4 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.65 (dd, J = 10.7, 6.9 Hz, 1H), 3.58 (ddd , J = 12.7, 8.7, 4.2 Hz, 1H), 3.48 (ddd, J = 12.2, 9.8, 7.1 Hz, 1H), 3.17 (d.sq. .d, J = 8.8, 7.3 Hz, 6.9 Hz, 1H), 2.84 (dddd, J = 15.1, 7.2, 4.2, 1.4 Hz, 1H), 2.50 (dt, J = 15.0, 9.3 Hz, 1H), 1.29 (d, J = 7.3 Hz, 3H).

¹³ C NMR (151 MHz, D ₂ O) δ 175.9, 78.0, 51.6, 51.1, 46.7, 37.8, 37.4, 16.6.

[Example 39] Preparation of (3S,4R)-3-methyl-1,6-diazaspiro[3.4]octane disuccinate (Compound [30-2])

[Chem. 206]

Stage 1

[Chem. 207]

SR-ZMDB [28] (5.38 kg, 15.4 mol) was dissolved in anhydrous ethanol (31.6 kg). 10% palladium on carbon (0.248 kg) was added followed by glacial acetic acid (2.29 kg, 38.1 mol) and water (0.284 kg). The reactor was filled with an inert gas during several cycles of evacuation and filling with nitrogen, then filled with hydrogen (2.8-3.1 bar) for 18 hours.

The pressure was released and the reactor was purged with nitrogen. The catalyst was filtered through a bed of Celite (registered trademark) saturated with ethanol. The filter cake was washed with ethanol (10 kg). The filtrate was evaporated to 30-35 L under reduced pressure to give the crude product [31].

Stage 2

[Chem. 208]

Succinic acid (4.261 kg, 36.08 mol) was dissolved in anhydrous ethanol (49.7 kg). Approximately 5% of the crude product [31] from Step 1 was added. When the product started to precipitate (with or without the addition of seed crystals), the rest of the concentrate was added. The resulting mixture was stirred for 1 hour at 20-25°C, then 2 hours at -2 to 2°C.

The product was filtered off and washed with cold ethanol (2 x 13.7 kg). The product was dried under reduced pressure to give Compound (5.143 kg, 14.19 mol) with an HPLC purity of 99.3%.

¹ H NMR (600 MHz, D ₂ O, internal standard d ₄ -TMSP) δ 4.18 (dd, J = 10.7, 8.9 Hz, 1H), 3.97 (dd, J = 14.3 , 1.4 Hz, 1H), 3.74 (d, J = 14.3 Hz, 1H), 3.64 (dd, J = 10.8, 6.8 Hz, 1H), 3.58 (ddd , J = 12.6, 8.6, 4.2 Hz, 1H), 3.47 (ddd, J = 12.3, 9.9, 7.1 Hz, 1H), 3.15 (ddd, J = 8.9, 7.3, 6.8 Hz, 1H), 2.84 (dddd, J = 15.1, 7.1, 4.3, 1.4 Hz, 1H), 2.56 - 2 .47 (m, 9H), 1.28 (d, J = 7.3 Hz, 3H).

¹³ C NMR (151 MHz, D ₂ O) δ 182.8, 78.0, 51.6, 51.1, 46.8, 37.8, 37.6, 34.3, 16.6.

[Example 40] Obtaining SR-MDOP (Compound [14])

[Chem. 209]

CPPY [12] (1.697 kg, 11.05 mol) and Compound [30-2] (4.000 kg, 11.04 mol) were mixed and molten 2-methylpropan-2-ol (13.0 kg) was added. The resulting suspension was heated to 28°C. A solution of potassium phosphate (4.92 kg, 23.2 mol) in water (13.0 kg) was added followed by an aqueous solution of potassium hydroxide (45 wt%, 5.5 kg, 44 mol). The reaction mixture was stirred at 40-50°C for 22 hours.

Added toluene (16 l) and lowered the temperature of the reaction mixture to 20-30°C. The organic layer was washed with a mixture of sodium chloride solution (saturated, 12.2 kg) and water (4.1 kg). The organic layer was evaporated under reduced pressure to a volume of not more than 16 L. 2-methylpropan-2-ol (7.42 kg) and toluene (8 L) were added to the reactor and the mixture was evaporated under reduced pressure to a volume of no more than 16 L. 2-methylpropan-2-ol (9.04 kg) and toluene (10 L) were added to the residue. The resulting mixture was filtered at 35-40°C and evaporated under reduced pressure to a volume of not more than 16 liters. The residue was heated to 45-50° C. and toluene (16 L) was added. The resulting mixture was kept at 45-50°C for 1 hour and evaporated under reduced pressure to a volume of not more than 16 liters. Toluene (16 L) was added to the suspension, which was then kept at 0-5°C for more than 1 hour.

The precipitate formed was filtered off and washed with toluene (8 L) and heptane (8 L). The resulting solid was dried under reduced pressure at 50°C for 20 hours to give SR-MDOP [14] (2.445 kg, 10.05 mol) with HPLC purity 95.25%.

[Example 41] Obtaining Compound [17]

[Chem. 210]

Compound [14] (2.38 kg, 9.78 mol) was suspended in acetonitrile (22.4 kg). Triethylamine (98.8 g, 0.976 mol) was added and the suspension was heated to 45-55°C. A solution of DPCN [18] (1.68 kg, 10.3 mol) in acetonitrile (13.4 kg) was added over 1 hour with additional acetonitrile (2.2 kg). The reaction mixture was stirred for 2.5 hours at 45-55°C.

Ethanol (2 L) was added to the reaction mixture, then evaporated under reduced pressure to a volume of not more than 24 L. Ethanol (24 L) was added to the residue and the solution was heated to 35-40°C. The resulting solution was filtered through a fine filter with ethanol (2 L). The resulting clear solution was evaporated under reduced pressure to a volume of not more than 24 liters. Ethanol (24 L) was added to the resulting suspension. The suspension was evaporated under reduced pressure to a volume of not more than 24 liters. Ethanol (4 L) was added. The resulting suspension was evaporated under reduced pressure to a volume of 19 liters. Withstood the resulting mixture for crystallization at 0-10°C for 2 hours.

The precipitate that formed was filtered off and washed with ethanol (10 L). The product was dried under reduced pressure for 20 hours to give an ethanol solvate of Compound [17] (3.11 kg, 8.73 mol) with an HPLC purity of 99.85%.

Butan-1-ol (43.7 kg) was added to the ethanol solvate of Compound [17] (3.10 kg). The resulting mixture was heated to 90-95°C and kept for 2 hours. The solution was cooled to 70-72°C. After 1 hour, Compound [17] (14.6 g, 47.0 mmol) was seeded and cooled to 8° C. over 12 hours.

The precipitate that formed was filtered off and washed on the filter with butan-1-ol (5.2 kg) and ethyl acetate (6 L). The resulting solid was dried under reduced pressure at 55-65° C. for 22 hours to give Compound [17] (2.46 kg, 7.93 mol) with an HPLC purity of 99.91%.

[Example 42] Preparation of S-MABB-HC (Compound [36])

[Chem. 211]

Stage 1

[Chem. 212]

S-BAPO [37] (35.0 g, 212 mmol) was added to water (175 ml) at room temperature under nitrogen atmosphere. Toluene (53 ml) and potassium carbonate (32.2 g, 233 mmol) were added to the resulting suspension at room temperature. TBBA (434.4 g, 223 mmol) was added dropwise to the resulting solution at room temperature, then the used addition funnel was washed with toluene (17 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at 65°C for 21 hours and cooled to room temperature. Toluene (105 ml) was added to the reaction mixture, the mixture was stirred and the organic layer was separated. The organic layer was washed with water (175 ml), the aqueous layer was separated and the solvent was removed from the organic layer in vacuo. Toluene (105 ml) was added to the residue and the resulting toluene solution was evaporated. This operation was repeated two more times, obtaining a toluene solution of S-BBMO [38] (74.0 g, 212 mmol theoretical). The resulting toluene solution of S-BBMO [38] was used in the next step, assuming the yield to be 100%.

The crude product S-BBMO [38], which was obtained according to the procedure described above, was evaporated to dryness and then examined by NMR and MS.

¹ H-NMR (DMSO-d ₆ ) δ: 7.36-7.13 (5H, m), 4.26 (1H, dd, J = 6.8, 3.9 Hz), 3.72 (2H , dd, J = 14.2, 6.8 Hz), 3.47-3.38 (1H, m), 3.30-3.08 (3H, m), 2.79 (1H, sextet, J = 6.8 Hz), 1.35 (9H, s), 0.96 (3H, d, J = 6.8 Hz).

MS: m/z = 280 [M+H] ⁺

Stage 2

[Chem. 213]

Toluene (200 ml), tetrahydrofuran (35 ml) and then triethylamine (25.7 g, 254 mmol) were added to a toluene solution of S-BBMO [38] (74.0 g, 212 mmol) at room temperature under nitrogen atmosphere. Methansulfonyl chloride (26.7 g, 233 mmol) was added dropwise to the resulting mixture at 0° C., then the used addition funnel was washed with toluene (10 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, then at 65°C for 22 hours and then cooled to room temperature. An aqueous solution of sodium bicarbonate (105 ml) was added to the reaction mixture, then the mixture was stirred and the organic layer was separated. The organic layer was washed with water (105 ml), the aqueous layer was separated and the solvent was removed from the organic layer in vacuo. Toluene (105 ml) was added to the residue and the toluene solution was evaporated. This operation was repeated two more times, obtaining a toluene solution of R-BCAB [39] (75.3 g, 212 mmol theoretical). The resulting toluene solution of R-BCAB was used in the next step, assuming a yield of 100%.

The crude product R-BCAB, which was obtained according to the method described above, was evaporated to dryness and then examined by NMR and MS.

¹ H-NMR (DMSO-d ₆ ) δ: 7.28-7.11 (5H, m), 4.24-4.11 (1H, m), 3.80 (2H, d, J = 3, 6 Hz), 3.24 (2H, d, J = 3.6 Hz), 2.98-2.78 (2H, m), 1.46-1.37 (12H, m).

MS: m/z = 298 [M+H] ⁺

Stage 3

[Chem. 214]

To a toluene solution of R-BCAB [39] (75.3 g, 212 mmol) at room temperature was added tetrahydrofuran (88.0 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H) -pyrimidinone (42.0 ml) under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide/tetrahydrofuran (195 ml, 233 mmol) was added dropwise to the resulting solution at 0°C, then the used addition funnel was washed with tetrahydrofuran (17.0 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature. Water (175 ml) and toluene (175 ml) were added to the reaction mixture, then the mixture was stirred and the organic layer was separated. The resulting organic layer was washed with an aqueous ammonium chloride solution (175 ml) and then with water (175 ml), and the solvent was removed from the organic layer in vacuo. Ethyl acetate (175 ml) was added to the residue and the resulting ethyl acetate solution was evaporated. This operation was repeated two more times to give an ethyl acetate solution of S-MABB [40] (66.5 g, 212 mmol theoretical). The resulting ethyl acetate solution of S-MABB was used in the next step, assuming a yield of 100%.

The crude product S-MABB [40], which was obtained by the method described above, was evaporated to dryness and then examined by NMR and MS.

¹ H-NMR (DMSO-d ₆ ) δ: 7.28-7.25 (10H, m), 3.75 (1H, d, J = 12.7 Hz), 3.68 (1H, d, J = 1.4 Hz), 3.66 (1H, d, J = 6.7 Hz), 3.46 (2H, d, J = 12.7 Hz), 3.30-3.17 (2H, m ), 2.95 (1H, dd, J = 6.2, 1.2 Hz), 2.77 (1H, dd, J = 6.1, 2.2 Hz), 2.65-2.55 ( 1H, m), 2.48-2.40(2H, m), 1.35(9H, s), 1.35(9H, s), 1.12(3H, d, J = 7.2 Hz ), 1.09 (3H, d, J = 6.2 Hz).

MS: m/z = 262 [M+H] ⁺

Stage 4

[Chem. 215]

To the resulting ethyl acetate solution of S-MABB [40] (66.5 g, 212 mmol theoretical) was added ethyl acetate (175 ml) and activated carbon (3.5 g) under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The activated carbon was removed by filtration, the filter cake was washed with ethyl acetate (175 ml). The washing solutions were added to the filtrate. A crystal of S-MABB-HC (17.5 mg), which was obtained according to the method described in this text, was added to the solution at 0°C, and then a 4M solution of hydrogen chloride in ethyl acetate (53.0 ml, 212 mmol) was added dropwise at 0 °C The reaction mixture was stirred at 0° C. for 17 hours, the precipitated solid was collected on a filter and washed with ethyl acetate (70 ml). The resulting wet solid was dried in vacuo to give S-MABB-HC [36] (48.3 g, 162 mmol, yield: 76.4%).

S-MABB-HC [36], which was obtained by the method described above, was examined by NMR, MS, and the Cl content was determined.

¹ H-NMR (DMSO-d ₆ ) δ: 11.08 (1H, brs), 10.94 (1H, brs), 7.52-7.42 (10H, m), 5.34 (1H, t, J = 8.4 Hz), 4.90 (1H, br.s), 4.45-4.10 (5H, m), 3.92-3.49 (3H, br.m ), 3.10-2.73 (2H, br.m), 1.35 (9H, s), 1.29 (9H, s), 1.24 (3H, d, J = 6.7 Hz) , 1.17 (3H, d, J = 7.4 Hz).

MS: m/z = 262 [M+H-HCl] ⁺

Cl content (ion exchange chromatography): 11.9% (theoretically: 11.9%).

[Example 43] Obtaining S-MACB-HC (Compound [41])

[Chem. 216]

To a solution of S-MABB-HC [36] (5.0 g, 16.8 mmol) in methanol (15.0 ml) was added 5% palladium on carbon (manufactured by Kawaken Fine Chemicals Co., Ltd., PH type, 54 1% water content, 1.0 g) at room temperature under nitrogen atmosphere. The reaction vessel was filled with hydrogen, the reaction mixture was stirred under a hydrogen pressure of 0.4 MPa at room temperature for 12 hours, the hydrogen in the reaction vessel was replaced with nitrogen, and 5% palladium-carbon was removed by filtration. The reaction vessel and 5% palladium on carbon were washed with methanol (10 ml). Wash solutions were added to the filtrate to give a methanolic solution of S-MACB-HC [41] (24.8 g, 16.8 mmol theoretical). The resulting methanolic solution of S-MACB-HC [41] was used in the next step, assuming a yield of 100%.

The crude product S-MACB-HC [41], which was obtained according to the procedure described above, was evaporated to dryness and then examined by NMR and MS.

¹ H-NMR (DMSO-d ₆ ) δ: 9.60 (br s, 1H), 4.97 (d, 1H, J = 9.2 Hz), 4.61 (d, 1H, J = 8 .4 Hz), 4.01 (dd, 1H, J = 10.0, 8.4 Hz), 3.78-3.74 (m, 1H), 3.54 (dd, 1H, J = 9, 6, 8.4 Hz), 3.35 (dd, 1H, J = 10.0, 6.0 Hz), 3.15-3.03 (m, 1H), 3.00-2.88 (m , 1H), 1.49 (s, 9H), 1.47 (s, 9H), 1.22 (d, 3H, J = 6.8 Hz), 1.14 (d, 3H, J = 7, 2 Hz).

MS: m/z = 172 [M+H] ⁺ (free form).

[Example 44] Preparation of S-ZMAB (Compound [42])

[Chem. 217]

N,N-diisopropylethylamine (4.8 g, 36.9 mmol) was added dropwise to a methanol solution of S-MACB-HC [41] (24.8 g, 16.8 mmol theoretical) at room temperature under nitrogen atmosphere, then the used addition funnel was washed with tetrahydrofuran (2.5 ml) and the washings were added to the reaction mixture. Benzyl chloroformate (3.0 g, 17.6 mmol) was added dropwise to the resulting reaction mixture at 0° C., then the used addition funnel was washed with tetrahydrofuran (2.5 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour, then the solvent was removed in vacuo. Toluene (25.0 ml) and an aqueous solution of citric acid (25.0 ml) were added to the residue, then the mixture was stirred, the organic layer was separated. The resulting organic layer was washed with an aqueous sodium bicarbonate solution (25.0 ml) and then with water (25.0 ml), and the solvent was removed from the organic layer in vacuo. Toluene (15.0 ml) was added to the residue and the resulting toluene solution was evaporated. This operation was repeated once more to obtain a toluene solution of S-ZMAB [42] (6.9 g, 16.8 mmol theoretical). The resulting toluene solution of S-ZMAB [42] was used in the next step, assuming the yield to be 100%.

The crude product S-ZMAB [42], which was obtained according to the procedure described above, was evaporated to dryness and then examined by NMR and MS.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (m, 10H), 5.16-5.04 (m, 4H), 4.60 (d, 1H, J = 9.2 Hz ), 4.18-4.12 (m, 2H), 4.04 (t, 1H, J = 8.6 Hz), 3.66 (dd, 1H, J = 7.6, 7.2 Hz) , 3.50 (dd, 1H, J = 8.0, 5.2 Hz), 3.05-2.94 (m, 1H), 2.60-2.50 (m, 1H), 1.43 (broad s, 18H), 1.33 (d, 3H, J = 6.5 Hz), 1.15 (d, 3H, J = 7.2 Hz).

MS: m/z = 328 ⁺

[Example 45] Receiving RS-ZMBB (Connection [43])

[Chem. 218]

To a toluene solution of S-ZMAB [42] (6.9 g, 16.8 mmol) was added tetrahydrofuran (15.0 ml) at room temperature under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide/tetrahydrofuran (14.7 ml, 17.6 mmol) was added dropwise to the toluene solution at -70°C. The used addition funnel was washed with tetrahydrofuran (2.5 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at -70°C for 6 hours, then a solution of TBBA (3.4 g, 17.6 mmol) in tetrahydrofuran (2.5 ml) was added dropwise to the reaction mixture at -70°C. The used addition funnel was washed with tetrahydrofuran (2.5 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at -70°C for 1 hour, then warmed to room temperature. An aqueous solution of ammonium chloride (25 ml) and toluene (25 ml) were added to the reaction mixture, the mixture was stirred, and the organic layer was separated. The resulting organic layer was washed with an aqueous citric acid solution (25 ml x 2), an aqueous sodium bicarbonate solution (25 ml) and then water (25 ml), and the solvent was removed from the organic layer in vacuo. Acetonitrile (15 ml) was added to the residue and the resulting acetonitrile solution was evaporated. This operation was repeated two more times. Acetonitrile (15 ml) and activated carbon (0.25 g) were added to the residue, the mixture was stirred at room temperature for 2 hours. The activated carbon was removed by filtration, and the reaction flask and filter cake were washed with acetonitrile (10 ml). The washings were added to the filtrate and the filtrate was evaporated in vacuo to give an acetonitrile solution of RS-ZMBB [43] (13.2 g, 16.8 mmol theoretical). The resulting acetonitrile solution of RS-ZMBB [43] was used in the next step, assuming the yield to be 100%.

The crude product RS-ZMBB [43], which was obtained according to the procedure described above, was evaporated to dryness and then examined by NMR and MS.

¹ H-NMR (DMSO-d ₆ ) δ: 7.38-7.29 (m, 5H), 5.09-4.96 (m, 2H), 3.91 (t, 0.4H, J= 8.0 Hz), 3.79 (t, 0.6H, J = 8.0 Hz), 3.55 (t, 0.4H, J = 7.2 Hz), 3.46 (t, 0, 6H, J = 7.5 Hz), 3.14-3.04 (m, 1H), 2.83-2.72 (m, 2H), 1.38 (brs, 9H), 1.37 (bd s, 3.6H), 1.34 (bd s, 5.4H), 1.12-1.09 (m, 3H).

MS: m/z = 420 [M+H] ⁺

[Example 46] Obtaining RS-ZMAA-DN•2H ₂ O (Compound [44])

[Chem. 219]

Acetonitrile (15 ml) was added to the resulting acetonitrile solution of RS-ZMBB [43] (13.2 g, 16.8 mmol theoretically) at room temperature under nitrogen atmosphere. p-Toluenesulfonic acid monohydrate (6.4 g, 33.6 mmol) was added to the solution at room temperature. The reaction mixture was stirred at 50°C for 12 hours, then cooled to room temperature, water (7.5 ml) was added dropwise to the reaction mixture. The reaction mixture was cooled to 0° C. and 4 mol/l aqueous sodium hydroxide solution (17.6 ml, 70.5 mmol) was added dropwise. After the reaction mixture was stirred at room temperature for 1 hour, acetonitrile (75 ml) was added dropwise at room temperature, and the mixture was stirred for 3 hours. The precipitated solid was collected on a filter and washed with a mixture of acetonitrile: water = 4 : 1 (10 ml) and then with acetonitrile (10 ml). The resulting wet solid was dried in vacuo to give RS-ZMAA-DN·2H ₂ O [44] (5.2 g, 13.4 mmol, yield: 85.4%).

RS-ZMAA-DN⋅2H ₂ O [44], which was obtained by the method described above, was analyzed by NMR, MS, Na content and water content were determined.

¹ H-NMR (DMSO-d ₆ ) δ: 7.32-7.22 (m, 5H), 4.97 (d, 1H, J = 12.7 Hz), 4.84 (d, 1H, J = 12.7 Hz), 3.79 (t, 1H, J = 8.0 Hz), 3.29 (d, 1H, J = 14.8 Hz), 3.16-3.12 (m, 1H ), 2.17-2.09 (m, 2H), 1.07 (d, 3H, J = 6.9 Hz).

MS: m/z = 352 [M+H] ⁺ (anhydrous).

Na content (ion exchange chromatography): 13.3% (after correcting for water content) (13.1% theoretical).

Water content (Karl Fischer method): 9.8% (9.3% theoretical).

[Example 47] Receiving RS-ZMAA (Connection [45])

[Chem. 220]

RS-ZMAA-DN•2H ₂ O [44] (30 g, 77.5 mmol) and acetonitrile (60 ml) were added to 1 mol/l hydrochloric acid (180 ml) and the mixture was stirred at room temperature for about 15 minutes. Ethyl acetate (240 ml) was added to the reaction mixture, the mixture was stirred, the organic layer was separated. The organic layer was washed with 10% sodium chloride solution (60 ml x 2). The organic layer was stirred with magnesium sulfate (6 g), the magnesium sulfate was removed by filtration and the filter cake was washed with ethyl acetate (60 ml). The filtrate and washings were combined and the solvent was removed in vacuo. Tetrahydrofuran (240 ml) was added to the residue and the resulting tetrahydrofuran solution was evaporated. This operation was repeated two more times. Tetrahydrofuran (60 ml) was added to the residue to give a tetrahydrofuran solution of RS-ZMAA [45]. The resulting tetrahydrofuran solution of RS-ZMAA [45] was used in the next step, assuming the yield to be 100%.

RS-ZMAA [45], which was obtained by the method described above, was studied by NMR and MS.

¹ H-NMR (DMSO-D ₆ ) δ: 7.35-7.28 (m, 5H), 5.06-4.94 (m, 2H), 3.86 (dt, 1H, J = 48, 4, 7.9 Hz), 3.50 (dt, 1H, J = 37.9, 7.4 Hz), 3.16-3.02 (broad m, 1H), 2.91-2.77 (breadth m, 2H), 1.08 (d, 3H, J = 6.9 Hz).

MS: m/z = 308 [M+H] ⁺

[Example 48] Obtaining RS-ZMOO (Connection [46])

[Chem. 221]

Tetrahydrofuran (50 ml) was added to a tetrahydrofuran solution of RS-ZMAA [45] (25.8 mmol theoretically) under a nitrogen atmosphere. Boron trifluoride complex etherate (4.40 g) was added dropwise at 0°C to 5°C. The used addition funnel was washed with tetrahydrofuran (5 ml) and the washings were added to the reaction mixture. A 1.2 mol/L solution of borane-tetrahydrofuran complex (43.0 ml) was added dropwise to the reaction mixture at 0°C to 5°C, and the reaction mixture was stirred at 0°C to 5°C for about 30 minutes, then further stirred at room temperature overnight. A 1.2 mol/L solution of borane-tetrahydrofuran complex (21.1 ml) was added dropwise to the reaction mixture at 0°C to 5°C, and the reaction mixture was stirred at room temperature overnight. After stirring, water (40 ml) was added dropwise to the reaction mixture at 0°C to 15°C. Sodium bicarbonate (5.42 g) was added to the reaction mixture at 0°C to 15°C. The sodium bicarbonate remaining in the vessel was washed off with water (10 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, then toluene (50 ml) was added and the reaction mixture was further stirred. The organic layer was separated. The resulting organic layer was washed with 10% sodium chloride solution (20 ml x 1), a mixture (x 3) of 5% aqueous sodium bicarbonate solution (20 ml) and 10% sodium chloride solution (20 ml), a mixture of ( x 1) 5% aqueous potassium hydrogen sulfate solution (10 ml) and 10% sodium chloride solution (10 ml), and then 10% sodium chloride solution (20 ml x 2). The organic layer was stirred with magnesium sulfate (8.9 g), the magnesium sulfate was removed by filtration and the filter cake was washed with toluene (20 ml). The washing solutions were added to the filtrate and the filtrate was evaporated in vacuo. Toluene (80 ml) was added to the evaporation residue. The solution was evaporated in vacuo and toluene (15 ml) was added to give a toluene solution of RS-ZMOO [46]. The resulting toluene solution of RS-ZMOO [46] was used in the next step, assuming the yield to be 100%.

RS-ZMOO [46], which was obtained by the method described above, was studied by NMR and MS.

¹ H-NMR (CDCl ₃ ) δ: 7.39-7.30 (m, 5H), 5.10 (s, 2H), 4.15-4.01 (bdm, 2H), 3.83 -3.73 (broad m, 3H), 3.48 (dd, 1H, J = 8.3, 6.4 Hz), 2.59-2.50 (broad m, 1H), 2.46 -2.40 (breadth m, 1H), 2.07-1.99 (m, 1H), 1.14 (d, 3H, J = 7.2 Hz).

MS: m/z = 280 [M+H] ⁺

[Example 49] Receiving RS-ZMSS (Connection [47])

[Chem. 222]

Toluene (55 ml) was added to a toluene solution of RS-ZMOO [46] (23.7 mmol theoretically) under a nitrogen atmosphere. Triethylamine (5.27 g) was added dropwise at -10°C to 10°C, the used addition funnel was washed with toluene (1.8 ml) and the washings were added to the reaction mixture. Methansulfonyl chloride (5.69 g) was added dropwise to the resulting reaction mixture at −10° C. to 10° C., then the used addition funnel was washed with toluene (1.8 ml) and the washings were added to the reaction mixture. The reaction mixture was stirred at 0°C to 10°C for about 2 hours and then water (28 ml) was added dropwise at 0°C to 20°C. The reaction mixture was stirred at 0°C to 20°C for about 30 minutes, the organic layer was separated. The resulting organic layer was washed twice with 10% sodium chloride solution (18 ml). The organic layer was stirred with magnesium sulfate (2.75 g), the magnesium sulfate was removed by filtration and the filter cake was washed with toluene (18 ml). The washing solutions were added to the filtrate and the solvent was removed from the filtrate in vacuo. Toluene was added to the evaporation residue to 18 ml, obtaining a toluene solution of RS-ZMSS [47]. The resulting toluene solution of RS-ZMSS [47] was used in the next step, assuming the yield to be 100%.

RS-ZMSS [47], which was obtained by the method described above, was studied by NMR and MS.

¹ H-NMR (DMSO-D ₆ ) δ: 7.37-7.27 (br. m, 5H), 5.10-4.98 (m, 2H), 4.58-4.22 (b.d. m, 4H), 3.84 (dt, 1H, J = 45.6, 8.1 Hz), 3.48-3.33 (breadth m, 1H), 3.17-3.10 (m, 6H), 2.81-2.74 (bdm, 1H), 2.22-2.12 (m, 2H).

MS: m/z = 436 [M+H] ⁺

[Example 50] Obtaining SR-ZMDB (Connection [28])

[Chem. 223]

Toluene (55 ml) was added to a toluene solution of RS-ZMSS [47] (23.7 mmol theoretically) under nitrogen atmosphere, benzylamine (17.8 g) was added dropwise at room temperature, the used addition funnel was washed with toluene (9.2 ml ) and added washing solutions to the reaction mixture. The reaction mixture was stirred at room temperature for about 1 hour at 55°C to 65°C for about 3 hours, and then at 70°C to 80°C for 6 hours. After the reaction mixture was cooled to room temperature, a 10% NaCl solution (28 ml) was added dropwise, and the reaction mixture was stirred at room temperature for about 30 minutes. Toluene (37 ml) was added to the reaction mixture, the mixture was stirred, the organic layer was separated. The resulting organic layer was washed with a mixture of (x 2) 10% sodium chloride solution (18 ml) and acetic acid (2.84 g), then 10% sodium chloride solution (11 ml x 1). The solvent from the organic layer was removed in vacuo to half volume and acetic anhydride (1.45 g) was added to the evaporation residue at room temperature. The mixture was stirred for about 3 hours. A solution of potassium hydrogen sulfate (3.87 g) and water (92 ml) were added dropwise to the reaction mixture at room temperature. The reaction mixture was stirred, the aqueous layer was separated. The obtained aqueous layer was washed with toluene (18 ml), toluene (73 ml) and sodium bicarbonate (6.56 g) were added to the aqueous layer at room temperature, and the mixture was stirred. The organic layer was separated and washed with 10% sodium chloride solution (11 ml). The organic layer was stirred with magnesium sulfate (2.75 g) and the magnesium sulfate was removed by filtration. The filter cake was washed with toluene (18 ml), the washings were added to the filtrate and then the filtrate was evaporated in vacuo. Toluene (44 ml) was added to the evaporation residue to give a toluene solution of SR-ZMDB [28]. The resulting toluene solution of SR-ZMDB [28] was used in the next step, assuming the yield to be 100%.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.20 (m, 10H), 5.08 (d, 2H, J = 23.6 Hz), 3.94 (q, 1H, J = 7 .9 Hz), 3.73-3.42 (breadth m, 2H), 3.30-3.23 (m, 1H), 3.05 (dd, 1H, J = 19.7, 9.5 Hz), 2.79 (dt, 1H, J = 69.6, 6.1 Hz), 2.57-2.32 (broad m, 4H), 1.96-1.89 (m, 1H) , 1.09 (d, 3H, J = 6.9 Hz).

MS: m/z = 351 [M+H] ⁺

Industrial Applicability

Compounds of the present invention can be used as intermediates for the synthesis of Compound A (Compound [17]). The methods described in the present invention provide stable production of Compound A (Compound [17]) with good chemical and optical purity. The methods described in the present invention provide stable production of Compound A (Compound [17]) in good yield and can also be applied to large-scale industrial synthesis. The processes described in the present invention for the preparation of intermediates for the synthesis of Compound A (Compound [17]) provide stable preparation of RR-MDDO and SR-MDBN-DSU, intermediates for the synthesis of Compound A (Compound [17]), with good chemical and optical purity .

Claims (83)

1. Method for obtaining a compound having the formula [17]:

or its salt using a compound having the formula [13]:

or its salt, comprising the following stages, in which: (1) a compound having the formula [10]:

or its salt with an organic acid is reacted with a compound having the formula [12]:

to obtain a compound having the formula [13] or a salt thereof, (2) benzyl is removed from a compound having the formula [13] or a salt thereof to obtain a compound having the formula [14]:

or its salt, and (3) carrying out cyanoacetylation of a compound having the formula [14] or a salt thereof to obtain a compound having the formula [17] or a salt thereof. 2. The method according to claim 1, further comprising adding an organic acid to a compound having the formula [10] to form a salt of the compound having the formula [10] with an organic acid. 3. The method according to claim 1 or 2, wherein the organic acid salt is a disuccinate, oxalate or hemioxalate. 4. The method of claim 1 or 2, wherein the organic acid salt is hemioxalate. 5. The method according to any one of paragraphs. 1-4, additionally including the stage at which the compound having the formula [9] is restored:

to obtain a compound having the formula [10], or its salt with an organic acid. 6. The method of claim 5 wherein the reduction is carried out in the presence of an acid and lithium aluminum hydride. 7. The method according to claim 5 or 6, further comprising the step of removing phthaloyl from the compound having the formula [8a]:

where R ¹ represents C _1-4 alkyl or benzyl; to obtain a compound having the formula [9]. 8. The method according to claim 5 or 6, further comprising the step of removing formyl from the compound having the formula [16a]:

where R ¹ represents C _1-4 alkyl or benzyl; to obtain a compound having the formula [9]. 9. The method according to p. 7, additionally including the stage at which the compound having the formula [7]:

is reacted with potassium phthalimide, followed by esterification to obtain a compound having the formula [8a]. 10. The method according to p. 8, additionally including the stage at which the compound having the formula [7]:

is reacted with sodium diformylamide followed by esterification to give a compound having the formula [16a]. 11. The method according to claim 9 or 10, additionally including the stage at which the compound having the formula [6]:

is reacted with a base to obtain a compound having the formula [7]. 12. The method of claim 11 wherein the base is lithium hexamethyldisilazide. 13. The method according to p. 5, additionally including the stage at which the cyclization of the compound having the formula [27a] is carried out:

where R ² and R ³ each independently represents methyl, ethyl or benzyl; to obtain a compound having the formula [9]. 14. The method according to p. 13, further comprising a step in which the compound having the formula [26a]:

where R ² and R ³ have the above meanings; or its salt is reacted with a compound having the formula [5]:

in the presence of a base to give a compound having the formula [27a]. 15. The method according to p. 14, additionally including the stage at which the compound having the formula [4]:

is reacted with a chlorinating agent to obtain a compound having the formula [5]. 16. The method according to claim 14 or 15, further comprising a step in which the compound having the formula [25a]:

where R ² and R ³ have the above meanings; or a salt thereof is reacted with benzaldehyde to obtain a compound having the formula [26a] or a salt thereof. 17. The method according to p. 16, additionally including the stage at which the esterification of the compound having the formula [24a] is carried out:

where R ² has the above meaning; or a salt thereof to obtain a compound having the formula [25a], or a salt thereof. 18. A compound having the formula [13]:

or its salt. 19. A compound having the formula [10]:

or its salt with an organic acid. 20. The compound according to claim 19, which is a salt with an organic acid, where the salt is a disuccinate, oxalate or hemioxalate. 21. The compound according to claim 19, which is a salt with an organic acid, where the salt is a hemioxalate. 22. Crystalline form of the disuccinate compound having the formula [10]:

having an X-ray powder diffraction spectrum containing at least one peak with a diffraction angle value (2θ) = 4.8° ± 0.2°, 11.2° ± 0.2°, 16.2° ± 0.2°, 18.1° ± 0.2° or 20.1° ± 0.2° when analyzed using CuKα radiation. 23. A compound having the formula [9]:

. 24. The crystalline form of the compound having the formula [9]:

having an X-ray powder diffraction spectrum containing at least one peak with a diffraction angle value (2θ) = 10.6° ± 0.2°, 16.0° ± 0.2°, 17.5° ± 0.2°, 18.3° ± 0.2° or 19.2° ± 0.2° when analyzed using CuKα radiation. 25. A compound having the formula [27a]:

where R ² and R ³ have the above meanings. 26. A compound having the formula [26a]:

where R ² and R ³ have the above meanings; or its salt.

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