WO2021242807A1

WO2021242807A1 - Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof

Info

Publication number: WO2021242807A1
Application number: PCT/US2021/034155
Authority: WO
Inventors: Dharma Rao Polisetti; Samuel Victory
Original assignee: Vtv Therapeutics Llc
Priority date: 2020-05-28
Filing date: 2021-05-26
Publication date: 2021-12-02
Also published as: TW202206412A

Abstract

The invention provides methods for preparing key intermediates for the synthesis of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid ("OAD2") and salts thereof. The key intermediates include methyl (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)-phenyl]-propionate and hydrochloric acid salts thereof. Compared with the prior art, the methods may not require column chromatographic separation and purification, and may have the advantages of potentially lower cost, higher yield, and suitability for industrial scale production.

Description

Methods for Preparing Methyl (S)-2-Amino-3-(4-(2,3-Dimethylpyridin-4-yl)Phenyl)Propionate and Hydrochloric Acid Salts Thereof

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to methods for preparing key intermediates for the synthesis of (S)-2-(3S,8S)-3-(4-(3,4- dichlorobenzyloxy)phenyl-7-((S)-l-phenylpropyl)-2,3,6,7,8,9-hexahydro-[l,4]-dioxino[2,3- g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid ("OAD2") and salts thereof. The key intermediates include Methyl (S)-2-amino-3-(4-(2,3-dimethylpyridin-4- yl)phenyl)propionate and hydrochloric acid salts thereof.

Background of the Invention

(S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-l-phenylpropyl)-2,3,6,7,8,9- hexahydro-[l,4]-dioxino[2,3-g]isoquinolin-8-ylformylamino)-3-(4-(2,3-dimethylpyridin-4- yl)phenyl)propionic acid dihydrochloride ("OAD2 dihydrochloride") is a small molecule, non peptide glucagon-like peptide 1 (GLP-1) receptor agonist. OAD2 dihydrochloride has an empirical formula of C50H49CI4N3O6 and a molecular weight of 929.76, and the following chemical structure:

OAD2 dihydrochloride has four chiral centers, among which, methyl (S)-2-amino-3-[4-(2,3- dimethylpyridin-4-yl)-phenyl]-propionate dihydrochloride salt can be used to introduce the last chiral center in the synthesis of OAD2 dihydrochloride. Thus, methyl (S)-2-amino-3-[4-(2,3- dimethyl py ridin-4-y l)-phenyl]-propionate and hydrochloric acid salts thereof are key intermediates for the synthesis of OAD2 dihydrochloride.

CN102378574B (and related international publication WO 2010/114824) discloses a method for the synthesis of OAD2, and particularly discloses a 3-step reaction route (Scheme 1) for preparing methyl (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)-phenyl]-propionate dihydrochloride (4). The reaction route uses methyl (S)-3-(4-bromo-phenyl)-2-tert- butoxycarbonylamino-propionate as the starting material and comprises three steps including Suzuki coupling and deprotection:

Scheme 1

More particularly, CN102378574B (WO 2010/114824) discloses the following reaction steps: adding bis(pinacolato)diboron (VII) to compound VI, stirring under the protection of nitrogen at 75°C for 3 hours, and purifying by using chromatographic column to give methyl (S)-2-tert- butoxycarbonylamino-3-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxacyclopentaboran-2-yl)-phenyl]- propionate (VIII); adding 4-bromo-2,3-dimethylpyridine (IX), a palladium catalyst, and stirring under the protection of nitrogen at 80°Cfor 18 hours, purifying by using chromatographic column to give methyl (S)-2-tert-butoxycarbonylamino-3-[4-(2,3-dimethylpyridin-4-yl)-phenyl]- propionate (X), and at last removing the protective group to give methyl (S)-2-amino-3-[4-(2,3- dimethyl py ridin-4-y l)-phenyl]-propionate dihydrochloride.

Therefore, it is necessary to optimize the preparation method of methyl (S)-2-amino-3-[4- (2,3-dimethylpyridin-4-yl)-phenyl]-propionate salt or related derivatives, to increase the yield, and lower the cost, so as to apply to industrial production. Summary of the Invention

The above reaction route in Scheme 1 requires multiple column chromatographic separations and purifications, and may have a total yield of only 49%; moreover, the starting materials, compound VI and compound IX may be too expensive for use in an economically practical industrial scale synthesis. Further, the researchers have found that the final product (4) is highly hygroscopic, and likely does not have acceptable storage stability, and it is difficult to obtain solid compound 4 through conventional solvent crystallization, hence it is difficult to store, transport and produce compound 4 on industrial scale.

The invention provides methods for preparing key intermediates useful for the synthesis of OAD2 dihydrochloride. The key intermediates include methyl (S)-2-amino-3-[4-(2,3- dimethylpyridin-4-yl)-phenyl]-propionate and hydrochloric acid salts thereof. Compared with the prior art, the methods disclosed herein to prepare these intermediates may not require column chromatographic separation and purification, may have the advantages of lower cost, higher yield, and suitability for industrial scale production.

In one aspect, the present invention is directed to preparing the compound of Formula III:

The process for preparing a compound of Formula III comprises the step of reacting a compound of Formula II:

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring, with a phenyl alanine derivative

wherein X is bromo or chloro, in the presence of a palladium catalyst, base and solvent to give a compound of Formula III:

In a second aspect, the present invention provides a process comprising reacting a compound of Formula II:

In a third aspect, the present invention provides a process for preparing the compound of

Formula II,

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring, wherein the process comprises reacting the compound of Formula I

with the compound

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring, in the presence of a solvent and a palladium catalyst to give a compound of Formula II

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring.

In a fourth aspect, the present invention provides a process for preparing the hydrochloric acid salt of a compound of Formula IV:

wherein R¹ is a Ci-₆ alkyl group, wherein process comprises condensing the compound of Formula III:

with a compound of the formula HO-R¹ to give the compound of Formula IV:

wherein R¹ is Ci-₆ alkyl.

In a fifth aspect, the present invention provides a process for preparing the hydrochloric acid salt of the compound of Formula IV:

IV , wherein R¹ is C_1-6 alkyl, wherein the process comprises (a) reacting the compound of Formula I Cl

with the compound ,

wherein R and R³ are independently C_1-6 alkyl, or R² and R³ are taken together to form a dioxaborolane ring, in the presence of a solvent and a palladium catalyst to give a compound of Formula II 2 OR B 3 OR ,

wherein R² and R³ are independently C1-6 alkyl, or R² and R³ are taken together to form a dioxaborolane ring, (b) reacting the compound of Formula II with a phenyl alanine derivative

wherein X is bromo or chloro_; in the presence of a palladium catalyst, base and solvent to give a compound of Formula III:

(c) reacting the compound of Formula III with an acyl chloride forming reagent followed by reacting with HO-R¹ to give the hydrochloric acid salt of the compound of Formula IV:

Detailed Description of the Invention

Definitions

The term "Ci-₆ alkyl" as used herein refers to saturated straight-chain or branched hydrocarbon radicals having 1 to 6 carbon atoms such as pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, 2,2-dimethylpropyl, 1-ethyl propyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethy Ibutyl, 2,2-dimethy Ibuty I, 2,3-dimethy Ibuty I, 3,3-dimethylbutyl, 1- ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-l-methylpropyl, and l-ethyl-2-methylpropyl.

The term "dioxaborolane ring" as used herein refers to a 1,3,2-dioxaborolane ring optionally substituted 1 to 4 times at the 4- and 5-positions with a Ci-₆ alkyl group. Non-limiting examples of dioxaborolane rings include 1,3,2-dioxaborolane and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The term “palladium catalyst” as used herein refers material in the form of a pre-formed complex of palladium(0), in form of a palladium(II) salt, in form of a palladium(II) complex, or in form of a palladium(0) source. Suitable Pd(II) salts may include Pd(II) acetate, PdCl₂ or Na₂PdCl₄. Suitable Pd(II) complexes may include Pd(II) acetylacetonate or bisacetonitrile Pd(II) chloride. A suitable Pd(0) source may include metallic palladium, optionally on a carrier, such as charcoal. In certain embodiments, a palladium catalyst is used alone or a mixed system of palladium catalyst and organophosphorus ligand, wherein the palladium catalyst is selected from the group consisting of Pd(OAc)₂, Pd₂(dba)₃, PdCl₂(PPh₃)_2, PdCl₂dppf, and Pd(PPh₃)₄, and the organophosphorus ligand is one, two or more selected from the group consisting of Ph₂P(CH₂)₂PPh₂(dppe), Ph₂P(CH₂)₃PPh₂(dppp), PCy₃, n-Bu₃P, P(OMe)₃, and PPh₃. The Pd source (calculated on the basis of the Pd content) can principally be used in an amount of up to 5 mol %, e.g. of from 0.0001 mol % to 5 mol %, relative to 1 mol of the limiting reagent such as compound I or the phenylalanine derivative (1 mol of the limiting reagent corresponding to 100%). In certain embodiments, the Pd source (calculated on the basis of the Pd content) is used in an amount of from 0.0001 mol % to 0.5 mol %, or from 0.0001 mol % to 0.1 mol %, of from 0.0001 mol % to 0.01 mol %, or from 0.001 mol % to 0.01 mol %, e.g. from 0.003 to 0.007 mol %, relative to 1 mol of the limiting reagent such as compound I or the phenyalanine derivative. The term “non-polar organic solvent” as used herein includes aliphatic hydrocarbons, such as alkanes, e.g. pentane, hexane, heptane, octane, mixtures thereof and technical mixtures, such as petrol ether; cycloaliphatic hydrocarbons, such as cycloalkanes, e.g. cyclohexane, cycloheptane, or cyclooctane; chlorinated aliphatic hydrocarbons, such as halogenalkanes, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethane or tetrachloroethane, aromatic hydrocarbons, such as benzene, toluene, the xylenes, ethylbenzene, cumene (isopropylbenzene), chlorobenzene, o-dichlorobenzene or nitrobenzene, or open-chained ethers, such as diethylether, dipropylether, methyl-tert-butylether or methyl-isobutylether. In certain embodiments, a non-polar organic solvent is selected from the group consisting of benzene, toluene, the xylenes, ethylbenzene, cumene (isopropylbenzene), chlorobenzene, o- dichlorobenzene and nitrobenzene. In other embodiments, a non-polar organic solvent is selected from the group consisting of toluene, xylenes, and chlorobenzene. The term “polar aprotic solvent” as used herein includes solvents which are water-miscible in a desired ratio of water/polar aprotic solvent to be used in a reaction. A polar aprotic solvent are solvents without a functional group from which a proton can dissociate. "Miscible" means that a homogenous solution is formed. Examples for suitable polar aprotic solvents are amides, such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide (DMSO); lactams, such as N-methylpyrrolidone (NMP); cyclic ethers, such as tetrahydrofuran, 1,3-dioxane and 1,4-dioxane; ketones, such as acetone and methylethylketone; nitriles, such as acetonitrile; lactones, such as gamma-butyrolactone; nitro compounds, such as nitromethane; ureas, such as tetramethyl urea or dimethylpropylene urea (DMPU); sulfones, such as sulfolan; and carbonic acid esters, such as dimethylcarbonate or ethylenecarbonate. In certain embodiments, the polar aprotic co-solvent is a cyclic ether, such as tetrahydrofuran, or 1,4- dioxane. The term “polar protic solvent” as used herein includes solvents such as water, acetic acid, formic acid, methanol, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert- butanol, n-propanol, isopropanol, 1,2 propan-diol, and glycerol. The term “base” as used herein refers to inorganic and organic bases. Suitable inorganic bases may include for example alkali metal carbonates, e.g. Li2CO3, Na2CO3, K2CO3 or Cs2CO3, earth alkaline metal carbonates, e.g. MgCO3 or CaCO3, alkali metal phosphates, e.g. Li3PO4, Na3PO4, K3PO4 or Cs3PO4, earth alkaline metal phosphates, e.g. Mg3(PO4)2 or Ca3(PO4)2, alkali metal hydrogenphosphates, e.g. Li2HPO4, Na2HPO4, K2HPO4 or Cs2HPO4, earth alkaline metal hydrogenphosphates, e.g. MgHPO4 or CaHPO4, alkali metal hydroxides, LiOH, NaOH or KOH, and earth alkaline metal hydroxides, e.g. Mg(OH)2 or Ca(OH)2. Suitable organic bases may include open-chained amines, e.g. trimethylamine, triethylamine, tripropylamine, ethyldiisopropylamine and the like, or basic N-heterocycles, such as morpoline, pyridine, lutidine, DABCO, DBU or DBN. Preference in a coupling reaction however given to inorganic bases, such as to the above alkali metal carbonates, earth alkaline metal carbonates, alkali metal phosphates, earth alkaline metal phosphates, alkali metal hydrogenphosphates, earth alkaline metal hydrogenphosphates, alkali metal hydroxides and earth alkaline metal hydroxides. In an embodiment, the alkali metal carbonates are used in the coupling reaction, such as the above-mentioned Li2CO3, Na2CO3, K2CO3 or Cs2CO3. In particular, Na2CO3 may be used. The term "acyl chloride forming reagent" refers to any reagent that forms an acyl chloride group (-C(O)CI) when reacted with a carboxylic acid group (-CO2H ). Examples of acyl chloride forming reagents include, but are not limited to, thionyl chloride, phosgene, and triphosgene, phosphorous trichloride.

Aspects of Invention First Aspect

In a first aspect, the present invention is directed to preparing the compound of Formula III:

wherein X is bromo or chloro, in the presence of a palladium catalyst, base, and solvent to give a compound of Formula III:

In an embodiment, the reaction is carried out under an inert atmosphere, such as under the protection of nitrogen.

In another embodiment, the solvent comprises at least one polar protic solvent. In a further embodiment, the solvent comprises water and another polar protic solvent, such as 1-propanol. In a further embodiment, the solvent comprises one, two, or more solvents selected from the group consisting of ethanol, n-propanol, n-butanol, tetrahydrofuran, 1,4-dioxane, toluene, and xylene. In another embodiment, the solvent comprises ethanol.

In another embodiment, prior to the reaction, compound II is dissolved in a solvent comprising water, and a first base is added to adjust the pH to approximately 7. The first base may be an alkali metal carbonate. In another embodiment, the first base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. In another embodiment, the first base is sodium carbonate.

In another embodiment, R² and R³ are taken together to form a 1,3,2-dioxaborolane ring. In another embodiment, R² and R³ are taken together to form a 4,4,5,5-tetramethyl-l,3,2- dioxaborolane ring. In another embodiment, R² and R³ are methyl.

In another embodiment, the phenyl alanine derivative is in the L configuration. In another embodiment, the phenyl alanine derivative and compound II are fed at a ratio in the range of 1:1.5~1:2.5, and preferably 1:2.

In another embodiment, after the adjustment of pH to approximately 7, a second base and the phenylalanine derivative are successively added to the reaction mixture. The second base may be an alkali metal carbonate. In another embodiment, the second base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. In another embodiment, the second base is sodium carbonate. In another embodiment, the second base is the same as the first base. In another embodiment, the reaction temperature is adjusted to 30~40°C before addition of the palladium catalyst In another embodiment, after completion of the addition of the compound II, the phenyl alanine derivative, and base, the palladium catalyst alone or a mixed system of palladium catalyst and organophosphorus ligand is added. In a further embodiment, the palladium catalyst is selected from the group consisting of Pd(OAc)2, Pd2(dba)3, PdCl2(PPh3)2, PdCl2dppf, and Pd(PPh3)4, and the organophosphorus ligand is one, two or more selected from the group consisting of Ph2P(CH2)2PPh2(dppe), Ph2P(CH2)3PPh2(dppp), PCy3, n-Bu3P, P(OMe)3, and PPh3. In a further embodiment, the palladium catalyst is a mixed system of Pd₂(dba)₃ and PCy₃; wherein the molar amount of the catalyst is 1~5% of that of the phenyl alanine derivative; and the reaction temperature is in the range of 60~90°C, or in the range of 75~85°C. In another embodiment, the completed reaction is worked up by concentrating under reduced pressure, evaporating off a certain part of solvent, further adding water to make up to the original volume, extracting with ethyl acetate or dichloromethane, and separating and removing out the organic phase; dropwise adding acid to the aqueous phase to adjust pH to 1~2, and filtering; extracting the filtrate with ethyl acetate or dichloromethane, separating and removing out the organic phase, adding sodium hydroxide aqueous solution to the aqueous phase to adjust pH to 5~8, stirring to crystalize, and giving isolated compound Ⅲ; the acid used to adjust pH is one of hydrochloric acid, sulfuric acid, and phosphoric acid, and preferably hydrochloric acid. Second Aspect In a second aspect, the present invention provides a process comprising reacting a compound of Formula II: 2 OR B 3 OR

wherein R and R³ are independently C1-6 alkyl, or R² and R³ are taken together to form a dioxaborolane ring, with a phenyl alanine derivative

I I I

In another embodiment, prior to the reaction, compound II is dissolved in a solvent comprising water, and a first base is added to adjust the pH to approximately 7. The first base may be an alkali metal carbonate. In another embodiment, the first base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. In another embodiment, the first base is sodium carbonate. In another embodiment, the phenyl alanine derivative is in the L configuration. In another embodiment, the phenyl alanine derivative and compound II are fed at a ratio in the range of 1:1.5~1:2.5, and preferably 1:2. In another embodiment, after the adjustment of pH to approximately 7, a second base and the phenylalanine derivative are successively added to the reaction mixture. The second base may be an alkali metal carbonate. In another embodiment, the second base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. In another embodiment, the second base is sodium carbonate. In another embodiment, the second base is the same as the first base. In another embodiment, the reaction temperature is adjusted to 30~40°C before addition of the palladium catalyst In another embodiment, after completion of the addition of the compound II, the phenyl alanine derivative, and base, the palladium catalyst alone or a mixed system of palladium catalyst and organophosphorus ligand is added. In a further embodiment, the palladium catalyst is selected from the group consisting of Pd(OAc)₂, Pd₂(dba)₃, PdCl₂(PPh₃)_2, PdCl₂dppf, and Pd(PPh₃)₄, and the organophosphorus ligand is one, two or more selected from the group consisting of Ph₂P(CH₂)₂PPh₂(dppe), Ph₂P(CH₂)₃PPh₂(dppp), PCy₃, n-Bu₃P, P(OMe)₃, and PPh₃. In a further embodiment, the palladium catalyst is a mixed system of Pd₂(dba)₃ and PCy₃; wherein the molar amount of the catalyst is 1~5% of that of the phenyl alanine derivative; and the reaction temperature is in the range of 60~90°C, or in the range of 75~85°C. In another embodiment, the completed reaction is worked up by concentrating under reduced pressure, evaporating off a certain part of solvent, further adding water to make up to the original volume, extracting with ethyl acetate or dichloromethane, and separating and removing out the organic phase; dropwise adding acid to the aqueous phase to adjust pH to 1~2, and filtering; extracting the filtrate with ethyl acetate or dichloromethane, separating and removing out the organic phase, adding sodium hydroxide aqueous solution to the aqueous phase to adjust pH to 5~8, stirring to crystalize, and giving isolated compound Ⅲ; the acid used to adjust pH is one of hydrochloric acid, sulfuric acid, and phosphoric acid, and preferably hydrochloric acid. Third Aspect

In a third aspect, the present invention provides a process for preparing the compound of Formula II,

with the compound

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring. In an embodiment, the reaction is carried out under an inert atmosphere, such as under the protection of nitrogen.

In another embodiment, the process includes the addition of an organic acid salt. In a further embodiment, compound I and an organic acid salt are first added into the solvent, and the temperature of the mixture is maintained in the range of -10~10°C. In a further embodiment, the organic acid salt is one, two or more selected from the group consisting of potassium acetate, sodium acetate, potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, L- potassium tartrate, L-sodium tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate, and preferably potassium acetate.

In another embodiment, the solvent comprises one or more non-polar organic solvents. In a further embodiment, the solvent comprises one, two or more non-polar organic solvents selected from the group consisting of xylene, toluene and chlorobenzene.

In another embodiment, R² and R³ of

form a dioxaborolane ring. In a further embodiment, R² and R³ form a 1,3,2-dioxaborolane ring. In a further embodiment, R² and R³ form a 4,4,5,5-tetramethyl-l,3,2-dioxaborolane ring.

In another embodiment, the compound

is added in two portions to the reaction. The first portion is added at a temperature of -10~10°C, and the second portion is added at a temperature of 20~30°C.

In another embodiment, after the completion of the addition and reaction of the borane compound , the palladium catalyst is added. In an embodiment, the palladium catalyst is alone or a mixed system of palladium catalyst and organophosphorus ligand, wherein the palladium catalyst is selected from the group consisting of Pd2(dba)3, PdChiPPhsh, and Pd(OAc)2, and the organophosphorus ligand is one, two or more selected from the group consisting of PCy3, PPfb, n-Bu3P, and P(OMe)3, and preferably a mixed system of Pd2(dba)3 and PCy3. In another embodiment, the reaction temperature after the addition of the palladium catalyst is in the range of 100~135°C, and preferably in the range of 110~120°C.

In another embodiment, the organic acid salt and the diboron compound are fed in a molar ratio in the range of 1:2:2~1:4:3, and the molar amount of the palladium catalyst is 0.1~1% of that of compound I.

In another embodiment, the completed reaction is worked up by adding heptane to dilute the mixture, filtering any insoluble substance, extracting the filtrate with diluted hydrochloric acid, washing the obtained aqueous layer with dichloromethane or ethyl acetate, removing out the organic layer, concentrating to a volume 2~5 times to the volume of compound I, and giving isolated compound II. As a specific embodiment, the concentration of the diluted hydrochloric acid used in the workup is l~2mol/L.

Fourth Aspect

and compound of the formula HO-R¹.

In an embodiment, the condensation reaction comprises reacting the compound of Formula III with an acyl chloride forming reagent followed by addition of HO-R¹ to give the hydrochloric acid salt of the compound of Formula IV:

wherein R¹ is Ci-6 alkyl.

In an embodiment, the acyl chloride forming reagent is thionyl chloride or oxalyl chloride. In another embodiment, R¹ is methyl.

In another embodiment, the compound of formula IV is a dihydrochloric acid salt.

In another embodiment, the reaction is conducted in a solvent. In a further embodiment, the reaction solvent is HO-R¹.

In a further embodiment, after completion of the reaction, the mixture is concentrated to remove solvent, optionally acidified, to provide isolated compound of Formula IV as a hydrochloric acid salt.

Fifth Aspect

wherein R¹ is Ci-6 alkyl, wherein the process comprises (a) reacting the compound of Formula I

with the compound

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring, in the presence of a first solvent and a first palladium catalyst to give a compound of Formula II

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring,

(b) reacting the compound of Formula II with a phenyl alanine derivative

wherein X is bromo or chloro, in the presence of a second palladium catalyst, base and a second solvent to give a compound of Formula III:

wherein R¹ is Ci-₆ alkyl.

In an embodiment_; the invention provides a process for preparing a hydrochloric acid salt of a compound of Formula IV as illustrated by Scheme 2

Scheme 2

As a specific embodiment_; step (a) is carried out under the protection of nitrogen.

As a specific embodiment_; in step (a), compound 1 and organic acid salt are first added into the first solvent, and the temperature of the mixture is maintained in the range of -10~10°C; wherein the organic acid salt is one, two or more selected from the group consisting of potassium acetate, sodium acetate, potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, L- potassium tartrate, L-sodium tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate, and preferably potassium acetate; and the solvent is one, two or more selected from the group consisting of xylene, toluene or chlorobenzene. As a specific embodiment, in step (a), bis(pinacolato)diboron is added in two portions; the first portion is added at a temperature of -10~10°C, and the second portion is added at a temperature of 20~30°C. As a specific embodiment, in step (a), after the completion of the second reaction of bis(pinacolato)diboron, palladium catalyst A is added; and the palladium catalyst A is palladium catalyst alone or a mixed system of palladium catalyst and organophosphorus ligand, wherein the palladium catalyst is selected from the group consisting of Pd2(dba)3, PdCl2(PPh3)2, and Pd(OAc)2, and the organophosphorus ligand is one, two or more selected from the group consisting of PCy3, PPh3, n-Bu3P, and P(OMe)3, and preferably a mixed system of Pd2(dba)3 and PCy3. As a specific embodiment, in step (a), the reaction temperature after the addition of the catalyst is in the range of 100~135°C, and preferably in the range of 110~120°C. As a specific embodiment, in step (a), compound 1, organic acid salt and bis(pinacolato)diboron are fed in a molar ratio in the range of 1:2:2~1:4:3, and the molar amount of the catalyst is 0.1~1% of that of compound 1. As a specific embodiment, the workup mode of step (a) is as follows: adding heptane to dilute, stirring the mixture, filtering out the insoluble substance, extracting the filtrate with diluted hydrochloric acid, washing the obtained aqueous layer with dichloromethane or ethyl acetate, removing out the organic layer, concentrating to a volume 2~5 times to the volume of compound 1, and giving compound 2. As a specific embodiment, in step (a), the concentration of the diluted hydrochloric acid used in the workup is 1~2mol/L. As a specific embodiment, step (b) is carried out under the protection of nitrogen. As a specific embodiment, in step (b), water and organic solvent are added to the concentrated solution of compound 2, and alkaline reagent A is added to adjust pH to approximate 7; wherein the organic solvent is one, two or more selected from the group consisting of ethanol, n-propanol, n-butanol, tetrahydrofuran, 1,4-dioxane, toluene, and xylene, and preferably ethanol; the alkaline reagent A is one, two or more selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and preferably sodium carbonate; and 4-bromo-L-phenylalanine and compound 2 are fed at a ratio in the range of 1:1.5~1:2.5, and preferably 1:2. As a specific embodiment, in step (b), after the adjustment of pH, alkaline reagent B and 4- bromo-L-phenylalanine are successively added, and the reaction temperature is adjusted to 30~40°C; wherein the alkaline reagent B is one, two or more selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, barium hydroxide, and potassium phosphate, and preferably sodium carbonate. As a specific embodiment, in step (b), palladium catalyst B is added, and the palladium catalyst B is a palladium catalyst alone or a mixed system of palladium catalyst and organophosphorus ligand, wherein the palladium catalyst is selected from the group consisting of Pd(OAc)2, Pd2(dba)3, PdCl2(PPh3)2, PdCl2dppf, and Pd(PPh3)4, and the organophosphorus ligand is one, two or more selected from the group consisting of Ph2P(CH2)2PPh2(dppe), Ph2P(CH2)3PPh2(dppp), PCy3, n-Bu3P, P(OMe)3, and PPh3, and preferably a mixed system of Pd2(dba)3 and PCy3; wherein the molar amount of the catalyst is 1~5% of that of 4-bromo-L- phenylalanine; and the reaction temperature is in the range of 60~90°C, and preferably in the range of 75~85°C. As a specific embodiment, the workup mode of step (b) is as follows: concentrating under reduced pressure, evaporating off a certain part of solvent that is 4 times in volume to the volume of 4-bromo-L-phenylalanine, further adding purified water to make up to the original volume, extracting with ethyl acetate or dichloromethane, and separating and removing out the organic phase; dropwise adding acid to the aqueous phase to adjust pH to 1~2, and filtering; extracting the filtrate with ethyl acetate or dichloromethane, separating and removing out the organic phase, adding sodium hydroxide aqueous solution to the aqueous phase to adjust pH to 5~8, stirring to crystalize, and giving compound 3; the acid used to adjust pH is one of hydrochloric acid, sulfuric acid, and phosphoric acid, and preferably hydrochloric acid. As a specific embodiment, in step (c), methanol serves as both solvent and reaction reagent, and optionally, oxalyl chloride or thionyl chloride is added, and the reaction temperature is controlled in the range of 40~70°C, and preferably 55~65°C.

As a specific embodiment, in step (c), after the completion of the reaction, the reaction mixture is concentrated to remove the solvent and give compound 4.

The methyl (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)-phenyl]-propionate and hydrochloric acid salt obtained herein are useful intermediates for the preparation of OAD2 dihydrochloride.

Examples

The invention will be further illustrated by combining the following specific examples. The following examples are used to explain the method of the invention and the core concept thereof, and for those skilled in the art, any possible change or substitution without departing from the inventive concept will fall within the protection scope of the invention. In the following examples, where the specific conditions of the experimental methods are not indicated, they are typically the conventional conditions, or are those recommended by the raw material or commodity manufactures; and the solvents without indicating the source are typically conventional solvents that are commercially available.

The amount of materials fed in Examples 1-2 is shown in Table 1.

Reference in Examples 1-2 and Table 1 to the Compounds 1, 2, 3, and 4 in Scheme 2 above.

Table 1. Amount of materials used in Examples 1-2

Example 1 Step (a) Under an inert atmosphere, Compound 1 (4-chloro-2,3-dimethylpyridine-1-oxide) (200.0 g, 1.269 mol) was added in xylenes (1400 mL, 7 vol) and potassium acetate (373.6 g, 3.807 mol) added. The mixture was cooled to -5 ºC and bis(pinacaloto)diboron (386.7 g, 1.523 mol, 1.2 equiv) added. The mixture was stirred at -5 ^oC to 0 ⁰C for at least 1 h, and then bis(pinacaloto)diboron (322.2 g, 1.269 mol, 1.0 equiv) added at -5 ^oC to 0 ⁰C. The mixture was stirred for at least 1 h, keeping the temperature below 15 ^oC. The reaction mixture was then stirred between 20 ºC to 30 ⁰C for at least 15 h. LC-MS showed >99.0% conversion to 4-chloro-2,3-dimethylpyridine. The mixture was degassed by bubbling with nitrogen for at least 10 minutes. Pd2dba3 (2.324 g, 2.538 mmol) and tricyclohexylphosphine (2.847 g, 10.152 mmol) were added and degassed again by bubbling with nitrogen for at least 10 minutes. The reaction mixture heated at ~125 ºC for 5 h but LC-MS appeared ~30% conversion. The reaction mixture was cooled to ~60 ^oC, degassed, added Pd2dba3 (1.16 g, 0.001 equiv) and tricyclohexylphosphine (1.42 g, 0.004 equiv), and degassed then again. The reaction mixture was heated at ~125 ºC overnight (14 h). LC-MS at both 254 and 215 nm appeared >99.5% conversion to the pyridine boronate ester. The reaction was cooled to 30 ⁰C, diluted with heptanes (2800 mL, 14 vol), and the slurry was stirred for at least 1 h. The insoluble solid was filtered through a pad of Celite (~100 g) and washed with heptanes (1200 mL, 6 vol). The pale yellow filtrate was warmed to 30 – 40 ^oC and then extracted with a preheated (30 – 40 ^oC) 1.5N HCl (973 mL, 1.459 mol, 1.15 equiv, 4.87 vol). The aqueous layer was washed with dichloromethane (200 mL, 1 vol) and followed by wash with ethyl acetate (200 mL, 1 vol). The aqueous layer was separated and afforded 1262.9 g (188.73 mg/mL) of a pale yellow product solution. The product solution was concentrated to 3.5 volume (~700 mL) under vacuum at 45 – 50 ^oC and afforded 725.1 g (density 1.104) of the desired product solution. The purity of aqueous solution appeared >97.5%. The actual yield is 251.2 g (84.9% yield, 725.1 g of a 346.5 mg/g solution or 382.5 mg/mL). Step (b) Under an inert atmosphere, water (280.5 mL, total 6.3 volumes including 385.9 g of boronate ester solution) and n-propanol (370 mL, 3.7 vol) were added to an acidic aqueous solution of 2,3- dimethyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyridine (133.7 g, 0.5736 mol, 385.9 g of a 346.5 mg/g solution) and the mixture was adjusted to pH ~7 with solid Na2CO3 (50 g, 0.4717 mol). Sodium carbonate (86.8 g, 0.8194 mol) and 4-bromo-L-phenylalanine (100.0 g, 0.4097 mol) were then added to this suspension. The slurry was heated to 30 – 40 ^oC and subjected to degas by bubbling with nitrogen at least 10 min, PdCl2(PPh3)2 (5.75 g, 8.19 mmol) added, and the mixture degassed with nitrogen bubbling again for at least 10 min. The reaction was heated at reflux (87 ± 2 ^oC of internal temperature). After heated for 24 h, the reaction was stopped for work-up. The reaction mixture was filtered, and the filtrate was concentrated to 500 mL in volume and washed with EtOAc (3 x 250 mL). The pH was adjusted to ~2 with conc. HCl (~120 mL) and removed insoluble solid by filtration. The aqueous filtrate was again washed with EtOAc (300 mL). The aqueous phase was filtered through a short pad of Florisil (50 g, 30 – 60 mesh) and washed with 0.5M HCl (1800 mL). The pH was adjusted to 6.5 – 7.0 with 10 M NaOH (~130 mL), and a precipitate formed upon standing. The slurry was concentrated to approximately 500 mL in volume and stirred at 10 – 15 ^oC for at least 1 h. The solid was filtered, washed with water (200 mL), washed with acetonitrile (150 mL) and dried under vacuum at 50 ^oC to afford 83.0 g (74.9% yield) of the desired product. The purity is >98.5% pure by HPLC. The aqueous filtrate (~700 mL) was adjusted to pH 7.0 – 7.5 with 5M NaOH, stirred at 10 – 15 ^oC for 30 minutes, and a precipitate formed. The resulting solid was filtered, washed with water (70 mL) and acetonitrile (50 mL), dried, and afforded an additional 10.4 g (9.4% yield) of the acid. The purity is >98.5% pure by HPLC. Total yield: 93.4 g (84.3% yield). Step (c) Compound 3 ((S)-2-Amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid) (10.0 g, 37.0 mmol) was suspended in MeOH (50 mL), and the mixture cooled to 0 ºC. Thionyl chloride (8.8 g, 74.0 mmol) was added drop-wise, and the resulting mixture warmed to 20 ºC over 1 h, and refluxed for 3 h. The reaction mixture was filtered, and the filtrate was concentrated. The resulting oily solid was slurried in EtOAc (50 mL) at room temperature overnight. The solid was filtered, washed with EtOAc and acetone, and dried under vacuum to provide Compound 4 as a di-HCl salt (11.0 g, 83.3% yield). Example 2 Step (a) Into a 100 L jacketed glass reaction vessel was charged xylenes (23.8 L), compound 1 (4- chloro-2,3-dimethyl- pyridine-1-oxide) (2.8 kg, 17.8 mol, 1.0 eq.). The stirred contents of the reaction vessel were cooled to -10^o C and potassium acetate (5.2 kg, 3.0 eq) was added. During addition, the temperature increased to 10^o C. Bis(pinacolato)diboron (5.4 kg, 1.2 eq.) was added while maintaining a temperature below 5 ^oC. Stirring was continued for 1 hour at 5 ^oC, and the remainder of the bis(pinacolato)diboron (4.5 kg, 1.0 eq.) was added. The reaction temperature was increased to 20 ^oC, and stirring was continued 16-18 hours. Conversion was checked by HPLC. After nearly complete conversion, the reaction mixture was degassed with a nitrogen flow and PCy3 (58.9 g, 0.012 eq.) and Pd2dba3 (48.8 g, 0.002 eq.) added. Degassing was continued for an additional 30 minutes. The stirred reaction mixture was heated to 120-140 ^oC during which a fast, exothermic reaction occurred. Conversion was monitored by LCMS. After heating 1 hour, only 0.06% of the starting material remained, and after an additional 2 hours no starting material was observed by LCMS. The reaction mixture was cooled to 35^o C and heptanes (40.0 L, 14 vol.) were added. The resulting mixture was stirred for 1 hour. The precipitate was separated by filtration, and the solids washed with heptanes (5 x 4.5 L). The filtrate and washings were pooled and transferred into a 100 L reaction vessel. The product was extracted into 1.5 N HCl solution (13.7 L). LCMS indicated no product remained in organic after extraction. The aqueous HCl solution was cooled to 20 ± 5^o C, and a white solid precipitated. The mixture was warmed to 30 ±5^o C, and all of the solids dissolved. The clear solution was extracted with cooled DCM (1 x 2.8 L) and Ethyl Acetate (1 x 2.8 L). The product boronate ester remained in the aqueous HCl layer. Upon cooling the solution to 5±5^o C, a white precipitate formed, which was removed by filtration. The filter cake was washed with 0.1N HCl solution (2 x 800 mL) then air dried to provide around 1.0 kg of white solids. The pooled filtrates were concentrated by vacuum distillation to approximately 7.1 kg. Product content was determined by HPLC assay. Analytical data determined 4.2 kg of product in the solution. The acidic aqueous solution of the product was transferred into a 50 L plastic carboy and stored below -10o C. A slightly modified work-up may be used to allow a better separation by precipitation of the excess and spent reagent. The aqueous, acidic product solution after extraction with aqueous HCl solution was cooled to 10^o C. The chilled suspension was agitated for 90 minutes, and the solids were removed by filtration. The filter cake was washed with chilled 0.05 N HCl (2 x 2.0 L). Then the pooled filtrates were washed with DCM. In order to reduce product loss, the DCM extraction was performed at lower temperature (5-10^o C). The ethyl acetate extractions were carried out at approximately 20^o C . Step (b) To a 100 L reaction vessel, under nitrogen, was charged with the boronate ester solution prepared in Step (a) (16.3 L, containing 6.2 kg, 1.60 eq.), water (6.7 L) and 1-propanol (13.5 L). The pH of the stirred solution was adjusted to pH 7.0 by addition of solid sodium carbonate (2.1 kg).4-Bromo-L-phenylalanine (3.5 kg, 1.0 eq.) was added followed by sodium carbonate (3.5 kg, 2.07 eq.). The contents of the 100 L jacketed reactor were heated to 35±5^o C and degassed by bubbling nitrogen into the solution. The catalyst was charged under nitrogen (286.7 g, 0.028 eq. of PdCl₂(PPh₃)₂), and the mixture degassed for an additional 30 minutes. The reaction mixture was heated to reflux under nitrogen (to an internal temperature of 87 ± 2^o C). After 24.5 hours, the contents of the reaction vessel (under nitrogen) were cooled to room temperature (22- 25^o C). The solids were removed by filtration through a pad of Celite 545 (1.9 kg). The reactor was rinsed with water (6.0 L), and the washes sent onto the filter. The filter cake was additionally washed with water (3 x 2.0 L). All filtrates were collected in carboys. The filtrates were concentrated by evaporation under vacuum on a 20 L rotary evaporator to approximately 10.0 L. The product solution was diluted with water (2.0 L) and washed with ethyl acetate (1 x 20 L and 2 x 15.0 L). The pH of the aqueous solution was adjusted to pH = 2±0.1 by addition of concentrated HCl (4.65 L). The solids were removed by filtration over Celite 545 (1.68 kg). The solids were washed with water (3x2.0 L). The combined filtrates were transferred to the 100 L reactor and washed with ethyl acetate (1 x 15.0 L). The pH of the aqueous solution was adjusted with sodium hydroxide (1.40 L, 50%) to pH = 6.7±0.2 and the crude product precipitated. Contents of the reactor were cooled over an hour to 5^o C and the mixture agitated at this temperature for an additional hour. The solids were collected by filtration on an 18 inch Table Top filter and washed with water (1 x 6.0 L). The solids were transferred into a 20 L evaporator flask and suspended in water (8.0 L). After stirring the suspension on the rotary evaporator for 30 minutes at room temperature (22-25^o C) then the solids were collected by filtration. The filter cake was washed with water (1 x 4.0 L). The solids were transferred into a 20 L evaporator flask and suspended in acetonitrile (4.0 L). The resulting solution was stirred for 30 minutes at room temperature (22-25^o C) and filtered. The filter cake was washed with acetonitrile (1 x 3.0 L). The isolated solids were transferred into trays and dried under vacuum at 60^o C until constant weight to give 2.40 kg of crude product with 93.7% purity and 58.2% isolated yield. [1] A process comprising reacting a compound of Formula II: 2 OR B 3 OR

wherein R² and R³ are independently C1-6 alkyl, or R² and R³ are taken together to form a dioxaborolane ring, with a phenyl alanine derivative

, wherein X is bromo or chloro, in the presence of a first palladium catalyst, first base and first solvent to give a compound of Formula III: . [2

] The process of [1], wherein the reaction is carried out under an inert atmosphere, such as under the protection of nitrogen. [3] The process of [1] or [2], wherein the first solvent comprises at least one polar protic solvent. [4] The process of [3], wherein the first solvent comprises water and another polar protic solvent. [5] The process of [4], wherein the polar protic solvent is 1-propanol. [6] The process of any one of [1] to [5], wherein R² and R³ are taken together to form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane ring. [7] The process of any one of [1] to [6], wherein the first solvent comprises one, two, or more solvents selected from the group consisting of ethanol, n-propanol, n-butanol, tetrahydrofuran, 1,4-dioxane, toluene, and xylene. [8] The process of any one of [1] to [7], wherein compound II is dissolved in a first solvent comprising water, and a first base is added to adjust the pH to approximately 7. [9] The process of [8], wherein the first base is an alkali metal carbonate. [10] The process of [9], wherein the first base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. [11] The process of [10], wherein the first base is sodium carbonate. [12] The process of any one of [1] to [11], wherein the phenyl alanine derivative and compound II are fed at a ratio in the range of 1:1.5~1:2.5. [13] The process of any one of [8] to [12], wherein after the adjustment of pH to approximately 7, a second base and the phenylalanine derivative are successively added to the reaction mixture. [14] The process of [13], wherein the second base is an alkali metal carbonate. [15] The process of [14], wherein the second base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate. [16] The process of [15], wherein the second base is the same as the first base. [17] The process of any one of [1] to [16], wherein after completion of the addition of the compound II, the phenyl alanine derivative, and base, the first palladium catalyst alone or a mixed system of a first palladium catalyst and organophosphorus ligand is added. [18] The process of any one of [1] to [17], wherein the first palladium catalyst is selected from the group consisting of Pd(OAc)2, Pd2(dba)3, PdCl2(PPh3)2, PdCl2dppf, and Pd(PPh3)4, and the organophosphorus ligand is one, two or more selected from the group consisting of Ph₂P(CH₂)₂PPh₂(dppe), Ph₂P(CH₂)₃PPh₂(dppp), PCy₃, n-Bu₃P, P(OMe)₃, and PPh₃. [19] The process of any one of [1] to [18], wherein the first palladium catalyst is a mixed system of Pd₂(dba)₃ and PCy₃; wherein the molar amount of the catalyst is 1~5% of that of the phenyl alanine derivative; and the reaction temperature is in the range of 60~90°C, or in the range of 75~85°C. [20] The process of any one of [1] to [19], further comprising isolating said compound of Formula III and optionally purifying the isolated compound of Formula III. [21] The process of any one of [1] to [20], further comprising condensing the compound of Formula III and a compound of the formula HO-R¹, wherein R¹ is C_1-6 alkyl, to give the hydrochloric acid salt of the compound of Formula IV:

IV . [22] The process of [21], wherein the condensation reaction comprises reacting the compound of Formula III with an acyl chloride forming reagent followed by addition of HO-R¹ to give the hydrochloric acid salt of the compound of Formula IV. [23] The process of [22], wherein the acyl chloride forming reagent is thionyl chloride or oxalyl chloride. [24] The process of any one of [21] to [23], wherein R¹ is methyl. [25] The process of any one of [21] to [24], wherein the compound of formula IV is a dihydrochloric acid salt. [26] The process of any one of [21] to [25], wherein the reaction is conducted in a second solvent and the reaction solvent is HO-R¹. [27] The process of any one of [21] to [26], further comprising isolating said compound of Formula IV and optionally purifying the isolated compound of Formula IV. [28] The process of any one of [1] to [27], wherein said compound of Formula II is prepared by reacting the compound of Formula I Cl

with the compound

wherein R² and R³ are independently Ci-₆ alkyl, or R² and R³ are taken together to form a dioxaborolane ring, in the presence of a third solvent and a second palladium catalyst to give a compound of Formula

[29] The process of [28], wherein the reaction is carried out under an inert atmosphere, such as under the protection of nitrogen.

[30] The process of [28] or [29], further comprising the addition of an organic acid salt.

[31] The process of [30], wherein compound I and an organic acid salt are first added into the third solvent, and the temperature of the mixture is maintained in the range of -10~10°C.

[32] The process of [30] or [31], wherein the organic acid salt is one, two or more selected from the group consisting of potassium acetate, sodium acetate, potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, L-potassium tartrate, L-sodium tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate, and preferably potassium acetate.

[33] The process of any one of [28] to [32], wherein the third solvent comprises one or more non-polar organic solvents.

[34] The process of [33], wherein the third solvent comprises one, two or more non-polar organic solvents selected from the group consisting of xylene, toluene and chlorobenzene.

[35] The process of any one of [28] to [34], wherein R² and R³ of

form a dioxaborolane ring.

[36] The process of [35], wherein R² and R³ form a 4,4,5,5-tetramethyl-l,3,2-dioxaborolane ring. [37] The process of any one of [28] to [36], wherein the compound is added in two portions to the reaction.

[38] The process of [37], wherein a first portion of is added at a temperature of -10~10°C, and the second portion is added at a te

mperature o 0~30°C. [39] The process of any one of [28] to [38], wherein after the completion of the addition and reaction of the borane compound , the second palladium catalyst is added. [40] The process of any one [28] to [39] wherein the second palladium catalyst is alone or a mixed system of the second palladium catalyst and organophosphorus ligand, wherein the second palladium catalyst is selected from the group consisting of Pd2(dba)3, PdCl2(PPh3)2, and Pd(OAc)2, and the organophosphorus ligand is one, two or more selected from the group consisting of PCy3, PPh3, n-Bu3P, and P(OMe)3. [41] The process of any one of [28] to [40], wherein the second palladium catalyst is a mixed system of Pd2(dba)3 and PCy3. [42] The process of any one of [28] to [41], wherein the reaction temperature after the addition of the second palladium catalyst is in the range of 100~135°C. [43] The process of any one of [28] to [42], wherein the organic acid salt and the diborane compound are fed in a molar ratio in the range of 1:2:2~1:4:3, and the molar amount of the second palladium catalyst is 0.1~1% of that of compound I. [44] The process of any one of [28] to [43], further comprising isolating said compound of Formula II and optionally purifying the isolated compound of Formula II.

Claims

Claims WHAT IS CLAIMED IS: 1. A process comprising reacting a compound of Formula II:

wherein X is bromo or chloro, in the presence of a palladium catalyst, base and solvent to give the compound of Formula III:

2. The process of claim 1, wherein the reaction is carried out under an inert atmosphere.

3. The process of claim 1 or 2, wherein the solvent comprises at least one polar protic solvent.

4. The process of claim 3, wherein the solvent comprises water and another polar protic solvent.

5. The process of claim 4, wherein the polar protic solvent is 1-propanol.

6. The process of any one of claim 1 to claim 5, wherein the solvent comprises one, two, or more solvents selected from the group consisting of ethanol, n-propanol, n-butanol, tetrahydrofuran, 1,4-dioxane, toluene, and xylene.

7. The process of any one of claim 1 to claim 6, wherein compound II is dissolved in a solvent comprising water, and a first base is added to adjust the pH to approximately 7.

8. The process of claim 7, wherein the first base is an alkali metal carbonate.

9. The process of claim 8, wherein the first base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate.

10. The process of claim 9, wherein the first base is sodium carbonate.

11. The process of any one of claim 1 to claim 10, wherein the phenyl alanine derivative and compound II are fed at a ratio in the range of 1:1.5~1:2.5.

12. The process of any one of claim 7 to claim 11, wherein after the adjustment of pH to approximately 7, a second base and the phenylalanine derivative are successively added to the reaction mixture.

13. The process of claim 12, wherein the second base is an alkali metal carbonate.

14. The process of claim 13, wherein the second base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate.

15. The process of claim 14, wherein the second base is the same as the first base.

16. The process of any one of claim 1 to claim 15, wherein after completion of the addition of the compound II, the phenyl alanine derivative, and base, the palladium catalyst alone or a mixed system of palladium catalyst and organophosphorus ligand is added.

17. The process of any one of claim 1 to claim 16, wherein the palladium catalyst is selected from the group consisting of Pd(OAc)2, Pd2(dba)3, PdCl2(PPh3)2, PdCl2dppf, and Pd(PPh3)4, and the organophosphorus ligand is one, two or more selected from the group consisting of Ph2P(CH2)2PPh2(dppe), Ph2P(CH2)3PPh2(dppp), PCy3, n-Bu3P, P(OMe)3, and PPh3.

18. The process of any one of claim 1 to claim 17, wherein the palladium catalyst is a mixed system of Pd₂(dba)₃ and PCy₃; wherein the molar amount of the catalyst is 1~5% of that of the phenyl alanine derivative; and the reaction temperature is in the range of 60~90°C, or in the range of 75~85°C.

19. The process of any one of claim 1 to claim 18, further comprising isolating said compound of Formula III and optionally purifying the isolated compound of Formula III.

20. The process of any one of claim 1 to claim 19, further comprising condensing the compound of Formula III and a compound of the formula HO-R¹, wherein R¹ is C1-6 alkyl, to give the hydrochloric acid salt of the compound of Formula IV:

21. The process of claim 20, wherein the condensation reaction comprises reacting the compound of Formula III with an acyl chloride forming reagent followed by addition of HO-R¹ to give the hydrochloric acid salt of the compound of Formula IV.

22. The process of claim 21, wherein the acyl chloride forming reagent is thionyl chloride or oxalyl chloride.

23. The process of any one of claim 20 to claim 22, wherein R¹ is methyl.

24. The process of any one of claim 20 to claim 23, wherein the compound of formula IV is a dihydrochloric acid salt.

25. The process of any one of claim 20 to claim 24, wherein the reaction is conducted in a solvent and the reaction solvent is HO-R¹.

26. The process of any one of claim 20 to claim 25, further comprising isolating said compound of Formula IV and optionally purifying the isolated compound of Formula IV.

27. The process of any one of claims 1 to 26, wherein said compound of Formula II is prepared by reacting the compound of Formula I

with the compound

wherein R² and R³ are independently C1-6 alkyl, or R² and R³ are taken together to form a dioxaborolane ring, in the presence of a solvent and a palladium catalyst to give a compound of Formula II.

28. The process of claim 27, wherein the reaction is carried out under an inert atmosphere.

29. The process of claim 27 or claim 28, further comprising the addition of an organic acid salt.

30. The process of claim 29, wherein compound I and an organic acid salt are first added into the solvent, and the temperature of the mixture is maintained in the range of -10~10°C.

31. The process of claim 29 or claim 30, wherein the organic acid salt is one, two or more selected from the group consisting of potassium acetate, sodium acetate, potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, L-potassium tartrate, L- sodium tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate, and preferably potassium acetate.

32. The process of any one of claim 27 to claim 31, wherein the solvent comprises one or more non-polar organic solvents.

33. The process of claim 32, wherein the solvent comprises one, two or more non-polar organic solvents selected from the group consisting of xylene, toluene and chlorobenzene.

34. The process of any one of claim 27 to claim 33, wherein R² and R³ of

form a dioxaborolane ring.

35. The process of claim 34, wherein R² and R³ form a 4,4,5,5-tetramethyl-1,3,2- dioxaborolane ring.

36. The process of any one of claim 27 to claim 35, wherein the compound is added in two portions to the reaction.

37. The process of claim 36, wherein a first portion of added at a

temperature of -10~10°C, and the second portion is added at a temperature of 20~30°C. 38. The process of any one of claim 27 to claim 37, wherein after the completion of the addition and reaction of the borane compound , the palladium catalyst is added. 39. The process of any one claim 27 to claim 38 wherein the palladium catalyst is alone or a mixed system of palladium catalyst and organophosphorus ligand, wherein the palladium catalyst is selected from the group consisting of Pd2(dba)3, PdCl2(PPh3)2, and Pd(OAc)2, and the organophosphorus ligand is one, two or more selected from the group consisting of PCy3, PPh3, n-Bu3P, and P(OMe)3. 40. The process of any one of claim 27 to claim 39, wherein the palladium catalyst is a mixed system of Pd₂(dba)₃ and PCy₃. 41. The process of any one of claim 27 to claim 40, wherein the reaction temperature after the addition of the palladium catalyst is in the range of 100~135°C. 42. The process of any one of claim 27 to claim 41, wherein the organic acid salt and the diborane compound are fed in a molar ratio in the range of 1:2:2~1:4:3, and the molar amount of the palladium catalyst is 0.1~1% of that of compound I. 43. The process of any one of claim 27 to claim 42, further comprising isolating said compound of Formula II and optionally purifying the isolated compound of Formula II.