EA046002B1 - METHODS FOR OBTAINING AMIDE COMPOUNDS AND THEIR CRYSTAL AND SALT FORMS - Google Patents

Description

This application claims priority to U.S. Provisional Patent Application Serial No. 62/985,918, filed March 6, 2020, which is hereby incorporated herein by reference.

Technical field of the invention

The present disclosed invention relates to methods for preparing amide compounds and their crystalline and salt forms.

Prior Art

ALPOOIE is a glucagon receptor antagonist and is used to treat diabetes mellitus. ALPOOIE is a Biopharmaceutical Classification System (BCS) Class II drug, indicating poor aqueous solubility but good membrane permeability. It is stable in the solid state and insensitive to light irradiation. However, the bulk of ALP001E undergoes hydrolytic decomposition in the presence of moisture. It is also sensitive to acidic or basic environments.

Due to these physicochemical and biopharmaceutical properties of ALP001E, several attempts have been made to prepare different forms of ALP001E that are stable and provide the desired in vitro release and bioavailability.

Therefore, it is desirable to provide a new form of ALP001E so that ALP001E can be used for clinical use.

Brief description of the invention

The present disclosed invention relates to methods for preparing amide compounds and their crystalline and salt forms.

One aspect of the present disclosed invention is directed to a crystalline form of the compound of formula (1) ° ° (1) characterized by an x-ray diffraction (XRD) pattern having peak values at approximately 14.2, 15.6, 16.4, 20.1, 20 .5 and 21.2°±0.2° 2θ.

Also included within the scope of the present disclosed invention is a method for preparing the above crystalline form of a compound of formula (1), comprising the following steps: crystallizing a compound of formula (1) in a solvent to obtain the above crystalline form of a compound of formula (1), wherein the solvent includes ethanol, isopropanol , 1-butanol, tert-butanol, ethyl acetate, butyl acetate, acetone, n-heptane, acetonitrile, or a combination thereof.

Another aspect of the present disclosed invention is directed to the crystalline form of the compound of formula (2)

characterized by an XRD XRD pattern having peak values at approximately 14.5, 18.6, 20.1, 21.8, 23.8, 25.0°±0.2° 2θ.

Also included within the scope of the present disclosed invention is a method for preparing the above crystalline form of a compound of formula (2), comprising the following steps: crystallizing a compound of formula (2) in a solvent to obtain the above crystalline form of a compound of formula (2), which solvent includes methanol, ethanol , isopropanol, 1-butanol, tert-butanol, ethyl acetate, butyl acetate, acetone, acetonitrile, dichloromethane, or a combination thereof.

Another aspect of the present disclosed invention is directed to a salt of the compound of formula (2).

Another aspect of the present disclosed invention is directed to the amorphous form of the compound of formula (1) or formula (2).

This disclosed invention also covers the use of a crystalline form of a compound of formula (1) or formula (2), an amorphous form of a compound of formula (1) or formula (2), or a salt of a compound of formula (2) described above for lowering the glycemic level of a patient or treating glucagon-related disorders.

Another aspect of the present disclosed invention is directed to a pharmaceutical composition

- 1 046002 tion to reduce the patient's glycemic level or treat glucagon-related disorders. This pharmaceutical composition contains: a crystalline form of a compound of formula (1) or formula (2), an amorphous form of a compound of formula (1) or formula (2) or a salt of a compound of formula (2) described above, and a pharmaceutically acceptable carrier, excipient or diluent .

This disclosed invention also covers the use of a pharmaceutical composition for lowering a patient's glycemic level or treating glucagon-related disorders.

The oral composition may be any dosage form suitable for oral administration, including capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are taken orally, the active ingredient may be suspended or dissolved in an oil phase in combination with emulsifying or suspending agents. Certain sweeteners, flavors, or colors may be added if desired. Solid dosage forms for oral administration can be prepared using spray drying techniques, hot melt extrusion strategies, micization and nanomilling technologies.

The nasal aerosol or inhalation composition can be prepared according to methods well known in the art of pharmaceutical compositions. For example, such a composition can be formulated dissolved in saline using benzyl alcohol or other suitable preservatives, absorption promoters, fluorocarbons and/or other solubilizing or dispersing agents known in the art. The composition containing the active compound may also be administered in the form of suppositories for rectal administration.

The carrier, excipient and diluent in the pharmaceutical composition must be "acceptable" in the sense that they are compatible with the active ingredient of the composition (and preferably capable of stabilizing the active ingredient) and are not harmful to the patient being treated. One or more solubilizing agents can be used as pharmaceutical excipients to deliver the active compound. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate and D&C Yellow #10.

Also within the scope of the present disclosed invention is a method for reducing the glycemic level of a patient or treating glucagon-related disorders.

This method includes: administering to a patient in need thereof an effective amount of a crystalline form of a compound of formula (1) or formula (2), an amorphous form of a compound of formula (1) or formula (2), or a salt of a compound of formula (2) described above, or a pharmaceutical composition , containing them.

The above-described crystalline form, amorphous form or salt of the compound of formula (1) or (2), or a pharmaceutical composition containing one or more of them, can be administered to a patient orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally or via implanted reservoir. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

The term treating, treating, or treatment refers to the use or administration of a compound by a patient for the purpose of treating, mitigating, ameliorating, modifying, correcting, ameliorating, or affecting a disease, symptom, or predisposition. An effective amount refers to the amount of a compound that is required to produce the desired effect in a patient. Effective amounts vary, as recognized by those skilled in the art, depending on the route of administration, the use of the excipient, and the possibility of concurrent use with other therapeutic treatments, such as the use of other active agents.

Also included within the scope of the present disclosed invention is a compound of formula (3) or a salt thereof

where R represents H, alkyl with 1-6 carbon atoms, optionally substituted with phenyl, alkenyl with 2-6 carbon atoms, -S(=O)R1, -P(=O)R ₂ R ₃ or phenyl, substituted - COOR ₄ ;

where R1 represents alkyl with 1-6 carbon atoms, R2 represents aryl, R ₃ represents

- 2 046002 is aryl and R ₄ is H or alkyl with 1-6 carbon atoms.

_The term alkyl as used herein refers to a straight or branched hydrocarbon group containing 1-12 carbon atoms (eg, _C1 - _C1o , _C1 - _C8 and _1-6 ). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term alkenyl as used herein refers to linear or branched hydrocarbon groups with at least one double bond and includes, for example, linear or branched hydrocarbon groups with 2-12 carbon atoms with at least one double bond, linear or branched hydrocarbon groups with 2 -8 carbon atoms with at least one double bond or linear or branched hydrocarbon groups with 2-6 carbon atoms with at least one double bond. Examples of alkenyl include, but are not limited to, vinyl, propenyl or butenyl.

The term aryl refers to the 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples of aryl groups include phenyl, naphthyl and anthracenyl.

Alkyl, alkenyl and aryl mentioned herein include both substituted and unsubstituted moieties. Possible alkenyl and aryl substituents include, but are not limited to, C1-C10 alkyl, C2-10C alkenyl, C2-10C alkynyl, 3-20C cycloalkyl, 3-20C cycloalkenyl carbon, heterocycloalkyl with 1-20 carbon atoms, heterocycloalkenyl with 1-20 carbon atoms, C ₁ -C ₁₀ -alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C ₁ -C ₁₀ -alkylamino, C ₁ -C ₂₀ - dialkylamino, arylamino, diarylamino, C ₁ -C ₁₀ alkylsulfonamino, arylsulfonamino, C ₁ -C ₁₀ -alkylimino, arylimino, C ₁ -C ₁₀ -alkylsulfonimino, arylsulfonimino, hydroxyl, halogen, thio, C ₁ -C ₁₀ -alkyltio, arylthio , C ₁ -C ₁₀ -alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amido, amidino, guanidine, ureido, thioureido, cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl and carboxylic acid ester. On the other hand, possible substituents on alkyl include all of the above substituents except alkyl having 1 to 10 carbon atoms. Cycloalkyl, heterocycloalkyl, aryl and heteroaryl can also be fused to each other.

Also included within the scope of the present disclosed invention is a method for preparing a compound of formula (3-1), comprising the following steps:

^NH 2 (3-1) reaction of methyl 4-formyl benzoate to form a compound of formula (3-1).

Also included within the scope of the present disclosed invention is a method for preparing a compound of formula (1), comprising the following steps: reacting a compound of formula (3-1) to form a compound of formula (1).

Also included within the scope of the present disclosed invention is a process for preparing a compound of formula (2), comprising the following steps: converting a compound of formula (1) to a compound of formula (2).

Details of one or more embodiments of the disclosed invention are set forth in the description below. Other features, objects and advantages of the disclosed invention will be apparent from the description and claims.

Brief description of drawings

Fig. 1 shows an X-ray diffraction pattern (XRD) of a crystalline form of the compound of formula (1) in accordance with Example 2 of the present disclosed invention.

Fig. 2 shows an XRD diffraction pattern of the crystalline form of the compound of formula (1) according to Example 3 of the present invention.

Fig. 3 shows an XRD diffraction pattern of the crystalline form of the compound of formula (1) according to Example 4 of the present invention.

Fig. 4 shows an XRD diffraction pattern of the crystalline form of the compound of formula (1) according to Example 5 of the present invention.

Fig. 5 shows an XRD diffraction pattern of the crystalline form of the compound of formula (2) according to Example 12 of the present invention.

Fig. 6 shows an XRD diffraction pattern of the crystalline form of the compound of formula (2) according to Example 13 of the present invention.

Fig. 7 shows an XRD pattern of the sodium salt of the compound of formula (2) according to Example 14 of the present invention.

Fig. 8 shows an XRD pattern of the potassium salt of the compound of formula (2) according to Example 15 of the present invention.

- 3 046002

Fig. 9 shows an XRD pattern of the magnesium salt of the compound of formula (2) according to Example 16 of the present invention.

Fig. 10 shows an XRD pattern of the calcium salt of the compound of formula (2) according to Example 17 of the present invention.

Fig. 11 shows an XRD pattern of the amorphous form of the compound of formula (1) according to Example 18 of the present invention.

Detailed description

The present disclosed invention provides a crystalline form of the compound of formula (1)

HN

° ⁰ (1) characterized by an X-ray diffraction (XRD) pattern having peak values at approximately 14.2, 15.6, 16.4, 20.1, 20.5 and 21.2°±0.2° 2θ.

In one embodiment, the x-ray diffraction pattern of the crystalline form of the compound of formula (1) may further have peaks at about 17.4, 21.7, or 23.7°±0.2° 2θ. A typical crystalline form of the compound of formula (1) is characterized by an x-ray diffraction pattern having peaks at approximately 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 21.7°±0 ,2° 2θ. Another typical crystalline form of the compound of formula (1) is characterized by an x-ray diffraction pattern having peaks at approximately 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 23.7°± 0.2° 2θ. Another typical crystalline form of the compound of formula (1) is characterized by an x-ray diffraction pattern having peaks at approximately 14.2, 15.6, 16.4, 20.1, 20.5, 21.2, 21.7 and 23.7°± 0.2° 2θ. Another typical crystalline form of the compound of formula (1) is characterized by an x-ray diffraction pattern having peaks at approximately 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 23.7°± 0.2° 2θ.

In the above embodiment, the X-ray diffraction pattern of the crystalline form of the compound of formula (1) may be substantially the same as depicted in any one of FIG. 1 according to FIG. 4.

In the above embodiments, the crystalline form of the compound of formula (1) may have a differential scanning calorimetry (DSC) curve having a melting endotherm peak at approximately 136-138°C.

The present disclosed invention also provides a method for preparing the above crystalline form of a compound of formula (1), comprising the following steps: crystallizing a compound of formula (1) in a solvent to obtain the above crystalline form of a compound of formula (1). The crystalline form of the compound of formula (1) can be obtained by recrystallization of ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl )propyl)amino)benzamido)propanoate in a suitable solvent. Examples of the solvent may include, but are not limited to, ethanol, isopropanol, 1-butanol, tert-butanol, ethyl acetate, butyl acetate, acetone, n-heptane, acetonitrile, or a combination thereof. Here, if two or more solvents are used, the compound of formula (1) can be dissolved in a mixture of two or more solvents, or the compound of formula (1) can be dissolved in one solvent to form a mixture, followed by sequential addition of other solvents to the mixture. In addition, the compound of formula (1) can be crystallized at a temperature varying from 0 to 40°C for a time of 2 to 12 hours, for example, from 5 to 10°C, from 15 to 25°C, or from 20 to 30° WITH. In addition, before crystallizing the compound of formula (1), a heating step can be selectively carried out to facilitate dissolution of the compound of formula (1). The temperature of this heating stage may be, for example, reflux temperature.

The present disclosed invention provides a crystalline form of the compound of formula (2)

characterized by an X-ray diffraction (XRD) pattern having peak values at approximately 14.5, 18.6, 20.1, 21.8, 23.8, 25.0° ±0.2° 2θ.

- 4 046002

In one embodiment, the XRD diffraction pattern of the crystalline form of the compound of formula (2) may further have peaks at about 19.9, 22.0, 28.5, or 31.0°±0.2° 2θ. A typical crystalline form of the compound of formula (2) is characterized by an x-ray diffraction pattern having peaks at approximately 14.5, 18.6, 19.9, 20.1, 21.8, 22.0, 23.8 and 25.0°±0 ,2° 2θ. A typical crystalline form of the compound of formula (2) is characterized by an x-ray diffraction pattern having peaks at approximately 14.5, 18.6, 20.1, 21.8, 23.8, 25.0, 28.5 and 31.0°±0 ,2° 2θ.

In the above embodiment, the X-ray diffraction pattern of the crystalline form of the compound of formula (2) may be substantially as shown in FIG. 5 or 6.

In the above embodiments, the crystalline form of the compound of formula (2) may have a DSC curve having a melting endotherm peak at about 168-170°C. In addition, the crystalline form of the compound of formula (2) may have a DSC curve further having another melting endotherm peak at about 85-95°C.

The present disclosed invention also provides a method for preparing the above crystalline form of a compound of formula (2), comprising the following steps: crystallizing a compound of formula (2) in a solvent to obtain the above crystalline form of a compound of formula (2). The crystalline form of the compound of formula (2) can be obtained by recrystallization of ^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2)-yl)phenyl )propyl)amino)benzamido)propanoic acid in a suitable solvent. Examples of the solvent may include, but are not limited to, methanol, ethanol, isopropanol, 1-butanol, tert-butanol, ethyl acetate, butyl acetate, acetone, acetonitrile, dichloromethane, or a combination thereof. Here, if two or more solvents are used, the compound of formula (2) can be dissolved in a mixture of two or more solvents, or the compound of formula (2) can be dissolved in one solvent to form a mixture, followed by sequential addition of other solvents to the mixture. In addition, the compound of formula (2) can be crystallized at a temperature varying from 0 to 40°C for a time of 2 to 12 hours, for example from 15 to 25°C. In addition, prior to crystallization of the compound of formula (2), a heating step may be selectively carried out to facilitate dissolution of the compound of formula (2). The temperature of this heating step may be, for example, reflux temperature.

The present disclosed invention provides a salt form of the compound of formula (2).

In one embodiment, the x-ray diffraction pattern of the salt form of the compound of formula (2) may be substantially as shown in either of FIG. 7 according to FIG. 10.

In the above embodiment, the salt form of the compound of formula (2) may be a Group IA or Group IIA metal salt.

In the above embodiments, the salt form of the compound of formula (2) may be a sodium salt, a potassium salt, a magnesium salt or a calcium salt.

The present disclosed invention provides an amorphous form of the compound of formula (1) or formula (2).

In one embodiment, the x-ray diffraction pattern of the amorphous form of the compound of formula (1) may be substantially as shown in FIG. eleven.

The present disclosed invention also provides the use of any of the crystalline form of a compound of formula (1) or formula (2), an amorphous form of a compound of formula (1) or formula (2), or a salt of a compound of formula (2) described above to reduce the level of glycemia in a patient or treatment of glucagon-related disorders.

The present disclosed invention also provides a pharmaceutical composition for reducing the glycemic level of a patient or treating glucagon-related disorders, which may contain: a crystalline form of a compound of formula (1) or formula (2), an amorphous form of a compound of formula (1) or formula (2) or a salt of the compound of formula (2) described above, and a pharmaceutically acceptable carrier, excipient or diluent.

The present disclosed invention also provides the use of the above pharmaceutical composition for lowering the glycemic level of a patient or treating glucagon-related disorders.

The present disclosed invention also provides a method of reducing the glycemic level of a patient or treating glucagon-related disorders, which may include: administering to a patient in need thereof an effective amount of a crystalline form of a compound of formula (1) or formula (2), an amorphous form of a compound of formula ( 1) or formula (2) or a salt of a compound of formula (2) described above, or a pharmaceutical composition containing them.

In the present disclosed invention, the above-mentioned patient may be a mammal, for example, a human, a pig, a horse, a cow, a dog, a cat, a mouse or a rat.

In the present disclosed invention, diseases, conditions or disorders associated with glucagon may be, for example, hyperglycemia, type II diabetes, metabolic syndrome, impaired glucose tolerance, glycosuria, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hyperinsulinemia, resistance syndrome. insulin, cataracts

- 5 046002 you, obesity, dyslipidemia, arterial hypertension and myocardial infarction. However, the present disclosed invention is not limited to this, and the pharmaceutical composition according to the present invention can be used for the treatment of any other diseases, conditions or disorders associated with the glucagon signaling pathway. In one aspect of the present disclosure, diseases, conditions or disorders associated with glucagon may be hyperglycemia, type II diabetes, impaired glucose tolerance, insulin resistance syndrome or obesity. In another aspect of the present disclosure, diseases, conditions or disorders associated with glucagon may be type II diabetes.

The present disclosed invention also provides new compounds of formula (3) or salts thereof

where R represents H, alkyl with 1-6 carbon atoms, optionally substituted with phenyl, alkenyl with 2-6 carbon atoms, -S(=O)R1, -P(=O)R ₂ R ₃ or phenyl, substituted - COOR4, wherein R ₁ is alkyl of 1-6 carbon atoms, R2 is aryl, R ₃ is aryl and R ₄ is H or alkyl of 1-6 carbon atoms.

In one embodiment, each of the compounds of formula (3) has R being H, benzyl, allyl, -S(=O)R1, -P(=O)R ₂ R ₃ or phenyl substituted with -COOR4, wherein R1 is is propyl, R2 is phenyl, _R3 is phenyl and R4 is H or ethyl. In this embodiment, the exemplified compound of formula (3) has R being H.

In the above embodiment, each of the compounds of formula (3) may be represented by the following formula (3')

In this embodiment, the exemplified compound of formula (3) is represented by the following formula (3-1)

The present disclosed invention also provides a method for preparing the above compound of formula (3-1), comprising the following steps: reacting methyl 4-formyl benzoate to form a compound of formula (3-1).

In one embodiment, the step of reacting methyl 4-formyl benzoate to form a compound of formula (3-1) may include the following steps:

reacting methyl 4-formyl benzoate to form a compound of formula (A)

reacting a compound of formula (A) to form a compound of formula (B)

L'Tsn

CO ₂ Me (B) interaction of a compound of formula (B) with the formation of a compound of formula (C)

- 6 046002 interaction of a compound of formula (C) with the formation of a compound of formula (D)

reacting a compound of formula (D) to form a compound of formula (E), and

reacting a compound of formula (E) to form a compound of formula (3-1).

In the step of reacting methyl 4-formyl benzoate to form a compound of formula (A), methyl 4-formyl benzoate can be reacted with (B)-2-methylpropane-2-sulfinamide to produce a compound of formula (A) using Cs ₂ CO ₃ . Alternatively, methyl 4formyl benzoate can be reacted with N)-2-methylpropane-2-sulfinamide to produce a compound of formula (A) using titanium tetraisopropoxide, in which case a compound of formula (A) can be further formed together with the compound of formula (A) (A')

In the step of reacting a compound of formula (A) to form a compound of formula (B), the compound of formula (A) may be reacted with isopropyl magnesium chloride to produce a compound of formula (B). In the case where a compound of formula (A) is formed together with a compound of formula (A), a compound of formula (B') can also be additionally formed together with a compound of formula (B).

In the step of reacting a compound of formula (B) to form a compound of formula (C), the compound of formula (B) can be converted to a compound of formula C using a base such as LiOH, NaOH or KOH. In the case where a compound of formula (B') is formed together with a compound of formula (B), the compound of formula (B') can also be converted into a compound of formula (C) using the above base.

In this case, the compound of formula (C) can be recrystallized using a suitable solvent. Examples of a suitable solvent may include, but are not limited to, acetone, ethyl acetate, methanol, ethanol, methyl tert-butyl ether (TBME), ether, or a combination thereof.

In the step of reacting a compound of formula (C) to form a compound of formula (D), the compound of formula (C) may be reacted with a benzohydrazide to form a compound of formula (D).

In the step of reacting a compound of formula (D) to form a compound of formula (E), the cyclization reaction can be carried out in the presence of p-toluenesulfonyl chloride and triethylamine.

In the step of reacting a compound of formula (E) to form a compound of formula (3-1), the sulfinyl group of the compound of formula (E) can be removed using an acid such as HCl.

In another embodiment, the step of reacting methyl 4-formyl benzoate to form a compound of formula (3-1) may include the following steps:

reacting methyl 4-formyl benzoate to form a compound of formula (G)

- 7 046002

reacting a compound of formula (G) to form a compound of formula (H)

reaction of a compound of formula (H) to form a compound of formula (I)

reacting a compound of formula (I) to form a compound of formula (J)

reacting a compound of formula (J) to form a compound of formula (K), and

reacting a compound of formula (K) to form a compound of formula (3-1).

In the step of reacting methyl 4-formyl benzoate to form a compound of formula (G), methyl 4-formyl benzoate may be reacted with diphenylphosphinamide to form a compound of formula (G).

In the step of reacting a compound of formula (G) to form a compound of formula (H), the compound of formula (G) may be reacted with isopropyl magnesium chloride to form a compound of formula (H).

In the step of reacting a compound of formula (H) to form a compound of formula (I), the compound of formula (H) can be converted to a compound of formula (I) using a base such as LiOH, NaOH or KOH.

In the step of reacting a compound of formula (I) to form a compound of formula (J), the compound of formula (I) may be reacted with a benzohydrazide to produce a compound of formula (J).

In the step of reacting a compound of formula (J) to form a compound of formula (K), the cyclization reaction can be carried out in the presence of p-toluenesulfonyl chloride and triethylamine.

In the step of reacting a compound of formula (K) to form a compound of formula (3-1), the phosphine group can be removed using an acid such as HCl.

In another embodiment, the step of reacting methyl 4-formyl benzoate to form a compound of formula (3-1) may include the following steps:

reacting methyl 4-formyl benzoate to form a compound of formula (L)

- 8 046002 interaction of a compound of formula (L) with the formation of a compound of formula (M)

reaction of a compound of formula (M) to form a compound of formula (O)

he (O) reacts a compound of formula (O) to form a compound of formula (P), and

OH(P) reacts a compound of formula (P) to form a compound of formula (3-1).

In the step of reacting methyl 4-formyl benzoate to form a compound of formula (L), methyl 4-formyl benzoate may be reacted with isopropyl magnesium chloride to form a compound of formula (L).

In the step of reacting a compound of formula (L) to form a compound of formula (M), the compound of formula (L) may be reacted with hydrazine to form a compound of formula (M).

In the step of reacting a compound of formula (M) to form a compound of formula (O), the compound of formula (M) may be reacted with benzoic acid to form a compound of formula (O).

In the step of reacting a compound of formula (O) to form a compound of formula (P), the cyclization reaction can be carried out in the presence of p-toluenesulfonyl chloride.

In one aspect, the step of reacting a compound of formula (P) to form a compound of formula (3-1) may include the following steps:

reaction of a compound of formula (P) to form a compound of formula (P1)

OMs (P1) reacting a compound of formula (P1) to form a compound of formula (P2), and

N ₃ (P2) reaction of a compound of formula (P2) to form a compound of formula (3-1).

In the step of reacting a compound of formula (P) to form a compound of formula (P1), the compound of formula (P) may be reacted with methanesulfonyl chloride to form a compound of formula (P1).

In the step of reacting a compound of formula (P1) to form a compound of formula (P2), the compound of formula (P1) may be reacted with sodium azide to form a compound of formula (P2).

In the step of reacting a compound of formula (P2) to form a compound of formula (3-1), the compound of formula (P2) can be converted to a compound of formula (3-1) by the Staudinger reaction.

In another aspect, the step of reacting a compound of formula (P) to form a compound of formula (3-1) may include the following steps:

reaction of a compound of formula (P) to form a compound of formula (P3)

- 9 046002

NHR (РЗ) where R represents benzyl or allyl, and reacting a compound of formula (P3) to form a compound of formula (3-1).

In the step of reacting a compound of formula (P) to form a compound of formula (P3), the compound of formula (P) may be reacted with an allylamine or benzylamine to form a compound of formula (P3).

In the step of reacting a compound of formula (P3) to form a compound of formula (3-1), the compound of formula (P3) can be converted to a compound of formula (3-1) by hydrogenolysis.

The present disclosed invention also provides a method for producing the above compound of formula (1), comprising the following steps: reacting the above compound of formula (3-1) to form a compound of formula (1).

In one aspect, a compound of formula (3-1) can be directly converted into a compound of formula (1). In this case, the compound of formula (3-1) can be reacted with ethyl 3-(4halobenzamido)propanoate to obtain the compound of formula (1).

In one embodiment, ethyl 3-(4-halogenbenzamido)propanoate may be ethyl 3-(4-bromobenzamido)propanoate or ethyl 3-(4-iodobenzamido)propanoate.

In the above embodiment, the compound of formula (3-1) can be reacted with ethyl 3-(4-halobenzamido)propanoate using a ligand and a base.

In the above embodiments, the ligand may be 2,2'bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) or 2-dicyclohexylphosphino-2',4',6'triisopropylbiphenyl (XPhos).

In the above embodiments, the base may be Cs ₂ CO ₃ .

In the above embodiments, the compound of formula (3-1) may be reacted with ethyl 3-(4-halogenbenzamido)propanoate at reflux temperature.

In another embodiment, the step of reacting a compound of formula (3-1) to form a compound of formula (1) may include the following steps:

reacting a compound of formula (3-1) to form a compound of formula (U)

converting a compound of formula (U) into a compound of formula (V), and

reacting a compound of formula (V) to form a compound of formula (1).

In the step of reacting a compound of formula (3-1) to form a compound of formula (U), the compound of formula (3-1) may be reacted with ethyl 4(((trifluoromethyl)sulfonyl)oxy)benzoate or ethyl 4-halobenzoate to form compounds of formula (U).

Examples of ethyl 4-halogenbenzoate may be ethyl 4-bromobenzoate or ethyl 4-iodobenzoate.

In one embodiment, the compound of formula (3-1) may be reacted with ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzoate or ethyl 4-halobenzoate at reflux.

In the above embodiment, the compound of formula (3-1) can be reacted with ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzoate or ethyl 4-halobenzoate using a ligand and a base.

- 10 046002

In the above embodiments, the ligand may be BINAP, XPhos, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) or (2-biphenyl)dicyclohexylphosphine (CyJohnPhos).

In the above embodiments, the base may be Cs ₂ CO3.

In the step of converting a compound of formula (U) to a compound of formula (V), the compound of formula (U) can be converted to a compound of formula (V) using a base such as LiOH, NaOH or KOH.

In the step of reacting a compound of formula (V) to form a compound of formula (1), the compound of formula (V) may be reacted with ethyl 3-aminopropanoate hydrochloride to form a compound of formula (1).

In one embodiment, compound (V) can be reacted with ethyl 3-aminopropanoate hydrochloride using a condensing agent to form a compound of formula (1).

In the above embodiment, the condensing agent may be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 2-(1H-benzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU ), 1-[bis(dimethylamino)methylene]-1H-1,2,3triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 2-chloro-4,6-dimethoxy-1,3,5 -triazine (CDMT), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), or a combination thereof.

The present disclosed invention also provides another method for preparing the above compound of formula (1), comprising the following steps:

reaction of methyl 4-formyl benzoate to form;

the above compound of formula (L);

reacting a compound of formula (L) to form the above compound of formula (M);

reacting a compound of formula (M) to form a compound of formula (O);

reacting a compound of formula (O) to form a compound of formula (P);

reaction of a compound of formula (P) to form a compound of formula (Q)

N.N. D? /—Ph ajCj ⁰ o (Q) interaction of a compound of formula (Q) to form a compound of formula (R)

reacting a compound of formula (R) to form a compound of formula (S)

reacting a compound of formula (S) to form the above compound of formula (V), and reacting a compound of formula (V) to form a compound of formula (1).

In this case, the steps for the formation of compounds of formulas (L), (M), (O) and (P) are similar to those illustrated previously and are not repeated. In addition, the step of forming the compound of formula (1) from the compound of formula (V) is also similar to the step illustrated previously and is not repeated.

In the step of reacting a compound of formula (P) to form a compound of formula (Q), the compound of formula (P) is reacted with pyridinium chlorochromate to form a compound of formula (Q).

In the step of reacting a compound of formula (Q) to form a compound of formula (R), the compound of formula (Q) is reacted with ethyl 4-aminobenzoate to form a compound of formula (R).

- 11 046002

In the step of reacting a compound of formula (R) to form a compound of formula (S), the compound of formula (R) is converted to a compound of formula (S) using a base such as LiOH, NaOH or KOH.

In the step of reacting a compound of formula (S) to form a compound of formula (V), the compound of formula (S) is converted to a compound of formula (V) using a chiral amine or chiral acid. Examples of a chiral amine may include, but are not limited to, (R)phenethylamine. Examples of a chiral acid may include, but are not limited to, (1R)-(-)-10 camphorsulfonic acid.

The present disclosed invention further provides another method for preparing the above compound of formula (2), comprising the following steps: converting the compound of formula (1) into the compound of formula (2).

In one embodiment, a compound of formula (1) can be converted to a compound of formula (2) using a base.

In the above embodiment, the base may be LiOH, NaOH or KOH.

The following embodiments are made to clearly demonstrate the above and other technical contents, features and/or effects of the present disclosed invention. Through explanation with the help of specific embodiments, people could better understand the technical means and effects that the present disclosed invention achieves the above-mentioned objects. Moreover, since the contents disclosed herein should be readily understood and can be implemented by one skilled in the art, all equivalent changes or modifications that do not depart from the spirit of the present disclosed invention are intended to be covered by the appended claims.

In addition, in the present description, the value of a value can be interpreted as covering a range within ±10% of that value and, in particular, a range within ±5% of that value, unless otherwise indicated; the range can be interpreted as being made up of multiple subranges defined by a minor endpoint, a minor quartile, a median, a major quartile, and a major endpoint unless otherwise noted.

Example

Without going into further detail, it is believed that one skilled in the art can, based on the above description, use the present disclosed invention to its fullest extent. Therefore, the following specific examples should be considered as illustrative only and in no way limiting the remainder of the invention disclosed. All publications cited herein are incorporated by reference in their entirety.

Unless otherwise noted, all starting materials used were commercially available and used as supplied. Reactions requiring anhydrous conditions were carried out in flame-dried glassware and cooled under argon or nitrogen. Unless otherwise stated, reactions were carried out under argon or nitrogen and monitored by analytical thin layer chromatography performed on glass backed plates (5 cm-10 cm) pre-coated with silica gel 60 F254, available from Merck. Visual observation of the resulting chromatograms was carried out under an ultraviolet lamp (λ=254 nm) followed by immersion in a solution of ninhydrin in n-BuOH (0.3% w/v) containing acetic acid (3% v/v), or in a solution of phosphomolybdic acid in ethanol (2.5% w/v) and firing using a heating hair dryer. Reaction solvents were dried under argon or nitrogen before use as follows: tetrahydrofuran (THF), toluene and dichloromethane (DCM) were dried on a 5A dry molecular sieve column (LC technologysolution Inc), and dimethylformamide (DMF) was used after calcium hydride or anhydrous , commercially available. Typically, flash chromatography has been used to purify and separate product mixtures using disposable RediSepRfSilicaGelDisposable Flash Columns, Gold® with 2040/40-60 µm silica gel and reusable ReusableRediSepRf Gold® C18 Reversed Phasecolumns, 20-40 µm , supplied by RediSep. Eluent systems are given in volume/volume concentrations. ¹³ C and ¹ H NMR spectra were recorded on a Bruker AVIII instrument (400 MHz). Chloroform-d or dimethyl sulfoxide-06 and CD3OD were used as solvent, aTMS (δ 0.00 ppm) as internal standard. Chemical shift values are in ppm. relative to TMS in units of delta (δ). Multiplicity is written as s (singlet), ush. s (wide singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet). Interaction constants (J) are expressed in Hz. Electrospray mass spectra (ESMS) were recorded using a Thermo LTQ XL mass spectrometer. Spectral data were recorded as m/z values.

- 12 046002

Example 1 Preparation of a compound of formula (1) or (2)

Scheme 1

Stage 1-a. Preparation of methyl-N,E)-4-(((tert-butylsulfinyl)imino)methyl)benzoate (A).

To a solution of methyl 4-formyl benzoate (500 g) in DCM (10 L) under N ₂ atmosphere at 15-35°C was added N)-2-methylpropane-2-sulfinamide (443 g, 3 mol), then finally , Cs ₂ CO ₃ (1172 g) was added. The mixture was stirred for 16 hours. The reaction mixture was filtered and the filtrate was dried by evaporation to give Compound A (720 g, 89%) as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.63 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz , 2H), 3.95 (s, 3H), 1.28 (s, 9H).

Stage 1-2. Preparation of methyl 4-(^)-1-((^)-tert-butylsulfinyl)amino)-2-methylpropyl)benzoate (B).

To a solution of compound A (106.8 g, 0.4 mol) in THF (954 ml) in an atmosphere of N ₂ at -25~-20°C was added a solution of ZnMe ₂ in toluene (1.2 M, 50 ml) over 20 min at -25-20°C. This reaction mixture was then kept under stirring for another 10 minutes at -25--20°C. A solution of isopropylmagnesium chloride in THF (2M, 240 ml) was added over 30 min and the temperature was maintained below -20°C. The mixture was stirred for an additional 1.5 hours at -25–20°C. The reaction was quenched with MeOH (25 ml) for 10 min at -20°C. Then a saturated solution of NH ₄ Cl(aq) (25 ml) was added at -10~0°C. The reaction temperature was returned to 15-25°C for one hour, then the mixture was filtered, the filtrate was dried by evaporation to obtain Compound B (124 g, 100%) as a colorless oil. ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.00 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 4.18 (t , J=6.4 Hz, 1H), 3.90 (s, 3H), 3.47 (d, J=6.4 Hz, 1H), 2.24-2.17 (m, 1H), 1 .23 (s, 9H), 0.93 (d, J=6.9 Hz, 3H), 0.80 (d, J=6.9 Hz, 3H). MS(M+1):312.

Stage 1-3. Preparation of 4-(^)-1-((^)-tert-butylsulfinyl)amino)-2-methylpropyl)benzoic acid (C).

To a solution of compound B (124 g, 0.4 mol) in EtOH (790 ml) at 20-30° C. was added NaOH (40 g) in deionized water (500 g). The mixture was stirred for 16 hours at 20-30°C or at 80-85°C for 2 hours. Then the reaction solvent was distilled off at 85-90°C in an amount of approximately 650 ml. The reaction mixture was neutralized with ΗΟ(^ _η .) (4N, 300-400 ml) at 4-6°C until pH = 4-5 and the formation of the desired solid. The solid was filtered and washed with deionized water (1000 g). This solid was stirred in acetone (300 ml) and MeOH (30 ml) for 30 minutes at 25-30°C, then filtered to give compound C (83 g, 70%) as a white solid. 1H-NMR (CDCl3, 400 MHz): δ 7.72 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 4.39 (d, J =6.8 Hz, 1H), 4.01 (t, J=6.8 Hz, 1H), 2.14-2.09 (m, 1H), 1.33 (s, 9H), 1.03 (d, J=6.9 Hz, 3H), 0.74 (d, J=6.9 Hz, 3H). MS(M+1): 298.

In addition, various recrystallization conditions were also investigated herein, and the results are shown in the following table. 1.

Table 1

Various recrystallization conditions used in step 1-3

Solvent A Solvent B T(°C) Exit(%) d.e.(%) Acetone MeOH 25-30 70 >99.5 Acetone TVME 25-30 90 90 Acetone Ether 25-30 95 85 Acetone EtOH 25-30 50 >99.5 Acetone — 25-30 80 95 EtOAc MeOH 25-30 65 95 - MeOH 25-30 thirty >99

- 13 046002

Scheme 2

Stage 1-b. Preparation of isopropyl-N,E)-4-(((tert-butylsulfinyl)imino)methyl)benzoate (A').

To a solution of methyl 4-formyl benzoate (50 g) in DCM (660 g) at 15-25°C was added (S)-2methylpropane-2-sulfinamide (44.4 g), purged 3 times with N ₂ , TTIP (173, 00 g) was slowly added to this mixture under a protective atmosphere of N2. The mixture was stirred for 16 hours at 20-25°C. When the temperature decreased to 5-10°C, 20% No. ₂ CO ₃ ( _B o _DN .) (150 g) and water (100 g) were added to this mixture to stop the reaction, the crude mixture was extracted with an additional amount of DCM (396 g). The aqueous layer was removed, and the organic layer was extracted with concentrated brine (200 g), then the concentrated brine layer was removed, anhydrous Na ₂ SO ₄ (25.00 g) was added to the organic layer, and then the mixture was filtered, and the filtrate was dried by evaporation and obtained Compound A' and Compound A (85:15, 81.46 g, 91%) as a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.63 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.8 Hz , 2H), 3.92 (m, 1H), 1.28 (s, 9H), 1.25 (d, J=6.9 Hz, 6H).

Stage 2-2. Preparation of isopropyl-4-(^)-1-((^)-tert-butylsulfinyl)amino)-2methylpropyl)benzoate (B').

To a solution of compound A' mixed with compound A (81.46 g) in THF (555 g) in an N2 atmosphere at -25-20°C, was added a solution of ZnMe ₂ in toluene (1 M, 39.1 g) over 20 minutes at -25-20°C. Then this reaction mixture was kept under stirring for another 10 minutes at -25-20°C. A solution of isopropyl magnesium chloride in THF (2M, 175.1 g) was added over 30 minutes and the temperature was maintained below -20°C. The mixture was stirred for an additional 1.5 hours at 25–20°C. The reaction was quenched with MeOH (21.1 g) for 10 min at -20°C. Then a saturated solution of K^O^da.) (21.1 g) was added at -10~0°C. The reaction temperature was returned to 15-25°C for one hour, then the mixture was filtered, the filtrate was dried by evaporation to obtain Compound B' and Compound B (85:15, 101.1 g, 100%) as a colorless oil. 1H-NMR (CDCI3, 400 MHz): δ 8.00 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 4.18 (t, J =6.4 Hz, 1H), 3.90 (s, ZN), 3.47 (d, J=6.4 Hz, 1H), 2.24-2.17 (m, 1H), 1.23 (s, 9H), 0.93 (d, J=6.9 Hz, ZN), 0.80 (d, J=6.9 Hz, ZN). MS(M+1): 340.

Stage 2-3. Preparation of 4-(^)-1-((^)-tert-butylsulfinyl)amino)-2-methylpropyl)benzoic acid (C).

To a solution of compound B' mixed with compound B (101.1 g) in EtOH (210 g) at 20-30° C. was added NaOH (61 g) in solution in deionized water (313 g). The mixture was stirred for 1.5 hours at 7075°C. Then the reaction solvent was distilled off at 85-90°C in an amount of approximately 650 ml. The reaction mixture was neutralized with HC1( _aq ) (4N, 550-600 ml) at 0-15°C to pH=1-2 and formation of the desired solid. The solid was filtered and washed with deionized water (300 g). This solid was stirred in acetone (180 g) and MeOH (16 g) for 30 min at 25-30°C and then filtered to give C (59.68 g, 66%).

- 14 046002

Scheme 3

m-N

Stage 3-4. Preparation of isopropyl-^)-M-(^)-1-(4-(2-benzoylhydrazine-1-carbonyl)phenyl)-2methylpropyl)-2-methylpropane-2-sulfinamide (D).

Benzohydrazide (37.4 g) and HBTU (123 g) were dissolved in THF (210 g) at 20-30°C, followed by the addition of Compound C (74 g, 0.25 mol). DIPEA (96.7 g) was charged into this solution and the mixture was stirred for 16 hours at 25-28°C. The mixture was filtered to remove unnecessary solids and then approximately 900 g of THF was removed by evaporation. Acetonitrile (ACN) (450 g) was added to the crude product to form a suspension solution and then stirred for approximately 2-2.5 hours, the solution was filtered to obtain product Compound D (103 g, 100%) as a white solid . 1H-NMR (CDCl3, 400 MHz): δ 9.17 (br.s, 1H), 7.89 (d, J=7.3 Hz, 2H), 7.77 (d, J=8.3 Hz , 2H), 7.537.34 (m, 5H), 4.15 (t, J=6.4 Hz, 1H), 2.24-2.19 (m, 1H), 1.24 (s, 9H) , 0.93 (d, J=6.9 Hz, 3H), 0.82 (d, J=6.9 Hz, 3H). MS(M+1): 416.

Stage 3-5. Preparation of ^)-2-methyl-N^)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)propane-2-sulfinamide (E).

Sulfinamide, compound D (74.9 g) was dissolved in dichloromethane (98.8 g) at 0-5° C. followed by the addition of p-toluenesulfonyl chloride (41.2 g). Triethylamine (54.7 g) was charged into this solution and the mixture was stirred for 6-8 hours at 0-5°C. 1.2M NaOH aqueous solution (393 mL) was added at the same temperature and stirred for 1 hour. The mixture was extracted with additional dichloromethane (100 g) and concentrated brine (150 g). Anhydrous Na ₂ SO ₄ (25.00 g) was added to the collected organic layer, and then the mixture was filtered and the filtrate was dried by evaporation. The residue was dissolved in methyl tert-butyl ether (48.7 g) and heptanes (44.9 g) were added to form a slurry mixture. The mixture was stirred for 4 hours and filtered to collect the product, Compound E (64.8 g, 90%) as a white solid. 1H-NMR (CDCl ₃ , 400 MHz): δ 8.158.10 (m, 4H), 7.57-7.53 (m, 3H), 7.45 (d, J=8.4 Hz, 2H), 4.22 (t, J=6.3 Hz, 1H), 3.51 (d, J=6.3 Hz, 1H), 2.28-2.21 (m, 1H), 1.26 (s , 9H), 0.98 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H). MS(M+1): 398.

Stage 3-6. Preparation of ^)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propan-1-amine (F) (compound (3-1)).

Sulfinamide, compound E (64.8 g) was dissolved in dichloromethane (98.8 g) at 15-25°C, followed by the addition of conc. HCl (162 g). The mixture was stirred for 4 hours at 25-30°C. The reaction solvent was removed by evaporation and purified water (162 g) was added. While cooling to 05°C, a 4M aqueous solution of NaOH (454.1) was added to adjust the pH to 11-12 at 0-15°C. The precipitated solid was filtered off and washed further with purified water (130 g). This precipitated solid was recrystallized from MeOH (40.2 g) at 30-40°C to form a clear solution and stirred for 4 hours at 20-25°C. The solid was filtered again and dried in vacuo to give Compound F (40.3 g, 84%) as a white solid. 1H-NMR (CDCl ₃ , 400 MHz): δ 8.17-8.08 (m, 4H), 7.58-7.46 (m, 5H), 3.73 (d, J=6.9 Hz , 1H), 1.94-1.86 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.82 (d, J=6.9 Hz, 3H). MS(M+1): 294.

- 15 046002

Scheme 4

Stage 1-c. Preparation of methyl (E)-4-(((diphenylphosphoryl)imino)methyl)benzoate (G).

To a solution of methyl 4-formyl benzoate (50 g) in DCM (1 L) under N2 atmosphere at 15-35°C was added P,Pdiphenylphosphinamide (66 g, 1 eq.) and 4A MS molecular sieves (250 g), then finally, pyrrolidine (4.3 g, 0.2 eq.) was added. The mixture was stirred at 65°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was dried by evaporation. The residue was then purified by silica gel chromatography to give Compound G (77 g, 70%) as a white solid.

Stage 4-2. Preparation of methyl-^)-4-(1-((diphenylphosphoryl)amino)-2-methylpropyl)benzoate (H).

To a solution of compound G (144 g) in THF (555 g) under N2 atmosphere at -25~-20°C was added a solution of ZnMe ₂ in toluene (1M, 39.1 g) for 20 minutes at 25~-20°C. . Then the reaction was kept with stirring for another 10 minutes at -25–20°C. A solution of isopropyl magnesium chloride in THF (2M, 175.1 g) was added over 30 minutes and the temperature was maintained below -20°C. This mixture was stirred for an additional 1.5 hours at -25-20°C. The reaction was quenched with MeOH (21.1 g) for 10 min at -20°C. Then saturated NII4C1,aq, (21.1 g) was added at -10~0°C. The reaction temperature returned 15-25°C for one hour, then the mixture was filtered and the filtrate was dried by evaporation to obtain compound H (90:10, 162.8 g, 100%). 1H-NMR (CDCl ₃ , 400 MHz): δ 8.35-8.15 (m, 10H), 8.00 (d, J=8.8 Hz, 2H), 7.91 (d, J=8 ,8 Hz, 2H), 4.18 (t, J=6.4 Hz, 1H), 3.90 (s, 3H), 3.47 (d, J=6.4 Hz, 1H), 2, 24-2.17 (m, 1H), 1.23 (s, 9H), 0.93 (d, J=6.9 Hz, 3H), 0.80 (d, J=6.9 Hz, 3H ). MS(M+1): 408.

Stage 4-3. Preparation of ^)-4-(1-((diphenylphosphoryl)amino)-2-methylpropyl)benzoic acid (I).

To a solution of compound H (132 g) in EtOH (210 g) at 20-30°C was added NaOH (61 g) in solution in deionized water (313 g). The mixture was stirred for 1.5 hours at 70-75°C. Then the reaction solvent was distilled off at 85-90°C in an amount of approximately 650 ml. The reaction mixture was neutralized with HCl( _aq ) (4N, 550-600 ml) at 0-15°C to pH=1-2 and formation of the desired solid. This solid was filtered and washed with deionized water (300 g). The solid was stirred in acetone (180 g) and MeOH (16 g) for 30 min at 25-30°C and then filtered to give compound I (89.3 g, 70%).

Scheme 5

Stage 5-4. Preparation of N)-N1-(4-(2-benzoylhydrazine-1-carbonyl)phenyl)-2-methylpropyl)-P,Pdiphenylphosphinamide (J).

Benzohydrazide (37.4 g) and HBTU (123 g) were dissolved in THF (210 g) at 20-30°C, followed by the addition of compound I (98.35 g, 0.25 mol). DIPEA (96.7 g) was charged into this solution and the mixture was stirred for 16 hours at 25-28°C. This mixture was filtered to remove unnecessary solids

- 16 046002 and then approximately 900 g of THF were removed by evaporation. Acetonitrile (450 g) was added to the crude material to form a slurry solution and then stirred for approximately 2-2.5 hours, the solution was filtered to collect the product, Compound J (127.9 g, 100%) as a white solid. 1H-NMR (CDCl3, 400 MHz): δ 9.17 (br.s, 1H), 8.48-8.23 (m, 10H), 7.89 (d, J=7.3 Hz, 2H) , 7.77 (d, J=8.3 Hz, 2H), 7.53-7.34 (m, 5H), 4.15 (t, J=6.4 Hz, 1H), 2.24- 2.19 (m, 1H), 1.24 (s, 9H), 0.93 (d, J=6.9 Hz, 3H), 0.82 (d, J=6.9 Hz, 3H). MS (M+1): 512.

Stage 5-5. Preparation of N)-N-(2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)-P,Pdiphenylphosphinamide (K).

Compound J (92 g) was dissolved in dichloromethane (98.8 g) at 0-5° C., followed by the addition of p-toluenesulfonyl chloride (41.2 g). Triethylamine (54.7 g) was charged into this solution and the mixture was stirred for 6-8 hours at 0-5°C. An aqueous solution of 1.2M NaOH (393 ml) was added at the same temperature and stirred for 1 hour. The mixture was extracted with additional dichloromethane (100 g) and concentrated saline (150 g). Anhydrous Na ₂ SO ₄ (25.00 g) was added to the collected organic layer, and then the mixture was filtered and the filtrate was dried by evaporation. The residue was dissolved in methyl tert-butyl ether (48.7 g) and heptanes (44.9 g) were added to form a slurry mixture. This mixture was stirred for 4 hours and filtered to collect the product, compound K (66.6 g, 75%) as a white solid. ^1H -NMR ( _CDCl3 , 400 MHz): δ 8.38-8.13 (m, 10H), 8.15-8.10 (m, 4H), 7.57-7.53 (m, 3H ), 7.45 (d, J=8.4 Hz, 2H), 4.22 (t, J=6.3 Hz, 1H), 3.51 (d, J=6.3 Hz, 1H), 2.28-2.21 (m, 1H), 1.26 (s, 9H), 0.98 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz , 3H). MS(M+1): 494.

Stage 5-6. Preparation of ^)-2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propan-1-amine (F) (compound (3-1)).

Compound K (80.4 g) was dissolved in dichloromethane (98.8 g) at 15-25°C, followed by the addition of conc. HCl (162 g). The mixture was stirred for 4 hours at 25-30°C. The reaction solvent was removed by evaporation and purified water (162 g) was added. When the temperature decreased to 0-5°C, an aqueous solution of 4MNaOH (454.1) was added to adjust the pH to 11-12 at 0-15°C. The precipitated solid was filtered off and washed further with purified water (130 g). This precipitated solid was recrystallized from MeOH (40.2 g) at 30-40°C to form a clear solution and stirred for 4 hours at 20-25°C. The solid was filtered again and dried in vacuo to give Compound F (36 g, 75%).

Scheme 6

Stage 6-1. Preparation of methyl 4-(1-hydroxy-2-methylpropyl)benzoate (L).

A solution of methyl 4-formyl benzoate (9.84 g, 60.0 mmol) in tetrahydrofuran (30 ml) was cooled to 78°C. To this solution, 2M/isopropyl magnesium chloride (30 ml) was added dropwise over 20 minutes. The reaction mixture was stirred at -78°C for 2 hours. The reaction was then quenched by adding saturated aqueous ammonium chloride. This mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by chromatography on silica gel gave methyl 4-(1-hydroxy-2-methylpropyl)benzoate, compound L. Colorless oil, yield (4.5 g, 36%).

Stage 6-2. Preparation of 4-(1-hydroxy-2-methylpropyl)benzohydrazide (M).

To a solution of methyl 4-(1-hydroxy-2-methylpropyl)benzoate (4.5 g, 21.59 mmol) in absolute EtOH (30 mL) was added hydrazine monohydrate (2.50 g, 50 mmol) at room temperature. The reaction mixture was refluxed overnight, then cooled to room temperature

- 17 046002 and concentrated under reduced pressure. The residue was suspended in 60 ml H2O, filtered, washed with H2O (2x50 ml) and EtOH (2x40 ml) to give the title compound M as an off-white solid (3.59 g, 80%).

Stage 6-3. Preparation of N-benzoyl-4-(1-hydroxy-2-methylpropyl)benzohydrazide (O).

Compound M (1.04 g, 5 mmol) was added to a solution of benzoic acid (0.67 g, 5.5 mmol), EDCI (1.44 g, 7.5 mmol) and HOBt (1.15 g, 7.5 mmol). 5 mmol) in 20 ml DMF. The reaction was stirred at room temperature overnight, then concentrated in vacuo. Water was added to the residue, and the aqueous layer was extracted with ethyl acetate. It was then further concentrated in vacuo to give a white solid, Compound O (0.99 g, 64%).

Stage 6-4. Preparation of 2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propan-1-ol (P).

Compounds O (0.99 g, 3.2 mmol), TsCl (0.91 g, 4.8 mmol) and TEA (1.5 ml, 9.6 mmol) were mixed in ACN (20 ml) and stirred at room temperature temperature for 1 hour. This reaction solution was concentrated to remove methanol and extracted with EtOAc. The organic layer was washed with water and dried over anhydrous magnesium sulfate. It was filtered and the solvent was evaporated under reduced pressure. Purification of the residue from the crude oil by column chromatography (ethyl acetate:hexane=30:100) gave a white solid, compound P (0.76 g, 81%).

Stage 6-5. Preparation of 2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propan-1-one (Q).

Compound P (0.76 g, 2.6 mmol) was dissolved in DCM (26 ml) and pyridinium chlorochromate (1.12 g, 5.2 mmol) was added. The reaction was stirred at room temperature for 2 hours. The solution was filtered through Celite-545 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (ethyl acetate:hexane=10:100). The product, compound Q, was a white solid (0.72 g, 95%).

Stage 6-6. Preparation of ethyl 4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzoate (R).

To a solution of compound Q (17 g, 58 mmol) in methanol (500 ml) were added ethyl 4-aminobenzoate (9 g, 53 mmol) and decaborane (4 g, 32 mmol) and stirred overnight. The reaction was monitored by TLC. After the starting material was consumed, it was extracted with EtOAc and H ₂ O, dried with Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:hexane=30:100) to give a white solid, compound R (18.7 g, 80%).

Stage 6-7. Preparation of 4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzoic acid (S).

Compound R (18.7 g, 42.4 mmol) was dissolved in dioxane (42 ml) followed by the addition of LiOH(aq) (2M, 42 ml). The reaction mixture was heated to 60°C for 1 hour. The reaction was monitored by TLC. Upon completion of the reaction, the solvent was removed by rotary evaporation and HC1( _aq ) was added to pH 4~5. The mixture was extracted with EtOAc. The combined organic layer was dried with anhydrous MgSO ₄ and concentrated in vacuo to give a crude white solid, compound S (17.5 g, 100%).

Stage 6-8. Preparation of ^)-4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzoic acid (V).

Compound S (18 g, 43.5 mmol) was dissolved in THF (144 ml) (solvent A) followed by the addition of N-phenethylamine (6.32 g, 1.2 eq). The mixture was stirred at 15-25°C for 12 hours. The precipitated solid was filtered and washed with additional THF (18 ml). The filter cake was dried in vacuum at 45-55°C for 4 hours. This crude product was dissolved in acetone (75 ml) (solvent B) and heated to 45-50°C for 4 hours, then cooled to 5-10 °C for 6 hours. The mixture was filtered and washed with additional acetone (21 ml). The pure salt was dried in vacuum at 45-55°C for 8 hours. Finally, this salt (15 g) was dissolved in MeOH (105 ml) followed by the addition of pure water (22.5 ml) and citric acid (7.5 g ). The mixture was stirred at 15-25°C for 6 hours. The solution was concentrated in vacuo and then pure water (125 ml) was added to suspend the mixture. After 1 hour, the mixture was filtered and the solid was washed with clean water (60 ml). This solid was dried in vacuo at 40-45°C to give Compound V (6.3 g, 35%, >99.5% eu).

In addition, various chiral acids or chiral amines were also investigated herein, and the results are shown in the following table. 2.

- 18 046002

table 2

Various reaction conditions used in step 6-8

Chiral amine or chiral acid Solvent A Solvent IN Exit(%) her.(%) Methanesulfonic acid THF - 95 0 (1R)-(-)-10camphorsulfonic acid THF Acetone 10 80 (Sform) (1S)-(-)-10- camphorsulfonic acid THF Acetone 5 85 (Yaforma) 1_(+)-tartaric acid THF - 95 0 O(+)-tartaric acid THF - 95 0 1_-(+)-mandelic acid THF - 95 0 1_-(-)-malic acid THF - 95 0 (-)-2,3-dibenzoyl-L- wine acid THF - 95 0 (I)-phenethylamine THF Acetone 35 >99.5 (Sform) (8)-phenethylamine THF Acetone 20 97 (Yaforma) (I)-phenethylamine THF EYAs 15 95 (Sform) (I)-phenethylamine THF Acetonitrile 15 95 (Sform) (I)-phenethylamine THF EUN 17 >99.5 (Sform)

Scheme 6b

Preparation of (rac)-2-methyl-1 -(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propan-1-amine (F1).

Compound P can be easily converted into compound P1 using methanesulfonyl chloride under basic conditions. Compound P1 was treated with sodium azide to obtain compound P2. On the other hand, compound P can also be converted to compound R3 by the Mitsunobus reaction with allyl amine or benzyl amine. Compound P2 was converted to racemic compound F1c using the Staudinger reaction. Compound P3 was converted to compound F1c by hydrogenolysis on activated carbon. The precipitated solid was filtered off and washed further

- 19 046002 purified water. This precipitated solid was recrystallized from MeOH at 30-40°C to form a clear solution and stirred for 4 hours at 20-25°C. The solid was again filtered and dried in vacuo to obtain compound F1.

Scheme 7

Stage 7-a. Preparation of ethyl-^)-4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzoate (U).

The chiral amine compound F (43.3 g, 147 mmol) was dissolved in toluene (350 ml) at 15-25°C. The mixture atmosphere was changed with N2 3 times. The temperature was then raised to 40-45°C and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (18.6 g) was added followed by cesium carbonate (14.4 g). Then the temperature was raised to 60-65°C and palladium(II) acetate (3.3 g) was added to this mixture and heated to 80-85°C, followed by the addition of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)benzoate (127.7 g) in toluene (86 ml). The temperature of the reaction mixture was raised to reflux temperature and stirred for 3 hours. After this, the temperature was reduced to 20-30°C, ethyl acetate (385 g) was added to this mixture and stirred for 0.5 hours, after which the mixture was filtered via celite545. The filtrate was extracted with water (433 ml) and NaHSO ₃ (130 g), then activated carbon (4.3 g) was added to the organic layer and stirred for 2 hours at 80-85°C, the mixture was again quickly filtered through Celite-545. The solution was extracted with ethylenediaminetetraacetate disodium salt dihydrate (0.13M, 430 ml). The organic layer was extracted with 220 ml of aqueous saturated NaCl solution and then dried with 43 g of anhydrous MgSO ₄ . The mixture was then filtered and dried by evaporation. The crude product was recrystallized from 170 g of anhydrous ethanol at 75-80°C for 1 hour, then cooled to 20-25°C, kept at 0-5°C for 16 hours, the solid was collected by filtration and dried under vacuum at 40 -45°C to obtain compound U (45 g, 70%) as a white solid. 1H-NMR (CDCis, 400 MHz): δ 8.14-8.08 (m, 4H), 7.78 (d, J=8.8 Hz, 2H), 7.56-7.51 (m, 3H), 7.46 (d, J=8.8 Hz, 2H), 6.47 (d, J=8.8 Hz, 2H), 4.56 (d, J=5.9 Hz, 1H) , 4.29-4.24 (m, 3H), 2.16-2.08 (m, 1H), 1.31 (t, J=6.8 Hz, 3H), 1.02 (d, J =6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H). MS(M+1): 442.

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 3.

Table 3

Various reaction conditions used in step 7-a

Ligand Base Solvent T(°C) Exit(%) her.(%) BINAP CS2CO3 Toluene 110 - 115 70 >99.5 XPhos CS2CO3 Toluene 110 - 115 89 90

- 20 046002

SPhos CS2CO3 Toluene 110 - 115 77 90 CyJohnPhos CS2CO3 Toluene 110 - 115 80 <90 BrettPhos CS2CO3 Toluene 110 - 115 33 n.d. BINAP CS2CO3 THF 65-70 45 n.d. BINAP CS2CO3 Dioxane 100 - 105 50 n.d. BINAP NaOtBu Toluene 110 - 115 60 n.d. BINAP KOtBu Toluene 110 - 115 55 n.d.

Stage 7-8. Preparation of ^)-4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzoic acid (V).

Benzoate, compound U (80 g, 193 mmol) was dissolved in THF (210 g) at 15-25°C. Methanol (190 g) was added and then the temperature was raised to 40-45°C. An aqueous solution of LiOH (2M, 255 g) was charged into this pure solution and stirred for 22 hours at 40-45°C. The temperature was reduced to 20-25°C. Pure water (360 ml) was added to the solution and then extracted with ethyl acetate (30 g) and heptanes (120 g), the organic layer was removed, citric acid (27 g) was added to the aqueous layer and the pH was adjusted to 4-5. The organic solvent from the solution was removed by evaporation at 40-45°C, then cooled to 10-15°C over 4 hours. The mixture was filtered and washed with water (320 ml). The solid was collected and dried in vacuo at 40-45°C to give Compound V (74 g, 98%) as a white solid. 'H-NMR (CDCl3, 400 MHz): δ 8.11-8.04 (m, 4H), 7.64-7.56 (m, 7H), 6.94 (d, J=7.8 Hz , 1H), 6.60 (d, J=8.8 Hz, 2H), 4.28 (t, J=7.8 Hz, 1H), 2.09-2.01 (m, 1H), 1 .03 (d, J=6.9 Hz, 3H), 0.81 (d, J=6.9 Hz, 3H). MS(M+1): 414.

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 4.

Table 4

Various reaction conditions used in step 7-8

Base Solvent T(°C) Time(h) Exit(%) NaOH EtOH 40-45 16 80 NaOH EtOH 60-65 4 70 NaOH EtOH 75-80 2 60 NaOH MeOH/THF 40-45 16 85 NaOH MeOH/THF 50-55 12 75 LiOH EtOH 40-45 8 80 LiOH EtOH 60-65 3 65 LiOH MeOH/THF 40-45 16 98 LiOH MeOH/THF 50-55 12 85

Stage 7-9. Preparation of ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoate (formula (1)).

Benzoic acid, compound V (120 g, 234 mmol) was dissolved in DMF (793 g) at 15-20°C under a protective atmosphere of N ₂ . The temperature was reduced to 0-10°C followed by the addition of BHTU (142.8 g). The mixture was stirred for 10 minutes at 0-10°C and then ethyl 3-aminopropanoate hydrochloride (60 g) was added. Finally, DIPEA (112.8 g) was added dropwise to the reaction mixture over 0.5 h. The mixture was stirred for an additional 4 hours at 0-10°C, then added dropwise to a solution of pure water (3700 ml) and sodium bicarbonate (166 g) over approximately 0.5 hour to form a suspension solution. This solution was then filtered and the filter cake was washed with another clean water (150 ml). The filter cake was dissolved in ethyl acetate (756 g) at 0-10°C, then HCl (1N, 120 ml) was added and stirred for 0.5 h. After removing the aqueous layer, the organic layer was extracted with 4.8 g of aqueous sodium bicarbonate solution (in 120 ml of water). The organic layer was extracted with saturated aqueous NaCl (360 ml) and then dried with anhydrous MgSO ₄ (65 g). The mixture was then filtered and dried by evaporation. The crude product was recrystallized from anhydrous ethanol (240 g) at 75-80°C for 1 hour, then cooled to 20-25°C for 16 hours, the solid was collected by filtration and dried under vacuum at 40-45°C to obtain compound of formula (1) (105 g, 70%) as a white solid. 1H-NMR (CDCl ₃ , 400 MHz): δ 8.13-8.07 (m, 4H), 7.56-7.51 (m, 5H), 7.45 (d, J=8.8 Hz , 2H), 6.60 (t, J=5.8 Hz, 1H), 6.48 (d, J=8.8 Hz, 2H), 4.26 (d, J=5.8 Hz, 1H ), 4.12 (kv, J=6.8 Hz, 2H), 3.66-3.62 (m, 2H), 2.57 (t, J=5.8 Hz, 2H), 2.14 -2.10 (m, 1H), 1.23 (t, J=6.8 Hz,

- 21 046002

3H), 1.03 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H). MS(M+1): 513.

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 5.

Table 5

Various reaction conditions used in step 7-9

Condensing reagent Solvent Time(h) Exit(%) EDCI/HOBt THF 12 70 EDCI/HOBt DMF 8 75 HBTU DMF 4 70 HBTU THF 8 72 HATU DMF 4 65 CDMT DMF 4 50 RuVOR THF 8 82

Stage 7-10. Preparation of ^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid (formula ( 2)).

The compound of formula (1) (62.9 g) was dissolved in MeOH (250 ml) or MeOH/THF (125/125 ml) at 1525°C. To this mixture was added NaOH (aq) (2M, 123 ml) and stirred for 15 hours. The reaction solvent was removed by rotary evaporation and the residue was added with ethyl acetate (500 ml) and extracted with aqueous citric acid (38.6 g/ 1 l). The organic layer was extracted with saturated aqueous NaCl (180 ml), then dried with anhydrous MgSO ₄ (30 g). The mixture was then filtered and dried by evaporation. The crude product was recrystallized from anhydrous ethanol (120 g) at 75-80°C for 1 hour, then cooled to 20-25°C for 16 hours, the solid was collected by filtration and dried under vacuum at 40-45°C to obtain compound of formula (2) (45 g, 75%) as a white solid. 1H-NMR (DMSO-d^ 400 MHz): δ 8.13-7.96 (m, 5H), 7.65-7.59 (m, 4H), 7.49 (d, J=8.8 Hz, 2H), 6.66 (d, J=7.8 Hz, 1H), 6.57 (d, J=8.8 Hz, 2H), 4.29 (d, J=5.8 Hz, 1H), 3.38-3.33 (m, 2H), 2.40 (t, J=5.8 Hz, 2H), 2.08-2.03 (m, 1H), 1.04 (d , J=6.9 Hz, 3H), 0.83 (d, J=6.9 Hz, 3H). MS(M+1): 485.

Scheme 8

stage/-o

Stage 7-b. Preparation of ethyl-^)-4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzoate (U).

The chiral amine compound F (50 g, 170 mmol) was dissolved in toluene (600 ml) at 15-25°C. The mixture atmosphere was changed 3 times with N2. The temperature was then raised to 40-45°C and 2,2'bis(diphenylphosphino)-1,1'-binaphthyl (21.2 g) was added followed by cesium carbonate (166 g). The temperature was then raised to 60-65°C and palladium(P) acetate (1.9 g) was added to the mixture and heated to 8085°C, followed by the addition of ethyl 4-bromobenzoate (46.8 g). The reaction temperature was raised to reflux and stirred for 4 hours. After this, the temperature was reduced to 20-30°C, ethyl acetate (440 g) was added to this mixture and stirred for 5 minutes, after which the mixture was filtered through celite. 545. The filtrate was extracted with water (500 ml) and NaHSO ₃ (150 g), then activated carbon (0.43 g) was added to the organic layer and stirred for 10 minutes at 80-85°C, and the mixture was again quickly filtered through celite. 545. The solution was extracted with Na ₂ EDTA (0.13M, 500 ml)/H ₂ O/ethylenediaminetetraacetate disodium dihydrate (1:2:1). The organic layer was extracted with saturated aqueous NaCl (250 ml) and then dried with anhydrous MgSO ₄ (50 g). The mixture was then filtered and dried by evaporation. The crude product was recrystallized from anhydrous ethanol (50 g) at 75-80°C for 1 hour, then cooled to 20-25°C, kept at 0-5°C for 16 hours, the solid was collected by filtration and dried under vacuum at 40-45°C to obtain compound U (56 g, 75%).

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 6.

- 22 046002

Table 6

Various reaction conditions in step 7-b

Pd cat. Ligand Base Solvent T(°C) Exit(%) her.(%) Pd(OAc) ₂ BINAP _{Cs2CO3 _} T oluene 110 - 115 75 >99.5 Pd(OAc) ₂ XPhos _{Cs2CO3 _} Toluene 110 - 115 84 90 Pd(OAc) ₂ SPhos _{Cs2CO3 _} Toluene 110 - 115 70 90 Pd(OAc) ₂ CyJohnPhos _{Cs2CO3 _} T oluene 110 - 115 78 <90 Pd(OAc) ₂ BrettPhos _{Cs2CO3 _} Toluene 110 - 115 thirty n.d. Pd ₂ (dba) ₃ XPhos _{Cs2CO3 _} Toluene 110 - 115 95 92 Pd(OAc) ₂ BINAP _{Cs2CO3 _} THF 65-70 n.d. n.d. Pd(OAc) ₂ BINAP _{Cs2CO3 _} Dioxane 100 - 105 45 n.d. Pd(OAc) ₂ BINAP NaOtBu T oluene 110 - 115 65 n.d. Pd(OAc) ₂ BINAP KOtBu Toluene 110 - 115 50 n.d.

Scheme 9

Stage 1-c. Preparation of ethyl-^)-4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzoate (U).

Chiral amine, compound F (50 g, 170 mmol) was dissolved in toluene (600 ml) at 15-25°C. The mixture atmosphere was changed 3 times with N ₂ . The temperature was then raised to 40-45°C and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (21.2 g) was added followed by cesium carbonate (166 g). The temperature was then raised to 60-65°C and palladium(II) acetate (1.9 g) was added to the mixture and heated to 80-85°C followed by the addition of ethyl 4-iodobenzoate (56.3 g). The reaction temperature was raised to reflux and stirred for 4 hours. After this, the temperature was reduced to 20-30°C, ethyl acetate (440 g) was added to this mixture and stirred for 5 minutes, after which the mixture was filtered through celite. 545. The filtrate was extracted with water (500 ml) and NaHSO ₃ (150 g), then activated carbon (0.43 g) was added to the organic layer and stirred for 10 minutes at 80-85°C, and the mixture was again quickly filtered through celite. 545. The solution was extracted with ethylene diamine tetraacetate dihydrate (0.13 M, 500 ml). The organic layer was extracted with saturated aqueous NaCl (250 ml) and then dried with anhydrous MgSO ₄ (50 g). The mixture was then filtered and dried by evaporation. The crude product was recrystallized from anhydrous ethanol (50 g) at 75-80°C for 1 hour, then cooled to 20-25°C, kept at 05°C for 16 hours, the solid was collected by filtration and dried under vacuum at 40 -45°C to give compound U (36.5 g, 49%).

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 7.

- 23 046002

Table 7

Various reaction conditions in step 7-c

Pd cat. Ligand Base Solvent T(°C) Exit(%) e.e.(%) Pd(OAc) ₂ BINAP _{Cs2CO3 _} T oluene 110-115 49 97 Pd(OAc) ₂ XPhos _{Cs2CO3 _} T oluene 110-115 68 94 Pd ₂ (dba) ₃ XPhos _{Cs2CO3 _} T oluene 110-115 55 90 Pd(OAc) ₂ BINAP _{Cs2CO3 _} THF 65-70 N.D. n.d. Pd(OAc) ₂ BINAP _{Cs2CO3 _} Dioxane 100-105 20 N.D. Pd(OAc) ₂ BINAP NaOtBu T oluene 110-115 40 n.d. Pd(OAc) ₂ BINAP KOtBu T oluene 110-115 35 n.d.

Scheme 10

Stage 7-d Formula (1}

Stage 7-d. Preparation of ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl))phenyl)propyl)amino)benzamido)propanoate (formula ( 1)).

The chiral amine compound F (5 g, 17 mmol) was dissolved in toluene (60 ml) at 15-25°C. The mixture atmosphere was changed 3 times with N2. The temperature was then raised to 40-45° C. and 2,2'bis(diphenylphosphino)-1,1'-binaphthyl (2.12 g) was added followed by cesium carbonate (16.6 g). Then the temperature was raised to 60-65°C and palladium(P) acetate (0.38 g) was added to the mixture and heated to 80-85°C, followed by the addition of ethyl 3-(4-bromobenzamido)propanoate (6.1 g ). The reaction temperature was raised to reflux and stirred for 2.5 hours. Palladium(II) acetate (0.2 g) was added to this mixture and stirred for an additional 2 hours. After this, the temperature was reduced to 20-30° C, ethyl acetate (44 g) was added to this mixture and stirred for 5 minutes, after which the mixture was filtered through Celite-545. The filtrate was extracted with water (50 ml) and NaHSO ₃ (15 g), then the organic layer was extracted with ethylenediaminetetraacetate disodium salt dihydrate (0.13 M, 50 ml). The organic layer was extracted with saturated aqueous NaCl (25 ml) and then dried with anhydrous MgSO ₄ (5 g). The mixture was then filtered and dried by evaporation. The crude product was recrystallized from anhydrous ethanol (10 g) at 75-80°C for 1 hour, then cooled to 20-25°C, kept at 0-5°C for 16 hours, and the solid was collected by filtration and dried under vacuum at 40-45°C to obtain the compound of formula (1) (5.6 g, 64%).

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 8.

Table 8

Various reaction conditions in step 7-d

Ligand Base Solvent T(°C) Exit(%) her.(%) BINAP CS2CO3 Toluene 110-115 64 >99.5 XPhos CS2CO3 Toluene 110-115 60 94 BINAP CS2CO3 THF 65-70 n.d. n.d. BINAP CS2CO3 Dioxane 100-105 thirty n.d. BINAP NaOtBu Toluene 110-115 47 n.d. BINAP KOtBu Toluene 110-115 45 n.d.

Scheme 11

- 24 046002

Stage 7th. Preparation of ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoate (formula (1 )).

The chiral amine compound F (5 g, 17 mmol) was dissolved in toluene (60 ml) at 15-25°C. The mixture atmosphere was changed 3 times with N2. The temperature was then raised to 40-45°C and 2,2'bis(diphenylphosphino)-1,1'-binaphthyl (2.12 g) was added followed by cesium carbonate (16.6 g). Then the temperature was raised to 60-65°C and palladium(P) acetate (0.38 g) was added to the mixture and heated to 80-85°C, followed by the addition of ethyl 3-(4-iodobenzamido)propanoate (7.1 g ). The temperature of the reaction mixture was raised to reflux and stirred for 2.5 hours. Palladium(II) acetate (0.2 g) was added to this mixture and stirred for an additional 2 hours. After this, the temperature was reduced to 20-30 °C, ethyl acetate (44 g) was added to this mixture and stirred for 5 minutes, and then the mixture was filtered through Celite-545. The filtrate was extracted with water (50 ml) and NaHSO ₃ (15 g), then the organic layer was extracted with ethylenediaminetetraacetate disodium salt dihydrate (0.13 M, 50 ml). The organic layer was extracted with saturated aqueous NaCl (25 ml) and then dried with anhydrous MgSO ₄ (5 g). The mixture was then filtered and dried by evaporation. The crude product was purified by flash chromatography (ethyl acetate:hexane = 55%~60%) to give the compound of formula (1) (1.3 g, 15%).

In addition, various reaction conditions were also investigated herein, and the results are shown in the following table. 9.

Table 9

Various reaction conditions in step 7

Ligand Base Solvent T(°C) Exit(%) her.(%) IN IN AR CS2CO3 Toluene 110-115 15 >99.5 XPhos CS2CO3 Toluene 110-115 50 94 IN IN AR CS2CO3 THF 65-70 n.d. n.d. IN IN AR CS2CO3 Dioxane 100-105 n.d. n.d. IN IN AR NaOtBu Toluene 110-115 n.d. n.d. IN IN AR KOtBu Toluene 110-115 n.d. n.d.

Example 2. Preparation of the crystalline form of the compound of formula (1).

Ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoate (10 g) was dissolved in EtOH (25 ml) and then heated to reflux and maintained at this temperature for 1 hour, then cooled to 5-10°C and maintained at this temperature for 12 hours, a solid formed. This solid was then filtered and dried under vacuum at 45-50°C to obtain a crystalline form. Yield: 5 g.

An X-ray diffraction pattern of the resulting crystalline form of the compound of formula (1) was obtained using a BrukerD2 Phaser and the result is shown in FIG. 1. This XRD pattern includes peaks at approximately 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 21.7° 2θ. In addition, DSC data of the resulting crystalline form of the compound of formula (1) was obtained using a PerkinElmerPyris 1 instrument, and the resulting DSC curve indicates that the peak melting endotherm of the resulting crystalline form of the compound of formula (1) is located at approximately 137.7°C.

Example 3 Preparation of the crystalline form of the compound of formula (1).

Ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoate (30 g) was dissolved in ethyl acetate (60 ml) at 20-30°C and kept at this temperature for 3-4 hours, a solid formed. This solid was then filtered and dried under vacuum at 45-50°C to obtain a crystalline form. Yield: 15 g.

The XRD pattern and DSC curve of the crystalline form of the compound of formula (1) in the present example were obtained by methods similar to those used in example 2.

The XRD diffraction pattern of the resulting crystalline form of the compound of formula (1) is shown in FIG. 2, which includes peaks at approximately 14.2, 15.6, 16.4, 17.4, 20.1, 20.5, 21.2 and 23.7° 2θ. In addition, the obtained DSC curve indicates that the peak of the melting endotherm of the obtained crystalline

- 25 046002 form of the compound of formula (1) is at approximately 136.1°C.

Example 4 Preparation of the crystalline form of the compound of formula (1).

Ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoate (10 g) was dissolved in acetone (30 ml) and then heated to reflux and maintained at this temperature for 1 hour, then cooled to 15-25°C and maintained at this temperature for 12 hours, and a solid formed. This solid was then filtered and dried under vacuum at 45-50°C to obtain a crystalline form. Yield: 3 g.

The XRD pattern and DSC curve of the crystalline form of the compound of formula (1) in the present example were obtained by methods similar to those used in example 2.

The XRD diffraction pattern of the resulting crystalline form of the compound of formula (1) is shown in FIG. 3, which includes peaks at approximately 14.2, 15.6, 16.4, 20.1, 20.5, 21.2, 21.7 and 23.7° 2θ. In addition, the resulting DSC curve indicates that the peak melting endotherm of the resulting crystalline form of the compound of formula (1) is located at approximately 137.9°C.

Example 5 Preparation of the crystalline form of the compound of formula (1).

Ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoate (10 g) was dissolved in ethyl acetate (30 ml), and then heated to reflux for 1 hour, and n-heptane (45 ml) was added at this temperature over 5 minutes. The mixture was stirred for an additional 1 hour, then cooled to 15-25°C and maintained at this temperature for 12 hours, during which time a solid formed. This solid was then filtered and dried under vacuum at 45-50°C to obtain a crystalline form. Yield: 9.5 g.

The XRD pattern and DSC curve of the crystalline form of the compound of formula (1) in the present example were obtained by methods similar to those used in example 2.

The XRD diffraction pattern of the resulting crystalline form of the compound of formula (1) is shown in FIG. 4, which includes peaks at approximately 14.2, 15.6, 16.4, 17.3, 20.1, 20.5, 21.2 and 23.7° 2θ. In addition, the resulting DSC curve indicates that the peak melting endotherm of the resulting crystalline form of the compound of formula (1) is located at approximately 136.2°C.

Examples 6-11 and comparative examples 1-5. Preparation of the crystalline form of the compound of formula (1).

In Examples 6-11 and Comparative Examples 1-5 (cf. Examples 1-5 in Table 10), various recrystallization conditions were used to obtain the crystalline form of the compound of formula (1). The solvents used in Examples 6-11 and Comparative Examples 1-5 are listed in Table. 10 below, and the methods used in these Examples 6-11 and Comparative Examples 1-5 are similar to those used in Examples 2-5 and are not described again. In table 10 O and X in the DSC column respectively indicate whether the melting endotherm peak was observed or not. Similarly, O or X in the XRD peak column respectively means whether XRD peak values were observed or not.

Table 10

Various conditions for recrystallization of the crystalline form of the compound of formula (1)

Solvent A Solvent IN DSK Exit(%) Peaks XRD Primerb Acetonitrile - ABOUT 35 ABOUT Example? 1-Butanol - ABOUT 90 ABOUT Example Butyl acetate - ABOUT 85 ABOUT ExampleE Isopropanol - ABOUT 80 ABOUT ExampleU Tert-butanol - ABOUT 84 ABOUT Example11 Ethanol n-Geptane ABOUT 70 ABOUT Comp. example 1 THF — X - X Comp. example2 1,4-Dioxane — X - X Comp. example3 Dichloromethane — X - X Comp. example4 Methanol — X - X Comp. example Toluene — X - X

- 26 046002

Example 12 Preparation of the crystalline form of the compound of formula (2).

HN

⁰ ° (2)

^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid (5 g) dissolved in EtOH (30 ml) and then heated to reflux and maintained at this temperature for 1 hour, then cooled to 15-25°C and maintained at this temperature for 12 hours, and a solid formed. This solid was then filtered and dried under vacuum at 45-50°C to obtain a crystalline form. Yield: 1.7 g.

The XRD pattern and DSC curve of the crystalline form of the compound of formula (2) in the present example were obtained by methods similar to those used in example 2.

The XRD diffraction pattern of the resulting crystalline form of the compound of formula (2) is shown in FIG. 5, which includes peaks at approximately 14.5, 18.6, 19.9, 20.1, 21.8, 22.0, 23.8 and 25.0° 2θ. In addition, the resulting DSC curve indicates that the melting endotherm of the resulting crystalline form of the compound of formula (2) peaks at approximately 91.7° C. (minor peak) and 168.4° C. (major peak).

Example 13 Preparation of the crystalline form of the compound of formula (2).

^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)propyl)amino)benzamido)propanoic acid (5 g) dissolved in acetone (40 ml) and then heated to reflux and maintained at this temperature for 1 hour, then cooled to 15-25°C and maintained at this temperature for 12 hours, and a solid formed. This solid was then filtered and dried under vacuum at 45-50°C to obtain a crystalline form. Yield: 3 g.

The XRD pattern and DSC curve of the crystalline form of the compound of formula (2) in the present example were obtained by methods similar to those used in example 2.

The XRD diffraction pattern of the resulting crystalline form of the compound of formula (2) is shown in FIG. 6, which includes peaks at approximately 14.5, 18.6, 20.2, 21.7, 23.8, 25.0, 28.5 and 31.0° 2θ. In addition, the resulting DSC curve indicates that the melting endotherm of the resulting crystalline form of the compound of formula (2) peaks at approximately 86.7° C. (minor peak) and 169.2° C. (major peak).

Example 14 Preparation of the sodium salt of the compound of formula (2).

^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoic acid (10 g) was dissolved in anhydrous EtOH (80 ml) at 15-25°C, and then NaOH (0.85 g) was added. The mixture was stirred for 12 hours, and then the solution was dried in vacuum at 40-45°C. Ethyl acetate (80 ml) was added to the residue and stirred for 2 hours, the mixture was filtered to obtain the sodium salt. Yield: 8 g.

The XRD diffraction pattern and DSC curve of the sodium salt of the compound of formula (2) in the present example were obtained by methods similar to those used in example 2.

The XRD pattern of the resulting sodium salt of the compound of formula (2) is shown in FIG. 7. No significant peaks were found in the DSC curve. In addition, the TGA result indicates a mass loss of approximately 4% when changing from ambient temperature to approximately 175°C.

Example 15 Preparation of the potassium salt of the compound of formula (2).

^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoic acid (10 g) was dissolved in anhydrous EtOH (50 ml) at 15-25°C, and then KOH (1.15 g) was added. The mixture was stirred for 12 hours, and then the solution was dried in vacuum at 40-45°C. Ethyl acetate (80 ml) was added to the residue and stirred for 2 hours, the mixture was filtered to obtain potassium salt. Yield: 10 g.

The XRD diffraction pattern and DSC curve of the potassium salt of the compound of formula (2) in the present example were obtained by methods similar to those used in example 2.

The XRD pattern of the resulting potassium salt of the compound of formula (2) is shown in FIG. 8. No significant peaks were found in the DSC curve. In addition, the TGA result indicates a mass loss of approximately 4% when changing from ambient temperature to approximately 325°C.

Example 16. Preparation of magnesium salt of the compound of formula (2).

The sodium salt of the compound of formula (2) obtained in Example 13 (5 g, 2 eq.) was dissolved in deionized water (70 ml) at 15-25°C, and then magnesium sulfate (0.59 g, 1 eq.) was added. ). This mixture was stirred for 12 hours and then the solution was filtered and washed with deionized water (50

-

Claims (3)

ml). The filter cake was dried in vacuum at 40-45°C to obtain magnesium salt. Yield: 3 g. The XRD pattern and DSC curve of the magnesium salt of the compound of formula (2) in the present example were obtained by methods similar to those used in Example 2. The XRD pattern of the resulting magnesium salt of the compound of formula (2) is shown in FIG. 9. No significant peaks were found in the DSC curve. In addition, the TGA result indicates a mass loss of approximately 4% when changing from ambient temperature to approximately 335°C. Example 17. Preparation of the calcium salt of the compound of formula (2). The sodium salt of the compound of formula (2) obtained in Example 13 (5.2 g, 2 eq.) was dissolved in deionized water (70 ml) at 15-25°C, and then calcium chloride (0.57 g, 1 eq.). This mixture was stirred for 12 hours and then the solution was filtered and washed with deionized water (50 ml). The filter cake was dried in vacuum at 40-45°C to obtain calcium salt. Yield: 2.5 g. The XRD pattern and DSC curve of the calcium salt of the compound of formula (2) in the present example were obtained by methods similar to those used in Example 2. The XRD pattern of the resulting calcium salt of the compound of formula (2) is shown in FIG. 10. No significant peaks were found in the DSC curve. In addition, the TGA result indicates a mass loss of approximately 4% when changing from ambient temperature to approximately 210°C. Example 18. Preparation of the amorphous form of the compound of formula (1). Ethyl-^)-3-(4-((2-methyl-1-(4-(5-phenyl-1,3,4-oxadiazol-2yl)phenyl)propyl)amino)benzamido)propanoate (10 g) was dissolved in acetone (30 ml), and then dried in a rotary evaporator at 30°C to obtain an amorphous form. Yield: 9.5 g. The XRD pattern and DSC curve of the amorphous form of the compound of formula (1) in the present example were obtained by methods similar to those used in Example 2. The XRD pattern of the resulting amorphous form of the compound of formula (1) is shown in FIG. 11. In addition, no significant peaks were found in the DSC curve. Other Embodiments All features disclosed herein may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is merely an example of a general series of equivalent or similar features. Moreover, from the above description, one skilled in the art can readily ascertain the essential characteristics of the present disclosed invention and, without departing from its spirit and scope, can make various changes and modifications to the disclosed invention in order to adapt it to various applications and conditions. Thus, other embodiments are also included in the claims. CLAIM 1. Crystalline form of the compound of formula (1) characterized by an X-ray diffraction (XRD) pattern having peak values at 14.2, 15.6, 16.4, 20.1, 20.5 and 21.2°±0.2° 2θ. 2. The crystalline form according to claim 1, wherein the X-ray diffraction pattern additionally has peak values at 17.4, 21.7 or 23.7°±0.2° 2θ. 3. The crystalline form according to claim 1, wherein the X-ray diffraction pattern is as shown in any of FIGS. 1-4. -