TW202206420A - Intermediates and methods for preparing a glp-1 receptor agonist - Google Patents

Abstract

The present invention relates to a methods and key intermediates useful for preparing the GLP-1 receptor agonist (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)propanoic acid dihydrochloride ("OAD2 dihydrochloride"). The methods may be run on industrial scale and in higher yield than previously disclosed methods.

Description

Intermediates and methods for the preparation of GLP-1 receptor agonists

The present invention belongs to the field of pharmaceutical synthesis, and particularly relates to a method for preparing (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-(( S)-1-Phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxo[2,3-g]isoquinoline Intermediates and methods for -8-ylcarbamoylamino)-3-(4-(2,3-lutidine-4-yl)phenyl)propanoic acid dihydrochloride.

。(S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3 ,6,7,8,9-hexahydro-[1,4]-dioxo[2,3-g]isoquinolin-8-ylcarbamoylamino)-3-(4- (2,3-Lutidine-4-yl)phenyl)propionic acid dihydrochloride (“OAD2 dihydrochloride”) is an oral, non-peptide glucagon peptide 1 (GLP-1) receptor agonists. OAD2 dihydrochloride has the molecular formula C ₅₀ H ₄₉ Cl ₄ N ₃ O ₆ , molecular weight 929.76, and the following chemical structure:

.

方案1Invention patent CN102378574B (and related international publication WO2010/114824) discloses a method for preparing OAD2 (summarized in Scheme 1) using 4-hydroxyacetophenone as a starting material and comprising 14 steps including pro- Nucleus substitution, bromination, asymmetric reduction, condensation, hydrolysis, etc.

plan 1

However, the preparation method in Scheme 1 includes many steps, requires multiple column chromatography separations, and has an overall yield of only 5%, which makes it difficult to apply to industrial production. Therefore, it is necessary to re-develop synthetic routes suitable for industrial production.

The present invention provides a method for preparing OAD2 dihydrochloride. Compared with the prior art, the method has fewer steps and increased yield, and employs a multi-step continuous feed reaction that does not require column chromatography separation and is suitable for industrial production . In addition, the method uses a different path than previously disclosed to add the center of the palm.

其中所述方法包括將式1化合物

與式12化合物反應：

以得到式13化合物或其鹽類，其中R^a 和R^b 獨立地選自C_1-6 烷基，R¹ 是C_1-6 烷基，並且R² 是C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷氧基、C_1-6 鹵代烷氧基或芳基甲氧基。In a first aspect, the present invention provides a method for preparing a compound of formula 13 or a salt thereof:

wherein the method comprises compounding the compound of formula 1

Reaction with compound of formula 12:

to obtain a compound of formula 13 or a salt thereof, wherein R ^a and R ^b are independently selected from C _1-6 alkyl, R ¹ is C _1-6 alkyl, and R ² is C _1-6 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy or arylmethoxy.

其中所述方法包括將式13化合物或其鹽類，

在水解條件處理以得到式14化合物或其鹽類，其中R¹ 是C_1-6 烷基並且R² 是C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷氧基、C_1-6 鹵代烷氧基或芳基甲氧基。In a second aspect, the present invention provides a method for preparing a compound of formula 14 or a salt thereof:

wherein the method comprises compounding a compound of formula 13 or a salt thereof,

Treatment under hydrolysis conditions to give a compound of formula 14 or a salt thereof, wherein R ¹ is C _1-6 alkyl and R ² is C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy or arylmethoxy.

其中所述方法包括(a)將式14化合物或其鹽類

與(S)-苯基丙基胺和還原劑反應以得到式15化合物，和(b)視需要地形成式15化合物的鹽。In a third aspect, the present invention provides a method for preparing a compound of formula 15 or a salt thereof:

wherein the method comprises (a) compounding the compound of formula 14 or a salt thereof

Reaction with (S)-phenylpropylamine and a reducing agent gives the compound of formula 15, and (b) optionally forms a salt of the compound of formula 15.

其中所述方法包括(a)將式15化合物或其鹽類

與甲醛同等物反應以得到式8化合物

， 和(b)視需要地形成式8化合物的鹼金屬鹽或鹼土金屬鹽。In a fourth aspect, the present invention provides a method for preparing a compound of formula 8 or a salt thereof:

wherein the method comprises (a) compounding the compound of formula 15 or a salt thereof

Reaction with formaldehyde equivalents to give compounds of formula 8

, and (b) optionally form an alkali metal or alkaline earth metal salt of the compound of formula 8.

其中所述方法包括將式8-M化合物：

，其中M是鹼金屬或鹼土金屬， 與式9化合物反應

以得到式10化合物或其鹽類

。In a fifth aspect, the present invention provides a method for preparing a compound of formula 10 or a salt thereof:

wherein the method comprises compounding a compound of formula 8-M:

, where M is an alkali metal or alkaline earth metal, reacts with the compound of formula 9

to obtain the compound of formula 10 or its salts

.

，和第二步：加入鹽酸以製備OAD2的單HCl鹽(式11化合物)

。In a sixth aspect, the present invention provides a method for preparing the mono-HCl salt of OAD2 (the compound of formula 11), wherein the method comprises a first step: hydrolysis of the methyl ester of the compound of formula 10

, and the second step: adding hydrochloric acid to prepare the mono-HCl salt of OAD2 (compound of formula 11)

.

In a seventh aspect, the present invention provides a method of preparing a bis-HCl salt of OAD2, wherein the method comprises reacting a mono-HCl salt of OAD2 (a compound of formula 11) with HCl to prepare a bis-HCl salt of OAD2.

According to the present invention, a specific preparation method may include one or more steps in Aspects 1 to 7 as shown in Scheme 2 below.

In an eighth aspect, the present invention provides compounds of formula 13 and compounds of formula 14.

definition

The term "alkyl" as used herein means a monovalent saturated hydrocarbon group, which may be straight or branched chain or a combination thereof. Unless otherwise defined, these alkyl groups typically contain 1-12 carbon atoms. Representative alkyl groups include, for example, methyl (Me), ethyl (Et), n-propyl ((n-Pr) or (nPr)), isopropyl ((i-Pr) or (iPr)) , n-butyl ((n-Bu) or (nBu)), sec-butyl, isobutyl, tert-butyl ((t-Bu) or (tBu)), n-pentyl, n-hexyl, 2,2- Dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like. When a specific number of carbon atoms is used in a specific term, the number of carbon atoms is shown before the term. For example, the term " _C1-3 alkyl" means an alkyl group having 1 to 3 carbon atoms, wherein the carbon atoms are in any chemically acceptable configuration, including straight or branched chain configurations.

The term "haloalkyl" as used herein refers to straight or branched chain alkyl groups (as mentioned above) containing from 1 to 12 carbon atoms, wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms. Examples of _C1-2 -haloalkyl include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro Methyl, 1-chloroethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.

The term "alkoxy," as used herein, refers to an alkyl group attached through an oxygen atom. The term " _C1-2 -alkoxy" is a _C1-2 -alkyl group as defined above attached through an oxygen atom. Examples of C _1-3 -alkoxy groups include methoxy, ethoxy, n-propoxy and 1-methylethoxy (isopropoxy).

The term "haloalkoxy," as used herein, refers to a haloalkyl group attached through an oxygen atom. Examples of C _1-3 haloalkoxy include OCH ₂ F, OCHF ₂ , OCF ₃ , OCH ₂ Cl, OCHCl ₂ , OCCl ₃ , 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoro Ethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2-trichloroethoxy oxy and 2-fluoropropoxy.

The term "aryl" as used herein refers to an aryl group having 6 to 14 carbon atoms as ring members. Aryl is a mono-, bi- or polycyclic carbocyclic (ie no heteroatoms as ring members) ring system in which one or more rings are aromatic. An example of a monocyclic aryl group is phenyl. In bicyclic rings, two rings can undergo condensation, ie they share two vicinal C atoms as ring members. An example of a bicyclic aryl group is naphthyl. In polycyclic aryl rings, three or more rings may be condensed. Examples of polycyclic aryl groups are fentanyl (9H-fentanyl), phenanthryl and anthracenyl. One or more hydrogens of the aryl group may be independently substituted with substituents independently selected from the group consisting of halogen, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy.

The term "arylmethoxy," as used herein, is an aryl group, as defined above, which is bound to the rest of the molecule through a methoxy group. Examples of arylmethoxy include benzyloxy, 9-intenylmethoxy, p-nitrobenzyloxy, 2,4-dichlorobenzyloxy, and 5-benzisoxazolylmethoxy base.

Suitable "coupling agents" for forming the amide bond between the compound of formula 14 and the compound of formula 9 can be selected from N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide ( DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxy-1,2,3-benzotriazole (HOBT), benzene Triazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tripyrrolidinyl-phosphonium hexafluorophosphate (PyBOP) , 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1-[bis (dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxi-de hexafluorophosphate)(HATU), O-benzotriazole-N,N,N', N'-tetramethylurea-hexafluorophosphate (HBTU), (2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylammonium Hexafluorophosphate (HCTU) and O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU).

As used herein, the term "formaldehyde equivalent" refers to formaldehyde or a chemical equivalent thereof, such as, but not limited to, metaformaldehyde, paraformaldehyde, or polyformaldehyde.

The term "non-polar organic solvent" as used herein includes aliphatic hydrocarbons, such as alkanes, such as pentane, hexane, heptane, octane, mixtures thereof and technical mixtures, such as petroleum ether; cycloaliphatic hydrocarbons, such as cycloalkanes , such as cyclohexane, cycloheptane or cyclooctane; chlorinated aliphatic hydrocarbons, such as halogenated alkanes, such as dichloromethane, chloroform, tetrachloromethane, dichloroethane or tetrachloroethane, aromatic hydrocarbons , such as benzene, toluene, xylene, ethylbenzene, cumene (cumene), chlorobenzene, o-dichlorobenzene or nitrobenzene, or open-chain ethers such as diethyl ether, dipropyl ether, methyl tert-butyl ether ether or methyl isobutyl ether. In certain embodiments, the non-polar organic solvent is selected from the group consisting of benzene, toluene, xylene, ethylbenzene, cumene (cumene), chlorobenzene, ortho-dichlorobenzene, and nitrobenzene. In other embodiments, the non-polar organic solvent is selected from the group consisting of toluene, xylene, and chlorobenzene.

The term "polar aprotic solvent" as used herein includes solvents that are miscible with water in the ideal ratio of water/polar aprotic solvent used in the reaction. Polar aprotic solvents are solvents that do not have functional groups from which protons can dissociate. "Miscible" means forming a homogeneous solution. Examples of suitable polar aprotic solvents are amides such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; methylenes such as dimethylsulfoxide (DMSO) ; lactamides such as N-methylpyrrolidone (NMP); cyclic ethers such as tetrahydrofuran, 1,3-dioxane and 1,4-dioxane; ketones such as acetone and methyl ethyl ketone; nitriles , such as acetonitrile; lactones, such as gamma-butyrolactone; nitro compounds, such as nitromethane; ureas, such as tetramethylurea or dimethylpropylene urea (DMPU); Carbonates such as dimethyl carbonate or ethylene carbonate. 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-butanol, Propanol, isopropanol, 1,2-propane-diol and glycerol.

The term "base" as used herein refers to both inorganic and organic bases. Suitable inorganic bases may include, for example, alkali metal carbonates such as Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ or Cs ₂ CO ₃ , earth alkaline carbonates such as MgCO ₃ or CaCO ₃ , Alkali metal phosphates such as Li ₃ PO ₄ , Na ₃ PO ₄ , K ₃ PO ₄ or Cs ₃ PO ₄ , alkaline earth metal phosphates such as Mg ₃ (PO ₄ ) ₂ or Ca ₃ (PO ₄ ) ₂ , alkali metals Hydrogen phosphates such as Li ₂ HPO ₄ , Na ₂ HPO ₄ , K ₂ HPO ₄ or Cs ₂ HPO ₄ , alkaline earth metal hydrogen phosphates such as MgHPO ₄ or CaHPO ₄ , alkali metal hydroxides, LiOH, NaOH or KOH, and alkaline earth metal hydroxides such as Mg(OH) ₂ or Ca(OH) ₂ . Suitable organic bases may include open chain amines such as trimethylamine, triethylamine, tripropylamine, ethyldiisopropylamine, etc., or basic N-heterocycles such as morpholine, pyridine, lutidine, DMAP, DABCO, DBU or DBN. Invention aspect

first aspect

其中所述方法包括將式1化合物

與式12化合物反應：

以得到式13化合物或其鹽類，其中R^a 和R^b 獨立地選自C_1-6 烷基，R¹ 是C_1-6 烷基，並且R² 是C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷氧基、C_1-6 鹵代烷氧基或芳基甲氧基。In a first aspect, the present invention provides a method for preparing a compound of formula 13 or a salt thereof:

wherein the method comprises compounding the compound of formula 1

Reaction with compound of formula 12:

to obtain a compound of formula 13 or a salt thereof, wherein R ^a and R ^b are independently selected from C _1-6 alkyl, R ¹ is C _1-6 alkyl, and R ² is C _1-6 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy or arylmethoxy.

In one embodiment, the reaction is carried out in a solvent comprising one or more selected from the group consisting of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. In another embodiment, the reaction is carried out in a non-polar organic solvent. In another embodiment, the reaction is carried out in toluene. In another embodiment, the reaction is carried out in 2-methyltetrahydrofuran.

In one embodiment, R ¹ , R ² , ^Ra and R ^b are methyl or ethyl.

In another embodiment, the reaction is carried out under basic conditions. In other embodiments, a base is added to the reaction to create basic conditions. In additional embodiments, the base is an organic base. In another embodiment, the organic base is one, two or more bases selected from the group consisting of DBU, DMAP, triethylamine, isopropylamine, dibutylamine, oxazine, oxidine, and morpholine. In another embodiment, the phosphonium is dimethylaminopyridine (DMAP).

In another embodiment, the compound of formula 1 and the compound of formula 12 and the basic reagent (base) are fed in a molar ratio ranging from 1:1.05:1.5 to 1:2:3.

In another embodiment, Compound 1 and acetamido-(dimethoxy-phosphoronyl)-ethyl acetate (1.1 equiv) can be suspended in dry dichloromethane (DCM). To this stirred solution can be added DBU (2 equiv.). During the addition, the internal temperature was allowed to rise to ^30-34 °C and the progress of the reaction was monitored by TLC (50:50 hexanes:EtOAc). After the reaction does not proceed further, 4 Angstrom (Å) molecular sieves can be added and the mixture is stirred at room temperature overnight. The solvent was evaporated and the residue suspended in MeOH and water was added with stirring. After at least 1 to 3 hours, the mixture was filtered and the filter cake was washed with MeOH:water (2:1) with stirring. Further purification to remove molecular sieves and other impurities may be required before the product (compound ¹³ , wherein R1 is ethyl and R2 is methyl ⁾ is suitable for use in subsequent steps.

In another embodiment, the workup mode is as follows: after the reaction is completed, an aqueous ammonium chloride solution is added to the reaction, and the reaction mixture is stirred and washed; the aqueous layer is separated and removed, and the organic layer is washed with saturated brine Washed, then concentrated; methanol/water was added to the concentrated solution and stirred to crystallize, and the precipitated crystals were filtered and dried to give the compound of formula 13.

second aspect

其中所述方法包括將式13化合物或其鹽類，

在水解條件處理以得到式14化合物或其鹽類，其中R¹ 是C_1-6 烷基並且R² 是C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷氧基、C_1-6 鹵代烷氧基或芳基甲氧基。In a second aspect, the present invention provides a method for preparing a compound of formula 14 or a salt thereof:

wherein the method comprises compounding a compound of formula 13 or a salt thereof,

Treatment under hydrolysis conditions to give a compound of formula 14 or a salt thereof, wherein R ¹ is C _1-6 alkyl and R ² is C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy or arylmethoxy.

In one embodiment, the reaction is carried out in a solvent. In one embodiment, the solvent is a polar aprotic solvent. In further embodiments, the solvent is one, two or more selected from the group consisting of 1,4-dioxane, N-methylpyrrolidone, dimethylsulfene, dimethylacetamide and dimethylformamide. In additional embodiments, the solvent is N-methylpyrrolidone.

In another embodiment, the reaction is carried out under acidic conditions. In other embodiments, an acid is added to the reaction to create acidic conditions. In further embodiments, the acid is an aqueous solution, wherein the acid is one, two or more selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid. In additional embodiments, the acid is an aqueous solution of hydrochloric acid.

In another embodiment, the compound of formula 13 and the acidic aqueous solution are fed in a molar ratio ranging from 1:10 to 1:13, and the concentration of the acidic aqueous solution is between 2 mol/L and 6 mol/L .

In another embodiment, the work-up mode is as follows: after the reaction is complete, reduce the temperature and add water, and stir until crystallization; obtain a wet product after filtration, which is then slurried with methanol/dichloromethane; Compound 14 was obtained after filtration and drying.

third aspect

其中所述方法包括(a)將式14化合物或其鹽類

與(S)-苯基丙基胺和還原劑反應以得到式15化合物，和(b)視需要地形成式15化合物的鹽。In a third aspect, the present invention provides a method for preparing a compound of formula 15 or a salt thereof:

wherein the method comprises (a) compounding the compound of formula 14 or a salt thereof

Reaction with (S)-phenylpropylamine and a reducing agent gives the compound of formula 15, and (b) optionally forms a salt of the compound of formula 15.

In one embodiment, the reaction is carried out in a solvent, wherein the solvent is one, two or more solvents selected from the group consisting of dioxane, N-methylpyrrolidone, dimethylsulfoxide, toluene , dimethylformamide and dimethylacetamide. In another embodiment, the solvent is a mixture of toluene and dimethylacetamide. In another embodiment, the solvent is a mixture of a polar aprotic solvent and a non-polar organic solvent.

In another embodiment, the reaction is carried out under basic conditions. In additional embodiments, the basic reaction conditions are created by the addition of an organic base. In further embodiments, the organic base is one, two or more selected from the group consisting of triethylamine, isopropylamine, diethylamine, n-butylamine, DBU, DMAP and N,N-diiso Propylethylamine. In another embodiment, the organic base is isopropylamine.

The reducing agent used in this reaction can be any reducing agent suitable for reducing the imine formed between the compound of formula 14 and (S)-phenylpropylamine without substantially interacting with the rest of the compound reaction. In one embodiment, the reducing agent may be a borohydride reagent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tris[2-(ethylhexanoic acid)]borohydride Sodium (sodium tris[2-(ethylhexanoic)]borohydride) and so on. In another embodiment, the reducing agent may be formed in situ. In another embodiment, the reducing agent is sodium tris[2-(ethylhexanoic acid)]borohydride. In another embodiment, the reducing agent is NaBH(OCOR ^c ) ₃ , wherein R ^c is C ₁ -C ₁₂ alkyl, and preferably C ₇ -C ₉ alkyl. The molar mass of the reducing agent may be between 1 and 3 times the molar mass of compound 14, preferably between 1.5 and 2 times.

In one embodiment, the reaction is worked up as follows: After the reaction is complete, part of the solvent is removed by concentration, then methanol is added and stirred until crystallization.

fourth aspect

其中所述方法包括(a)將式15化合物或其鹽類

與甲醛同等物反應以得到式8化合物

， 和(b)視需要地形成式8化合物的鹼金屬鹽或鹼土金屬鹽。In a fourth aspect, the present invention provides a method for preparing a compound of formula 8 or a salt thereof:

wherein the method comprises (a) compounding the compound of formula 15 or a salt thereof

Reaction with formaldehyde equivalents to give compounds of formula 8

, and (b) optionally form an alkali metal or alkaline earth metal salt of the compound of formula 8.

In one embodiment, the reaction forms the sodium salt of the compound of formula 8.

In one embodiment, the reaction solvent is a mixture of a polar aprotic solvent and a non-polar organic solvent. In another embodiment, the solvent is one, two or more selected from the group consisting of toluene, xylene, chlorobenzene, ethyl acetate, isopropyl acetate, propyl acetate and butyl acetate. In another embodiment, the solvent is a mixture of chlorobenzene and isopropyl acetate.

In another embodiment, an acid catalyst is added to the reactant. In further embodiments, the acid catalyst is one, two or more selected from the group consisting of trifluoroacetic acid, concentrated sulfuric acid, hydrochloric acid, and trifluoromethanesulfonic acid. In another embodiment, the acid catalyst is trifluoromethanesulfonic acid.

In another embodiment, the reaction is carried out at a temperature in the range of 20 to 50°C, and preferably in the range of 30 to 40°C.

In another embodiment, the post-treatment mode is as follows: reduce the temperature, add 1 to 4 mol/L sodium hydroxide solution, the weight of which is 8 to 11 times that of compound 15; after stirring and extraction, separate the organic layer, and then use Wash with saturated brine; add high boiling point solvent, then remove low boiling point solvent by stirring and concentration; stop concentration until the remaining concentrated solution is about 4 times the weight of compound 15; and use the remaining concentrated solution directly in the next reaction. The high boiling point solvent is one, two or more selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide, and preferably It is N,N-dimethylacetamide.

fifth aspect

其中所述方法包括將式8-M化合物：

，其中M是鹼金屬或鹼土金屬， 與式9化合物反應

以得到式10化合物或其鹽類

。In a fifth aspect, the present invention provides a method for preparing a compound of formula 10 or a salt thereof:

wherein the method comprises compounding a compound of formula 8-M:

, where M is an alkali metal or alkaline earth metal, reacts with the compound of formula 9

to obtain the compound of formula 10 or its salts

.

In one embodiment, the reaction solvent is a polar aprotic solvent. In another embodiment, the reaction solvent is one, two or more selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethylformamide asian. In another embodiment, the reaction solvent is N,N-dimethylacetamide.

In another embodiment, M is an alkali metal. In additional embodiments, M is sodium.

In another embodiment, the reaction is carried out at a temperature in the range of 10 to 40°C, and preferably in the range of 20 to 30°C.

In another embodiment, a coupling agent is added to the reactant. In another embodiment, the coupling agent is selected from the group consisting of HATU, HBTU, HCTU, PyBOP and TBTU. In another embodiment, the coupling agent is PyBOP.

In another embodiment, the reaction is carried out under basic conditions. In another embodiment, the basic reaction conditions are achieved by adding a base to the reaction. In one embodiment, the base is an organic base. In further embodiments, the base is selected from triethylamine, N-methylmorpholine, diisopropylethylamine, and 4-methylaminopyridine. In another embodiment, the base is N-methylmorpholine.

In another embodiment, Compound 8-M and the coupling agent are fed in a molar ratio ranging from 1:1.1 to 1:3. In another embodiment, Compound 8-M, Compound 9, and the organic base are fed in a molar ratio ranging from 1:1.05:1 to 1:1.1:3.

In another embodiment, the work-up mode is as follows: after the reaction is complete, add ethyl acetate and water for extraction with stirring, separate and remove the aqueous layer, pour the organic layer into the reaction solvent used in the next step, and then concentrate until The remaining concentrated solution was about 2 times by weight of compound 8-M; the remaining concentrated solution was directly used in the next reaction without isolation.

sixth aspect

，和第二步：加入鹽酸以製備OAD2的單HCl鹽(式11化合物)

。In a sixth aspect, the present invention provides a method for preparing the mono-HCl salt of OAD2 (the compound of formula 11), wherein the method comprises a first step: hydrolysis of the methyl ester of the compound of formula 10

, and the second step: adding hydrochloric acid to prepare the mono-HCl salt of OAD2 (compound of formula 11)

.

In one embodiment, the reaction solvent is a polar aprotic solvent. In another embodiment, the reaction solvent is selected from 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, acetone and acetonitrile, and is preferably tetrahydrofuran. In another embodiment, the solvent is 4 to 8 times the weight of OAD2.

In another embodiment, the reaction is carried out in a temperature range of 10 to 40°C, and preferably in a range of 15 to 25°C.

In one embodiment, an alkaline solution is added to the reactants. In additional embodiments, the alkaline solution is a 2 to 4 mol/L sodium hydroxide solution, and Compound 10 and sodium hydroxide are fed in a molar ratio ranging from 1 :4 to 1 :6.

In another embodiment, the process of adding 1 to 2 mol/L hydrochloric acid solution; and adjusting the pH to the range of 1 to 4, preferably to the range of 2 to 3.

In another embodiment, the work-up mode is as follows: After adjusting the pH to between 1 and 4, the reaction mixture is stirred until crystallisation or standing crystallisation, and preferably standing crystallisation.

seventh aspect

In a seventh aspect, the present invention provides a method of preparing a bis-HCl salt of OAD2, wherein the method comprises reacting a mono-HCl salt of OAD2 (a compound of formula 11) with HCl to prepare a bis-HCl salt of OAD2.

In one embodiment, the reaction is carried out in a solvent mixture comprising water and a polar aprotic solvent. In another embodiment, the reaction is carried out in a solvent mixture comprising water and a solvent selected from the group consisting of acetic acid, tetrahydrofuran and acetone. In another embodiment, the reaction is carried out in a solvent mixture comprising water and tetrahydrofuran, and the weight of the reaction solvent is 15 to 20 times the weight of the mono-HCl salt of OAD2.

In another embodiment, during the reaction, hydrochloric acid solution A is first added and stirred, then water is added and further stirred, and then hydrochloric acid solution B is added and stirred until crystallization. The weight of hydrochloric acid solution A was 2 to 3 times that of the mono-HCl salt of OAD2, and the weight of hydrochloric acid solution B was 6 to 8 times that of the mono-HCl salt of compound OAD2. The concentrations of the hydrochloric acid solutions A and B are 3 to 6 mol/L, preferably 4 to 5 mol/L.

方案2According to the present invention, a specific preparation method may include one or more steps in Aspects 1 to 7 as shown in Scheme 2 below.

Scenario 2

eighth aspect

，其中R¹ 是C_1-6 烷基，並且R² 是C_1-6 烷基或芳基甲氧基。在式13化合物或其鹽類的另一個實施方案中，R¹ 是甲基。在式13化合物或其鹽類的另一個實施方案中，R² 是甲基。在式13化合物或其鹽類的另一個實施方案中，R¹ 是甲基並且R² 是甲基。In an eighth aspect, the present invention provides intermediate compounds of formula 13 and compounds of formula 14. In one embodiment, the present invention provides a compound of formula 13 or a salt thereof:

, wherein R ¹ is C _1-6 alkyl, and R ² is C _1-6 alkyl or arylmethoxy. In another embodiment of the compound of formula 13 or ^a salt thereof, R1 is methyl. In another embodiment of the compound of ^formula 13 or a salt thereof, R2 is methyl. In another embodiment of a compound of ^formula 13 or ^a salt thereof, R1 is methyl and R2 is methyl.

。In another embodiment, the present invention provides a compound of formula 14 or a salt thereof:

.

The present invention can achieve the following beneficial effects: compared with the prior art method, the method for preparing OAD2 dihydrochloride has fewer steps, does not require separation and purification by column chromatography, and is suitable for industrial mass production. In addition, in the method of the present invention, the step of preparing the mono-HCl salt of OAD2 from compound 15 can be carried out in a continuous feeding mode, and no purification process can be required; the post-processing is simplified and the product loss is minimized; the solid product can be passed through the acid And the basic salt-forming mode is precipitated from a certain solvent to achieve the purification effect, and at the same time obtain high-purity OAD2 mono-HCl salt, and then obtain the target compound OAD2 di-HCl salt through a further salt-forming step. The preparation method of the present invention, from compound 1 to the final product compound OAD2 dihydrochloride, can have an overall yield of more than 35%, and the purity of the final product can exceed 98%. Compared with the prior art, the method of the present invention can have a significantly improved yield and is suitable for large-scale industrial production. Certain embodiments of the present method have reached batch sizes of 50 kg and exhibit good process stability and controllable product quality. Example

The invention will be further illustrated by combining the following specific embodiments. The following embodiments are used to explain the method of the present invention and its core concept, and for those skilled in the art, any possible changes or substitutions without departing from the concept of the present invention fall within the protection scope of the present invention. In the following examples, where specific conditions of the experimental methods are not indicated, they are generally conventional conditions, or those recommended by the manufacturers of raw materials or commercial products; and solvents that do not indicate sources are generally commercially available conventional solvents . Compounds 1, 12 and 9 can be prepared according to the methods described in CN102378574B and WO2007093013 A1, which are hereby incorporated by reference in their entirety.

Example ¹ : Method for the preparation of compound ¹³ wherein R1 is ethyl and R2 is methyl

To a solution of compound 1 (30 kg) in DCM was added acetamido-(dimethoxy-phosphoronyl)-ethyl acetate (19.2 kg). The mixture was cooled to 16.8°C and DBU (22.17kg) was added over 2 hours, keeping the internal temperature below 34°C. The reaction mixture was stirred at 25°C-30°C overnight. Saturated aqueous _NH4Cl (250 L) was added and the mixture was stirred for 1.5 hours, then allowed to stand for 1 hour. The organic layer was separated and DCM (199.3 kg) was added and the mixture was stirred for 1 hour. Brine (300 L) was added and the mixture was stirred for 30 minutes and allowed to stand overnight. The organic layer was separated. The aqueous phase was stirred with DCM (150.4 kg) for 1 hour and the organic layer was separated. The combined organic phases were filtered and the filtrate was concentrated to a volume of 170L. MeOH (199.4 kg) was added and the mixture was concentrated to a volume of 165 L. MeOH (199.7 kg) was added and the mixture was concentrated to a volume of 180 L. MeOH (68.4 kg) and water (150.2 kg) were added and the mixture was stirred at room temperature overnight and filtered. The filtered solid was treated with MeOH (159.6 kg) and water (100.0 kg) and stirred overnight.

About half of the mixture was filtered and the collected solids were washed with water (10.0 kg) and MeOH (16.0 kg). The solid was dried to obtain 14.18 kg of 13 as a grey solid.

The remaining half of the above-mentioned mixture was filtered and the collected solids were washed with water (15.0 kg) and MeOH (24.0 kg). The solid was dried to give 19.45 kg of 13 as a grey solid in an overall yield of 33.63 kg.

Example 2: Preparation of Compound 14

Compound ¹³ (31.3 kg) (wherein R1 is ethyl and R2 is methyl ⁾ was treated with dioxane (242.8 kg) and stirred at ambient temperature. The mixture was treated with 6N hydrochloric acid (prepared from 58.7 kg of water and 70.4 kg of concentrated aqueous HCl). The mixture was heated to reflux (84-94.3 °C) with stirring for 19.5 hours. The mixture was cooled to 25 °C and treated with water (782.5 kg). After stirring for 1.5 hours at 20 °C the mixture was filtered and the collected solid was washed twice with 30 kg of water. With stirring, the solid was triturated with water (300 kg) at 17-19 °C for 1 hour. The solid was collected by filtration, and the collected solid was washed twice with 30 kg of water. With stirring, the solid was triturated with 86.7 kg of methanol at 20°C for 2 hours. The solid was collected by filtration and washed with 12.4 kg methanol. The solids were collected and dried under reduced pressure at 39°C. With stirring, the solid was triturated with dichloromethane (165.9 kg) at 20 °C for 2 hours. The solid was collected by filtration, washed with 20.8 kg of dichloromethane, and dried under reduced pressure at 40 °C to obtain 20.76 kg of compound 14 as a beige/off-white solid.

Example 3: Preparation of Compound 15

Anhydrous dioxane (2.4 L), sodium borohydride (278 g) and toluene (2.4 L) were added to the reaction vessel. The mixture was stirred at 25°C for 15-20 minutes. The mixture was cooled to -7°C and 2-ethylhexanoic acid (1.56 L) was added over 90 minutes while maintaining the temperature at -5±2°C. The temperature was raised to 10 °C to initiate an exothermic reaction, then external cooling was applied to maintain the internal temperature at 15 °C. The reaction mixture was stirred at 15°C for 18 hours. The reducing agent solution was used in the next step without further modification.

Toluene (22.0 L) and 14 (2.2 kg) were combined and tri-n-butylamine (1.22 L) was added to the stirred suspension while maintaining the temperature below 25 °C. Continue stirring at 25°C for 30 minutes until all starting material is dissolved. To the mixture was added (S)-1-phenylpropan-1-amine (810 mL), and the mixture was stirred at 25 °C for 1.5 hours. The mixture was cooled to 10°C, keeping the temperature below 15°C, and the reducing agent (prepared above) was added dropwise. The obtained mixture was stirred at 15°C for 18 hours. The reaction mixture was quenched by adding MeOH (600 mL) and the mixture was stirred at 25 °C for 1 hour. The quenched reaction mixture was concentrated to dryness and the residue was treated with DMF (8.1 L). The suspension was heated at 75-80 °C for 30 minutes, the clear solution was cooled to 25 °C and sample 15 (5 g) was crystallized. The mixture was cooled to 15°C and stirred for 30 minutes. The solid product was collected by filtration and washed three times with 2 L of methanol. The product was dried to obtain 1.98 kg of compound 15.

Example 4A: Preparation of Compound 8-M (wherein M is Na)

Dioxane (1.93 L), TFA (6.43 L), toluene (10 L) and paraformaldehyde (324 g, 10.8 mol) were combined and cooled to 27 ^° C. Compound 15 (1606 g, 2.713 mol) was added along with additional toluene (7.4 L). The reaction mixture was stirred at 27 ^° C for 20 hours until the reaction was complete. The mixture was cooled to 22 ^° C and diluted with EtOAc (22 L) and washed with brine (20 L). Brine (8 L) was added to the organic layer and the pH of the mixture was adjusted to 6.5 with 2M sodium carbonate (19 L was added over 3 hours). The organic and aqueous layers were separated, and the organic layer was washed with brine (15 L). The organic layer was dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The residue was dissolved in 10 L of EtOAc and stirred with saturated sodium carbonate (10 L) for 15 minutes. Brine (10 L) was added and the mixture was stirred for 10 minutes. The organic and aqueous layers were separated, and the organic layer was filtered through a pad of sodium sulfate. The pad was washed with EtOAc. Methyl tert-butyl ether (MTBE) (110 L) was added to the filtrate and stirred for 1 hour. The obtained solid was filtered under gravity and the collected solid was washed with MTBE (2 L). A vacuum was then applied to remove the solvent and the material was air dried overnight. The obtained solid was dried on a stirred rotary evaporator for 6 hours to obtain 1406 g of product 8-M.

Example 4B: Alternative Preparation of Compound 8-M (wherein M is Na)

Paraformaldehyde (1176.0 g), TFA (26.0 kg), toluene (48.4 kg) and iPrOAc (12.1 kg) were mixed. The temperature of the mixture was adjusted to 22.0 °C and compound 15 (5.9 kg) was added along with an additional 6.0 kg of toluene. The mixture was stirred at 25.7-30.8 °C for about 3.5 hours. Isopropyl acetate (10.2 kg) was added and the resulting mixture was cooled to 5.9 °C. 4N NaOH (68 kg) solution was added over 26 minutes while keeping the temperature below 25°C. The temperature of the mixture was adjusted to 20.4°C, and the obtained mixture was stirred at 20.4-21.1°C for 10 minutes. The layers were separated and the organic layer was washed with brine (2 x 14.6 kg). The organic layer was diluted with DMF (10.8 kg) and the mixture was concentrated under reduced pressure to a volume of 12 L. DMF (10.8 kg) was added and the mixture was stirred at 22.4-25.0 °C for 10 minutes. An 8-M solution in DMF was used as the starting material in Example 5B.

Example 5A: Preparation of Compound 10

Under nitrogen, compound 9 ((S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl-]-propionic acid methyl ester) (702.4 g ) was dissolved in DMF (4.75 L) and the temperature was adjusted to 20 ^° C. Compound 8-M (1406 g, 2.246 mol), HBTU (937 g, 2.47 mol) and DMF (2.75 L) were added. NMM (4-methylmorpholine) (493ml) was added and the temperature was raised to 28 ^° C. The mixture was immediately brought to 23-25 ^° C and stirred for 1 hour. The mixture was poured into vigorously stirred water (35 L) and the resulting suspension was stirred for 1 hour. The solids were filtered and washed with water (10L) and hexanes (10L). The solid was dissolved in EtOAc (12 L) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained solid was dissolved in MTBE-DCM (3.1 L, 30:1) and chromatographed on silica gel (6 kg) using MTBE as eluent to give compound 10 (1851 g).

Example 5B: Alternative Preparation of Compound 10

A solution of compound 9 (3.1 kg) in 8 L DMF was treated with 4-methylmorpholine (2001.2 g). The solution of Compound 8-M in DMF (from Example 4B) was added with additional DMF (3.5 kg). The temperature of the mixture was adjusted to 0 °C. HBTU (4.1 kg) was added while keeping the temperature below 15 °C. The mixture was warmed to 17.9 ^° C and stirred at 17.9 ^° C to 22.6°C for 3 hours. The reaction mixture was diluted with EtOAc (42.1 kg) and the temperature was adjusted to 12.3 °C. Water (69.6 kg) was added and the resulting mixture was stirred at 19.1°C to 20.4°C for 30 minutes. The separated organic layer was concentrated under reduced pressure to a volume of 6 L. 2-Methyltetrahydrofuran (9.9 kg in two portions) was added and the mixture was concentrated under reduced pressure to a volume of 6 L. The obtained solution of compound 10 was kept at -10±5°C and used in the next step Example 6.

OAD2二鹽酸鹽Example 6: Preparation of OAD2 dihydrochloride.

OAD2 dihydrochloride

The solution of compound 10 from Example 5B was diluted with 2-methyltetrahydrofuran (29.9 kg). The mixture was warmed to 17.9 °C and stirred at 17.9-21.3 °C for 1 hour. The mixture was cooled to 9.5 °C. 2N NaOH (prepared from NaOH 1568.9g, water 19.4kg) was added while keeping the temperature below 20°C. The mixture was brought to 15.3 °C and held between 15.3-22.9 °C for 21 hours. The reaction mixture was cooled to 4.6 °C and the pH of the mixture was adjusted to 3.94 with 1 N HCl. The temperature of the reaction mixture was adjusted to 8.8 °C. The mixture was stirred at 5.7-8.8 °C for 2.5 hours, which resulted in the formation of a slurry. The slurry was warmed to 16.5 °C and stirred at 16.5-18.7 °C for 1 hour. The solid was collected by filtration, then washed with water (5.8 kg) and 2-methyltetrahydrofuran (5.1 kg). The solid product was dried under reduced pressure at 39 ^° C to obtain 6.4 kg of crude OAD2-HCl as a white solid.

Combine crude OAD2-HCl (6.4 kg), 2-methyltetrahydrofuran (110.2 kg) and water (12.8 kg). The mixture was heated to 55.0°C and stirred at 55.0-65.0°C for 2 hours. The mixture was cooled to 25.0 °C over 1 h and stirred at 19.8-25.0 °C for 1 h. The solid was filtered, washed with 2-methyltetrahydrofuran (4.1 kg) and dried under reduced pressure at 39 °C to obtain 4.2 kg of OAD2-HCl as a white solid.

OAD2-HCl (4.1 kg) was treated with AcOH (8.9 kg), the temperature of the mixture was adjusted to 19.7 °C, and the mixture was stirred at 19.4-19.7 °C for 30 minutes. 5N HCl (prepared from water 5.0kg, 37% HCl 4.2kg) was added over 10 minutes while keeping the temperature below 25°C. The mixture was stirred at 19.1-21.2 °C for 1 hour. Water (84.0 kg) was added over 1 hour while maintaining the temperature below 25°C. The mixture was stirred at 19.7-22.4 °C for 1.5 hours to obtain a clear solution, which was transferred to a second reaction vessel along with AcOH (4.1 kg) and water (8.5 kg). 5N HCl (prepared from water 14.6kg, HCl 37% 12.6kg) was added while keeping the temperature below 25°C. The mixture was stirred at 19.4-20.2 °C for 1 hour. The solid obtained was collected by filtration and washed with 1N HCl (4.5 kg). The collected solid was treated with IN HCl (42.8 kg). The mixture was stirred at 19.2-19.3 °C for 30 minutes, filtered, and the collected solids were washed with 1 N HCl (5.3 kg). The collected solid was treated with IN HCl (42.8 kg). The mixture was stirred at 19.2-19.6 °C for 40 minutes, filtered, and the collected solids were washed with 1N HCl (6.1 kg). The solid product was dried under reduced pressure at 40 °C to obtain 4.1 kg of OAD2-2HCl as a white solid.

without.

without.

Claims (54)

A compound of formula 13 or salts thereof:

, wherein R ¹ is C _1-6 alkyl, and R ² is C _1-6 alkyl or arylmethoxy. The compound of claim 1, wherein R ¹ is methyl and R ² is methyl. A compound of formula 14 or salts thereof:

. A method for preparing a compound of formula 15 or a salt thereof:

wherein the method comprises (a) compounding a compound of formula 14 or a salt thereof,

Reaction with (S)-phenylpropylamine and a reducing agent provides a compound of formula 15, and (b) optionally forms a salt of the compound of formula 15. The method of claim 4, wherein the reaction is carried out in a solvent, wherein the solvent is selected from the group consisting of dioxane, N-methylpyrrolidone, dimethylsulfoxide, toluene, dimethylformamide, and dimethylformamide Methylacetamide. The method of claim 4 or 5, wherein the reaction is carried out under basic conditions. The method of claim 6, wherein the alkaline reaction conditions are created by adding an organic base. The method of claim 7, wherein the organic base is selected from the group consisting of triethylamine, isopropylamine, diethylamine, n-butylamine, DBU, DMAP and N,N-diisopropylethylamine. The method of any one of claims 4 to 8, wherein the reducing agent is a borohydride reagent. The method of claim 9, wherein the borohydride reagent as the reducing agent is NaBH(OCOR ^c ) ₃ , wherein R ^c is a C ₁ -C ₁₂ alkyl group. The method of claim 10, wherein the borohydride reagent is sodium tris[2-(ethylhexanoic)]borohydride. The method of any one of claims 4 to 11, wherein the molar mass of the reducing agent may be between 1 and 3 times the molar mass of compound 14. The method of any one of claims 4 to 12, further comprising the step of isolating the compound of formula 15, and optionally purifying the isolated compound of formula 15. The method of any one of claims 1 to 13, further comprising the step of: (a) reacting the compound of formula 15 or a salt thereof with a formaldehyde equivalent to obtain a compound of formula 8-M

, wherein M is an alkali metal or an alkaline earth metal, (b) reacting the compound of formula 8-M with a compound of formula 9:

to obtain a compound of formula 10 or a salt thereof:

, (c) hydrolyzing the methyl ester of the compound of formula 10 and adding hydrochloric acid to the reaction to prepare the mono-HCl salt compound of formula 11:

. The method of claim 14, wherein the compound of formula 8-M is the sodium salt. The method of claim 14 or 15, wherein the reaction solvent used in step (a) is a mixture of a polar aprotic solvent and a non-polar organic solvent. The method of claim 14 or 15, wherein the reaction solvent used in step (a) is selected from the group consisting of toluene, xylene, chlorobenzene, ethyl acetate, isopropyl acetate, propyl acetate and butyl acetate. The method of claim 17, wherein the reaction solvent used in step (a) is a mixture of chlorobenzene and isopropyl acetate. The method of any one of claims 14 to 18, wherein step (a) comprises adding an acid catalyst. The method of claim 19, wherein the acid catalyst is selected from the group consisting of trifluoroacetic acid, concentrated sulfuric acid, hydrochloric acid and trifluoromethanesulfonic acid. The method of claim 20, wherein the acid catalyst is trifluoromethanesulfonic acid. The method of any one of claims 14 to 21, wherein step (a) is carried out in a temperature range of 20 to 50°C, and preferably carried out in a range of 30 to 40°C. The method of any one of claims 14 to 22, wherein step (a) further comprises the step of isolating the compound of formula 8-M. The method of any one of claims 14 to 23, wherein the reaction solvent used in step (b) is a polar aprotic solvent. The method of claim 24, wherein the reaction solvent used in step (b) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide. The method of claim 24 or 25, wherein step (b) is carried out in a temperature range of 10 to 40°C. The method of any one of claims 24 to 26, wherein step (b) includes adding a coupling agent. The method of claim 27, wherein the coupling agent is selected from the group consisting of HATU, HBTU, HCTU, PyBOP and TBTU. The method of claim 28, wherein the couplant is PyBOP. The method of any one of claims 24 to 29, wherein step (b) comprises adding a base to create alkaline reaction conditions. The method of claim 30, wherein the base is selected from the group consisting of triethylamine, N-methylmorpholine, diisopropylethylamine and 4-methylaminopyridine. The method of any one of claims 27 to 31, wherein the compound 8-M and the coupling agent are fed in a molar ratio ranging from 1:1.1 to 1:3. The method of any one of claims 24 to 32, wherein step (b) further comprises the step of isolating the compound of formula 10. The method of any one of claims 4 to 33, wherein the reaction solvent used in step (c) is a polar aprotic solvent. The method of claim 34, wherein the reaction solvent is selected from the group consisting of 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, acetone and acetonitrile. The method of claim 34 or 35, wherein the reaction in step (c) is carried out in a temperature range of 10 to 40°C. The method of any one of claims 34 to 36, wherein step (c) comprises adding an alkaline solution. The method of claim 37, wherein the alkaline solution is a 2 to 4 mol/L sodium hydroxide solution. The method of claim 38, wherein the compound of formula 10 and sodium hydroxide are fed in a molar ratio ranging from 1:4 to 1:6. The method of any one of claims 34 to 40, wherein the solution of hydrochloric acid is 1 to 2 mol/L and the pH is adjusted to a range of 1 to 4. The method of any one of claims 34 to 42, wherein step (c) further comprises the step of isolating the mono-HCl salt of the compound of formula 11. The method of any one of claims 34 to 41, further comprising step (d), wherein the mono-HCl salt of the compound of formula 11 is reacted with HCl to prepare the bis-HCl salt of the compound of formula 11. The method of claim 41, wherein the reaction in step (d) is carried out in a solvent mixture comprising water and a solvent selected from the group consisting of acetic acid, tetrahydrofuran and acetone. The method of any one of claims 41 to 43, wherein the weight of the reaction solvent is 15 to 20 times that of the mono-HCl salt of OAD2. The method according to any one of claims 41 to 44, wherein during the reaction, firstly, a hydrochloric acid solution A is added and stirred, then water is added and further stirred, and then a hydrochloric acid solution B is added and stirred until crystallization. The method of claim 45, wherein the weight of the hydrochloric acid solution A is 2 to 3 times that of the mono-HCl salt of the compound of formula 11, and the weight of the hydrochloric acid solution B is 6 to 3 times that of the compound of formula 11 8 times. The method of claim 46, wherein the concentrations of the hydrochloric acid solutions A and B are 3 to 6 mol/L. The method of any one of claims 1 to 47, wherein the compound of formula 13 or a salt thereof is prepared by compounding the compound of formula 1:

Reaction with compound of formula 12:

to obtain a compound of ^formula 13 or ^a salt thereof, wherein ^Ra and ^Rb are independently selected from _C1-6 alkyl, R1 is _C1-6 alkyl, and R2 is _C1-6 alkyl or aryl Methoxy. The method of claim 48, wherein the reaction for preparing the compound of formula 13 is carried out in a solvent comprising one or more solvents selected from the group consisting of dichloromethane, toluene, tetrahydrofuran and 2-methyltetrahydrofuran. The method of claim 48 or 49, wherein R ¹ , R ² , ^Ra and R ^b are methyl or ethyl. The method of any one of claims 48 to 50, wherein the reaction to prepare the compound of formula 13 is carried out under basic conditions. The method of claim 51, wherein an organic base is added to the reaction. The method of claim 52, wherein the organic base is selected from the group consisting of DBU, DMAP, triethylamine, isopropylamine, dibutylamine, oxazine, oxidine and morpholine. The method of claim 53, wherein the compound of formula 1 and the compound of formula 12 and the organic base are fed in a molar ratio ranging from 1:1.05:1.5 to 1:2:3.