TW202012417A - Process for preparing an optically active pyrimidinium compounds - Google Patents

Abstract

The present invention relates to a process for preparing optically active compounds of formula X and intermediates thereof,

Description

Method for preparing optically active pyrimidinium compound

The invention relates to a method for preparing an optically active pyrimidinium compound of formula X according to the following reaction sequence:

It is known from WO2014/167084 that pyrimidinium compounds of formula X have insecticidal properties. However, the method of preparing the optically enriched pyrimidinium compound of Formula X is not described in the prior art. The method of the invention for the preparation of optically active pyrimidinium compounds is based on the asymmetric transfer hydrogenation of acyclic imine derivatives of formula V, which contain a leaving group at the α-carbon atom relative to the imine functional group, such as halogen . Usually hydrogenated α-haloimines, such as α-haloimines of formula V, where W represents halogen, produce a mixture of corresponding original dehalogenated compounds (where W is hydrogen in formula VI), and remove the desired α- Haloamines, such as compounds of formula VI, form aziridine derivatives by replacing the α-halogen atom with an amine nitrogen. In addition, it is known from the literature that enantiomers can exhibit different ranges of pesticidal or insecticidal activity. It is also possible that although a particular enantiomer exhibits insecticidal activity, its counterpart may be completely inactive against insects. Therefore, the strict requirement for any approved application is to use only the palmitate compounds with pesticidal or insecticidal activity only in the form of their corresponding active enantiomers. Therefore, there is a need for a method of preparing an optically active compound of formula X having an enantiomeric excess greater than 90% and a high yield.

The present invention relates to a method for preparing an optically active pyrimidinium compound of formula X. This objective is achieved by the method described in detail below.

其中 C*為S或R-組態之不對稱碳原子； R¹ 為C₁ -C₄ 烷基、C₃ -C₆ 環烷基、C₂ -C₄ 烯基或-CH₂ -苯基，該等基團未經取代或經鹵素或C₁ -C₄ 烷基取代； R² 為5員或6員飽和、部分不飽和或芳族碳環或雜環，其中該環未經取代或經R^2a 取代； Het係選自D-1、D-2及D-3：

其中 R^a 各自獨立地為鹵素、C₁ -C₄ 鹵烷基、C₁ -C₄ 烷氧基、C₁ -C₄ 烷硫基或苯基； n為0、1或2，及 #表示式X中之鍵； R^2a 為鹵素、C₁ -C₆ 鹵烷基、C₁ -C₆ 鹵烷氧基、OR^c 、C(=O)OR^c 、C(=O)NR^b R^c 、苯基或吡啶基，該等基團未經取代或經鹵素、C₁ -C₆ 鹵烷基或C₁ -C₆ 鹵烷氧基取代； R^b 為氫、C₁ -C₆ 烷基、C₁ -C₆ 鹵烷基、C₁ -C₆ 烷氧基或C₁ -C₆ 鹵烷氧基； R^c 為氫、C₁ -C₄ 烷基、C₁ -C₄ 鹵烷基或C₁ -C₆ 環烷基； 其中兩個偕鍵結之基團R^c R^b 與其所鍵結之原子一起可形成3員至7員飽和、部分不飽和或芳族雜環； 其包含至少以下步驟， (A) 式V化合物，

其中 R^A 為S(=O)_o R^x 、P(=O)(R^x )₂ 、C₁ -C₄ 烷氧基或-CH₂ -苯基，其中苯基未經取代或經鹵素、甲氧基或硝基取代； 其中R^x 為C₁ -C₆ 烷基或芳基，其未經取代或經鹵素取代；及 o為1或2； W為鹵素、羥基、O-對甲苯磺醯基、O-甲烷磺醯基或O-三氟甲烷磺醯基； Het係如式X化合物中所定義； 在氫化催化劑MXLn(ƞ-芳烴)_m ， 其中 M為來自元素週期表第VIII族至第XII族之過渡金屬； X為陰離子； m為0或1； Ln為Ln1或Ln2， 其中 Ln1為式Ln1之對掌性配體

其中 C*為S或R-組態之不對稱碳原子； R¹⁰ 為OH或NH-SO₂ -R¹¹ ；其中 R¹¹ 為未經取代或經鹵素、C₁ -C₁₀ 烷基、C₁ -C₄ 烷氧基、C₃ -C₆ 環烷基、SO₃ H或SO₃ Na取代之芳基； 或 C₁ -C₁₀ 全氟烷基，或R¹³ R¹⁴ N，其中R¹³ 及R¹⁴ 獨立地表示未經取代或經C₆ -C₁₀ 芳基取代之C₁ -C₁₀ 烷基，或R¹³ 及R¹⁴ 各自獨立地表示C₆ -C₁₀ 環烷基； R¹² 獨立地表示C₆ -C₁₀ 芳基環或C₆ -C₁₀ 環烷基環，其中該環未經取代或彼此獨立地經鹵素、C₁ -C₁₀ 烷基、C₁ -C₄ 烷氧基、C₃ -C₆ 環烷基、SO₃ H或SO₃ Na取代，或兩個R¹² 連接在一起以形成3員至6員碳環或5員至10員部分不飽和碳環； Ln2為對掌性磷配體； 及選自以下之氫源存在下氫化：a)氫氣；b) N(R)₃ 與HCOOH之混合物，其中R為H或C₁ -C₆ 烷基；c) HCOONa或HCOOK；d) C₁ -C₈ 醇及t-BuOK、t-BuONa或t-BuOLi之混合物；及e) a)至d)中之兩者或更多者之組合； 以獲得式VI化合物，

其中C*、R^A 、Het及W係如式V化合物中所定義。 (B) 在酸或鹼存在下，水解如本文所定義之式VI化合物， 以獲得式VII化合物

其中C*、Het及W係如式VI化合物中所定義。 (C) 在鹼存在下，使如本文所定義之式VII化合物與R¹ NCS反應，其中R¹ 為C₁ -C₄ 烷基、C₃ -C₆ 環烷基、C₂ -C₄ 烯基或-CH₂ -苯基，該等基團未經取代或經鹵素或C₁ -C₄ 烷基取代， 以獲得式VIII化合物，

其中C*、Het及R¹ 係如式VII化合物中所定義； (D) 使如本文所定義之式VIII化合物與式IX化合物反應，

其中， LG為選自鹵素、OR^u 或SR^u 之離去基；其中 R^u 為C₁ -C₆ 烷基或芳基，其未經取代或經鹵素取代； R² 係如式X化合物中所定義； 以獲得式X化合物。 製備式X化合物之方法視情況進一步包含藉由至少以下步驟製備式V化合物之方法： (E) 使式I化合物，

其中W係如本文所定義，且X¹ 為鹵素； 與NH(R^Q )(R^p ).HCl在鹼存在下反應，其中R^Q 及R^p 獨立地為C₁ -C₆ 烷基或C₁ -C₆ 烷氧基，或R^Q 及R^p 連接在一起以形成5員至7員碳環或雜環； 以獲得式II化合物，

其中R^Q 、R^p 及W係如本文所定義； (F) 使如本文所定義之Het與如本文所定義之式II化合物在R^L MgX¹ 或R^L Li存在下反應；其中R^L 為C₁ -C₆ 烷基；X¹ 為鹵素及金屬鹵化物，其中金屬為鋰、鈉、鉀或鎂； 以獲得式III化合物，

其中Het及W係如本文所定義； (G) 藉由使如本文所定義之式III化合物 與式IV化合物，

其中R^A 係如式V化合物中所定義， 在諸如烷醇鈦(IV)或乙酸銅(II)之路易斯酸(Lewis acid)存在下，或在有機酸或無機酸存在下反應， 以獲得如本文所定義之式V化合物。The first aspect of the present invention relates to a method for preparing an optically active pyrimidinium compound of formula X,

Where C* is an asymmetric carbon atom of S or R-configuration; R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl or -CH ₂ -phenyl , These groups are unsubstituted or substituted with halogen or C ₁ -C ₄ alkyl; R ² is a 5- or 6-membered saturated, partially unsaturated, or aromatic carbocyclic or heterocyclic ring, where the ring is unsubstituted or Substitution by R ^2a ; Het is selected from D-1, D-2 and D-3:

Where R ^{a is} independently halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio or phenyl; n is 0, 1 or 2, and # represents Bond in formula X; R ^2a is halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, OR ^c , C(=O)OR ^c , C(=O)NR ^b R ^c , Phenyl or pyridyl, these groups are unsubstituted or substituted with halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ haloalkoxy; R ^b is hydrogen, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy; R ^c is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl Or C ₁ -C ₆ cycloalkyl; where two gem-bonded groups R ^c R ^b together with the atoms to which they are bonded can form a 3- to 7-membered saturated, partially unsaturated or aromatic heterocyclic ring; it contains At least the following steps, (A) compound of formula V,

Where R ^A is S(=O) _o R ^x , P(=O)(R ^x ) ₂ , C ₁ -C ₄ alkoxy or -CH ₂ -phenyl, where phenyl is unsubstituted or halogenated, Methoxy or nitro substitution; where R ^x is C ₁ -C ₆ alkyl or aryl, which is unsubstituted or substituted with halogen; and o is 1 or 2; W is halogen, hydroxy, O-p-toluenesulfonate Acyl, O-methanesulfonyl, or O-trifluoromethanesulfonyl; Het is as defined in the compound of formula X; in the hydrogenation catalyst MXLn (ƞ-aromatic hydrocarbon) _m , where M is from Group VIII of the periodic table Transition metal to Group XII; X is an anion; m is 0 or 1; Ln is Ln1 or Ln2, where Ln1 is a palmitate ligand of formula Ln1

Where C* is an asymmetric carbon atom with S or R-configuration; R ¹⁰ is OH or NH-SO ₂ -R ¹¹ ; where R ¹¹ is unsubstituted or halogenated, C ₁ -C ₁₀ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, SO ₃ H or SO ₃ Na substituted aryl; or C ₁ -C ₁₀ perfluoroalkyl, or R ¹³ R ¹⁴ N, where R ¹³ and R ¹⁴ independently represents a C ₁ -C ₁₀ alkyl group that is unsubstituted or substituted with a C ₆ -C ₁₀ aryl group, or R ¹³ and R ¹⁴ each independently represent a C ₆ -C ₁₀ cycloalkyl group; R ¹² independently Represents a C ₆ -C ₁₀ aryl ring or a C ₆ -C ₁₀ cycloalkyl ring, wherein the rings are unsubstituted or independently of one another via halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, SO ₃ H or SO ₃ Na substitution, or two R ^{12 are} joined together to form a 3- to 6-membered carbocyclic ring or a 5- to 10-membered partially unsaturated carbocyclic ring; Ln2 is a pair Palm phosphorus ligand; and hydrogenation in the presence of a hydrogen source selected from: a) hydrogen; b) a mixture of N(R) ₃ and HCOOH, where R is H or C ₁ -C ₆ alkyl; c) HCOONa or HCOOK; d) a mixture of C ₁ -C ₈ alcohol and t-BuOK, t-BuONa or t-BuOLi; and e) a combination of two or more of a) to d); to obtain a compound of formula VI,

Wherein C*, R ^A , Het and W are as defined in the compound of formula V. (B) in the presence of an acid or base, hydrolyze the compound of formula VI as defined herein to obtain the compound of formula VII

Where C*, Het and W are as defined in the compound of formula VI. (C) In the presence of a base, the compound of formula VII as defined herein is reacted with R ¹ NCS, wherein R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkene Group or -CH ₂ -phenyl group, these groups are unsubstituted or substituted with halogen or C ₁ -C ₄ alkyl to obtain the compound of formula VIII,

Where C*, Het and R ¹ are as defined in the compound of formula VII; (D) reacting the compound of formula VIII as defined herein with the compound of formula IX,

Wherein LG is a leaving group selected from halogen, OR ^u or SR ^u ; wherein R ^u is C ₁ -C ₆ alkyl or aryl, which is unsubstituted or substituted by halogen; R ² is as in the compound of formula X Defined; to obtain the compound of formula X. The method for preparing the compound of formula X optionally includes a method for preparing the compound of formula V by at least the following steps: (E) using the compound of formula I,

Where W is as defined herein, and X ¹ is halogen; react with NH(R ^Q )(R ^p ).HCl in the presence of a base, where R ^Q and R ^{p are} independently C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, or R ^Q and R ^{p are} joined together to form a 5- to 7-membered carbocyclic or heterocyclic ring; to obtain a compound of formula II,

Wherein R ^Q , R ^p and W are as defined herein; (F) reacting Het as defined herein with a compound of formula II as defined herein in the presence of R ^L MgX ¹ or R ^L Li; wherein R ^L is C ₁ -C ₆ alkyl; X ¹ is halogen and metal halide, wherein the metal is lithium, sodium, potassium or magnesium; to obtain the compound of formula III,

Where Het and W are as defined herein; (G) by using a compound of formula III and a compound of formula IV as defined herein,

Where R ^A is as defined in the compound of formula V, reacted in the presence of Lewis acid such as titanium (IV) alkoxide or copper (II) acetate, or in the presence of an organic or inorganic acid to obtain, for example Compounds of formula V as defined herein.

The compound of formula III can also be prepared similarly to the method as described herein or the method known in WO 2014/167084 or other methods known in the literature.

The starting materials used in the method are commercially available or can be prepared by methods known in the literature.

Another aspect of the present invention relates to a method for preparing an optically active compound of formula X as defined herein, which includes steps (G), (F), (E), (D), (( One or more of C), (B) and (A), preferably in the order described herein (G)→(F)→(E)→(A)→(B)→(C)→ (D).

Amine compounds, especially optically enriched amine compounds having a leaving group at a carbon atom adjacent to the amine functional group such as in Formula VI, can be used as general intermediates for preparing several heterocyclic derivatives. In addition, the optically enriched amine of formula VI can be used as a general intermediate for the preparation of fine chemicals, pharmaceuticals and agricultural chemicals. In addition, compounds of formula VI are useful intermediates for the preparation of pesticidal agents having amine derivatives or N-containing heterocyclic moieties, such as compounds of formula VII, VIII or compounds of formula X, such as WO Reported in 2014/167084 can be used against invertebrate pests. However, the method of preparing the optically enriched compound of formula VI having a leaving group at the carbon atom adjacent to the amine functional group is unknown, and methods known in the literature for preparing compounds similar to the compound of formula VI are in reaction Conditions, yields, and/or processing requirements are unfavorable, or suffer from a number of restrictions, making them almost unsuitable for industrial-scale production

Therefore, there is a need to develop a method for preparing optically enriched compounds of formula VI, more specifically, a method for preparing an enantiomeric excess of preferably >70%, more preferably >85%, and best >90% Formula VI is a method of optically enriching compounds.

This object is achieved by providing an optically active compound of formula VI and a method for preparing an optically active compound of formula VI having an enantiomeric excess.

其係藉由如本文步驟(A)中所述，使如本文所定義之式V化合物氫化。

Other aspects of the invention relate to methods of preparing compounds of formula VI as defined herein,

This is by hydrogenating the compound of formula V as defined herein by as described in step (A) herein.

Other aspects of the invention relate to compounds of formula V or their salts and N-oxides.

其中C*、R^A 、Het及W係如本文所定義。Other aspects of the invention relate to compounds of formula VI or their salts and N-oxides.

Where C*, R ^A , Het and W are as defined herein.

Amine compounds, especially optically enriched amine compounds having a leaving group at a carbon atom adjacent to the amine functional group such as in Formula VII, can be used as general intermediates for preparing several heterocyclic derivatives. In addition, the optically enriched amine of formula VII can be used as a general intermediate for the preparation of fine chemicals, pharmaceuticals and agricultural chemicals. In addition, compounds of formula VII are useful intermediates for the preparation of pesticidal agents having amine derivatives or N-containing heterocyclic moieties, such as compounds of formula VIII or compounds of formula X, such as WO2014/167084 Reported in can be used against invertebrate pests. However, the method of preparing optically enriched compounds of formula VII having a leaving group at the carbon atom adjacent to the amine functional group is unknown, and methods known in the literature for preparing compounds similar to compounds of formula VII are in reaction Conditions, yields, and/or processing requirements are unfavorable, or suffer from a number of restrictions, making them almost unsuitable for industrial-scale production

Therefore, there is a need to develop a method for preparing an optically active compound of formula VII, more specifically, a method for preparing an enantiomeric excess of preferably >80%, more preferably >85%, and best >90% Method of optically active compounds of formula VII.

This object is achieved by providing an optically active compound of formula VII and a method for preparing an optically active compound of formula VII having an enantiomeric excess.

其係藉由如本文步驟(B)中所述，在酸或鹼存在下水解如本文所定義之式VI化合物。

Other aspects of the invention relate to a method of preparing a compound of formula VII as defined herein,

It is by hydrolyzing the compound of formula VI as defined herein in the presence of acid or base as described in step (B) herein.

Other aspects of the invention relate to compounds of formula VII, or their salts and N-oxides.

Where C*, R ¹ and W are as defined herein.

In addition, the optically enriched thiazolidine-2-imine compound of formula VIII can be used as a general intermediate compound for preparing the compound of formula X. The compound of formula X can be used against invertebrate pests as reported in WO2014/167084. In addition, the literature does not report methods for preparing optically enriched thiazolidine-2-imine compounds of formula VIII as defined herein.

Therefore, there is a need to develop a method for preparing optically enriched compounds of formula VIII, more specifically, a method for preparing an enantiomeric excess of preferably >80%, more preferably >90%, and best >95% A method of optically active compounds of formula VIII.

This object is achieved by providing an optically active compound of formula VIII and a method for preparing an optically active compound of formula VIII having an enantiomeric excess.

其係藉由如本文步驟(C)中所述，在鹼存在下使如本文所定義之式VII化合物與R¹ NCS反應，其中R¹ 係如本文所定義。

Other aspects of the invention pertain to a method of preparing a compound of formula VIII as defined herein,

This is by reacting a compound of formula VII as defined herein with R ¹ NCS in the presence of a base as described in step (C) herein, where R ¹ is as defined herein.

Other aspects of the invention relate to compounds of formula VIII or their salts and N-oxides.

Where C*, Het and R ¹ are as defined herein.

Another aspect of the present invention relates to a method of preparing a compound of formula X as defined herein, which is as described in step (D) herein, such that a compound of formula VIII as defined herein and a compound of formula IX as defined herein reaction.

The molecular structure of the compound of formula X can exist in different isoelectronic formulas, and each isoelectronic formula has formal positive and negative charges on different atoms, as shown below. The invention extends to methods for preparing all representative isoelectronic structures of compounds of formula X.

"Invention", "Invention" or "Invention Method" means one or more of steps (G), (F), (E), (D), (C), (B) and (A) , Preferably refers to one or more of steps (D), (C), (B) and (A). "Compound of the invention" or "compound according to the invention", ie compounds of formula VI, VII or VIII as defined herein, including compounds and their salts, tautomers or N-oxides, if such derivatives It is possible.

The term "stereoisomer" encompasses optical isomers such as enantiomers or diastereomers, the latter of which exists due to more than one opposite palmitic center in the molecule, as well as geometric isomers (cis/trans isomer). The present invention or the compound of the present invention relates to each possible stereoisomer of the compound of the present invention, that is, a single enantiomer or diastereomer, and a mixture thereof.

The compounds according to the invention may be amorphous or may exist in one or more different crystalline states (polymorphs), which may have different macroscopic properties, such as stability or exhibit different biological properties, such as activity. The present invention relates to amorphous and crystalline compounds according to the present invention, mixtures of different crystalline states of the compounds according to the present invention, and amorphous or crystalline salts thereof.

The salts of the compounds according to the invention can be formed in conventional ways, for example if the compounds according to the invention have basic functional groups, by reacting the compounds with the acid of the anion in question, or by allowing the acidic compounds according to the invention to Suitable alkali reaction. The salt of the compound according to the present invention is preferably an agriculturally and/or veterinarily acceptable salt, preferably an agriculturally acceptable salt.

The term "N-oxide" includes any compound of the present invention having at least one tertiary nitrogen atom oxidized to an N-oxide moiety.

As used herein, the term "hydrogenation catalyst" encompasses homogeneous hydrogenation catalysts. It is known in the art that rhodium, ruthenium, iridium, platinum, palladium, iron or nickel form highly active catalysts. The preferred hydrogenation catalysts according to the invention are further provided below.

Useful anions of acid addition salts are mainly halide ions such as chloride, bromide and fluoride; sulfonate, phosphate, nitrate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate and C The anion of _1- C ₄ alkanoic acid is preferably formate, acetate, propionate and butyrate. It can be formed by reacting M or MLn with the acid of the corresponding anion, preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid.

The organic moieties or groups mentioned in the definition of variables above (such as the term halogen) are collective terms for individual lists of individual group members. In each case, the prefix C _n -C _m indicates the number of possible carbon atoms in the group.

"Halogen" will mean fluorine, chlorine, bromine and iodine.

The term "partially or fully halogenated" means that one or more of a given group, for example 1, 2, 3, 4, or 5 or all hydrogen atoms have been replaced by halogen atoms, especially by fluorine or chlorine.

As used herein (and in C _n -C _m alkylamine group, di-C _n -C _m alkylamine group, C _n -C _m alkylaminocarbonyl group, di-(C _n -C _m alkylamine group ) Carbonyl, C _n -C _m alkylthio, C _n -C _m alkylsulfinyl and C _n -C _m alkylsulfonyl)) The term "C _n -C _m alkyl" means having n to m, for example, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, branched or unbranched saturated hydrocarbon groups, such as methyl, ethyl, propyl, 1-methylethyl, butyl , 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2 ,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl Group, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- Dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl Group, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, Nonyl and decyl and their isomers. C ₁ -C ₄ alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethyl Ethyl.

The term "C _n -C _m haloalkyl" as used herein (and in C _n -C _m haloalkylsulfinyl and C _n -C _m haloalkane sulfonyl) refers to having n to m Carbon atoms, for example, straight-chain or branched-chain alkyl groups of 1 to 10, especially 1 to 6 carbon atoms (as mentioned above), wherein some or all of the hydrogen atoms in these groups may be as mentioned above And halogen atom substitution, such as C ₁ -C ₄ haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorine Fluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2 ,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2, 2-trichloroethyl, pentafluoroethyl and similar groups. The term C ₁ -C ₁₀ haloalkyl specifically includes C ₁ -C ₂ fluoroalkyl groups, which are synonymous with methyl or ethyl groups in which 1, 2, 3, 4 or 5 hydrogen atoms are replaced by fluorine atoms, such as fluoromethyl , Difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and pentafluoromethyl.

Similarly, "C _n -C _m alkoxy" and "C _n -C _m alkylthio" (or C _n -C _m alkylsulfenyl, respectively) refer to any bond in the alkyl Straight-chain or branched-chain alkyl groups having n to m carbon atoms, such as 1 to 10, especially 1 to 6, or 1 to 4 carbon atoms, bonded via oxygen (or sulfur linkage, respectively) (as above Mentioned). Examples include C ₁ -C ₄ alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, second butoxy, isobutoxy and third butoxy, In addition, C ₁ -C ₄ alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio and n-butylthio.

Therefore, the terms "C _n -C _m haloalkoxy" and "C _n -C _m haloalkylthio" (or C _n -C _m haloalkylsulfenyl respectively) refer to the Straight or branched chain alkyl groups having n to m carbon atoms, such as 1 to 10, especially 1 to 6, or 1 to 4 carbon atoms, bonded at any bond via oxygen or sulfur linkages (as above Mentioned), wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example C ₁ -C ₂ haloalkoxy, such as chloromethoxy, bromomethoxy , Dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy And pentafluoroethoxy, in addition C ₁ -C ₂ haloalkylthio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethyl Sulfur, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio , 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-di Fluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio, pentafluoroethylthio and similar groups. Similarly, the term C ₁ -C ₂ fluoroalkoxy and fluoroalkyl C ₁ -C ₂ alkylthio means, respectively via a C atom or an oxygen atom bonded to the remainder of the molecule of the sulfur ₁ -C ₂ fluoroalkyl group.

The term "C ₂ -C _m alkenyl" as used herein means a branched or unbranched chain unsaturated hydrocarbon group having 2 to m, such as 2 to 10 or 2 to 6 carbon atoms and a double bond at any position , Such as vinyl, 1-propenyl, 2-propenyl, 1-methyl-vinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl , 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4 -Pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2 -Methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3- Butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1- Propylene, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1- Pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2- Methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl Alkenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl Yl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2 -Dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butene Alkenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-di Methyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl , 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2- Ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl -1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

The term "C ₂ -C _m alkynyl" as used herein refers to a branched or unbranched chain unsaturated hydrocarbon group having 2 to m, such as 2 to 10 or 2 to 6 carbon atoms, and containing at least one reference bond , Such as ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.

The suffix "-carbonyl" or "C(=O)" of the group in each case means that the group is bonded to the rest of the molecule via the carbonyl C=O group. This is the case, for example, in alkylcarbonyl, haloalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, haloalkoxycarbonyl.

The term "aryl" as used herein refers to monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups, such as phenyl or naphthyl, especially phenyl (also refers to C ₆ H ₅ as a substituent).

The term "ring system" means two or more directly connected rings.

As used herein, the term "C ₃ -C _m cycloalkyl" refers to a 3-member to m-membered monocyclic saturated cycloaliphatic group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl and cyclodecyl.

The term "5-membered to 10-membered partially unsaturated carbocyclic ring" as used herein refers to a partially unsaturated monocyclic or bicyclic ring containing 5 to 10 carbon atoms, such as indane.

The term "3- to 7-membered carbocyclic ring" as used herein refers to cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane rings.

The term "heterocycle" means "a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated, partially unsaturated ring or aromatic heterocyclic ring, which may contain 1, 2, 3 or 4 heteroatoms" or " "Heteroatom-containing groups", wherein their heteroatoms (groups) are selected from N (N-substituted groups), O, and S (S-substituted groups), as used herein, heterocyclic groups refer to single Ring groups, such monocyclic groups are saturated, partially unsaturated or aromatic (fully unsaturated). The heterocyclic group can be attached to the rest of the molecule via a carbocyclic member or via a nitrogen ring member.

Examples of 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered saturated heterocyclic groups or heterocyclic rings include: ethylene oxide, aziridinyl, azetidine, 2-tetrahydrofuranyl, 3- Tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5 -Isoxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 1,2, 4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazole Pyridin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2-tetrahydropiperanyl, 4-tetrahydropiperanyl, 1,3-dioxan-5-yl, 1,4-dioxane- 2-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydropyrazinyl, 4-hexahydropyrazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl Group, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl, 2-morpholinyl , 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl , 1,1-bi- pendant thiomorpholin-2-yl, 1,1-bi- pendant thiomorpholin-3-yl, hexahydronitrogen-1-, -2-, -3- Or -4-yl, hexahydrooxyazo, hexahydro-1,3-diazoa, hexahydro-1,4-diazao, hexahydro-1,3-oxazo, hexahydro -1,4-oxazo, hexahydro-1,3-dioxa, hexahydro-1,4-dioxa and similar groups.

Examples of 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered partially unsaturated heterocyclic groups or heterocyclic rings include: 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl , 2,4-dihydrofuran-2-yl, 2,4-dihydrofuran-3-yl, 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2 ,4-dihydrothiophen-2-yl, 2,4-dihydrothiophen-3-yl, 2-pyrrolidin-2-yl, 2-pyrrolidin-3-yl, 3-pyrrolidin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4 -Yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-iso Oxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3- Isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2, 3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazole-4-yl Group, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazole- 4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydroox Azole-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-di Hydroxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4 -Dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or 6-dihydropyridyl or tetrahydropyridyl, 3-dihydropyridazinyl or tetrahydropyrazinyl, 4- Dihydropyrazinyl or tetrahydropyrazinyl, 2-dihydropyrimidinyl or tetrahydropyrimidinyl, 4-dihydropyrimidinyl or tetrahydropyrimidinyl, 5-dihydropyrimidinyl or tetrahydropyrimidinyl, dihydro Pyrazinyl or tetrahydropyrazinyl, 1,3,5-dihydrotriazine or tetrahydrotriazin-2-yl, 1,2,4-dihydrotriazine or tetrahydrotriazin-3-yl, 2,3,4,5-tetrahydro[1H] aza-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5, 6-Tetrahydro[2H] Aza-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H] Aza- 1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro [1H] aza--1-, -2- , -3-, -4-, -5-, -6- or -7-yl, tetrahydrooxyl, such as 2,3,4,5-tetrahydro[1H]oxa-2-,-3-,-4-,-5-,-6- Or -7-yl, 2,3,4,7-tetrahydro[1H]oxa-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3, 6,7-Tetrahydro[1H]oxa-2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydro-1,3-diazepine, tetrahydro -1,4-diazino, tetrahydro-1,3-oxazo, tetrahydro-1,4-oxazo, tetrahydro-1,3-dioxa, and tetrahydro-1 ,4-dioxanyl.

Examples of 5-membered or 6-membered aromatic heterocyclic groups (heteroaryl) or heteroaromatic rings are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3- Pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5 -Thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,3,4-triazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4- Tazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.

The term "palladium phosphorus ligand" encompasses all palladium phosphorus ligands known in the art, which are used as ligands in metal-catalyzed hydrogenation reactions, for example from "Rhodium-Catalyzed Asymmetric Hydrogenation, Yongxiang Chi, Wenjun Tang and Xumu Zhang In: Modern Rhodium-Catalyzed Organic Reactions , P. Andrew Evans, Wiley, pages 1-31 (2005)" and " Molecules 2000, 5 , 4-18" body.

If not specified otherwise, the term "substituted" means substituted with 1, 2, or the largest possible number of substituents. If there are more than one substituent as defined in the compound of formula I, if not mentioned otherwise, these substituents are independently the same or different from each other.

The meaning of terms not defined herein is generally known to those skilled in the art or known in the literature.

The preferred embodiments of the present invention are described below.

In one embodiment of the present invention, R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or C ₂ -C ₄ alkenyl.

In another embodiment, R ¹ is C ₁ -C ₄ alkyl.

In another embodiment, R ¹ is methyl or ethyl.

In another embodiment, R ¹ is methyl.

In one embodiment of the invention, R ² is phenyl, pyridyl or thienyl, which is unsubstituted or substituted with R ^2a .

In another embodiment, R ² is phenyl, which is unsubstituted or substituted with R ^2a , wherein R ^2a is halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, OR ^c , C(=O)OR ^c , C(=O)NR ^b R ^c , phenyl or pyridyl, these groups are unsubstituted or halogenated, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ Haloalkoxy substitution.

In another embodiment, R ² is phenyl, which is unsubstituted or substituted with halogen, C ₁ -C ₄ alkyl, or C ₁ -C ₃ haloalkyl.

In another embodiment, R ² is phenyl, which is unsubstituted or substituted with trifluoromethyl or halogen, preferably substituted with chlorine;

In another embodiment, R ² is phenyl, 3,5-dichlorophenyl, or 3-trifluoromethylphenyl.

In another embodiment, R ² is phenyl.

In another embodiment, R ² is 3,5-dichlorophenyl.

In another embodiment, R ² is 3-trifluoromethylphenyl.

In one embodiment, R ^a is halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ - C ₆ cycloalkyl or CN.

In another embodiment, R ^a is halo, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio or phenyl.

In one preferred embodiment, R ^a is halogen or C ₁ -C ₆ alkyl;

In a more preferred embodiment, R ^a is halogen or C ₁ -C ₆ alkyl group embodiment;

In a preferred embodiment, R ^a is halogen, preferably Cl.

In another preferred embodiment, R ^a is a phenyl group.

In one embodiment, R ^A is S(=O)R ^x .

In another embodiment, R ^A is S(=O) ₂ R ^x .

In another embodiment, R ^A is P(=O)(R ^x ) ₂ .

In another embodiment, R ^A is C ₁ -C ₄ alkoxy.

In another embodiment, R ^A is -CH ₂ -phenyl, wherein phenyl is unsubstituted or substituted with halogen, methoxy, or nitro.

In one embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In one embodiment of the present invention, Het is D-2;

In one embodiment of the present invention, Het is selected from D-1, D-2 and D-3, wherein R ^a is chloro, n is 1.

In another embodiment, Het is D-1a, D-2a and D-3a:

In another embodiment, Het is D-1a.

In another embodiment, Het is D-2a.

In another embodiment, Het is D-3a.

In an embodiment of the invention, the compound of formula X is one of the following compounds X-1 to X-6:

In one embodiment of the invention, the compound of formula X is compound X-1.

In another embodiment of the present invention, the compound of formula X is compound X-2.

In another embodiment of the present invention, the compound of formula X is compound X-3.

In another embodiment of the present invention, the compound of formula X is compound X-4.

In another embodiment of the present invention, the compound of formula X is compound X-5.

In another embodiment of the present invention, the compound of formula X is compound X-6.

In one embodiment, W is halogen, hydroxy, O-p-toluenesulfonyl, O-methanesulfonyl or O-trifluoromethanesulfonyl.

In a preferred embodiment, W is halogen, O-p-toluenesulfonyl, O-methanesulfonyl or O-trifluoromethanesulfonyl;

In a more preferred embodiment, W is halogen.

In one embodiment, R ^x is C ₁ -C ₆ alkyl;

In a preferred embodiment, R ^x is C ₁ -C ₄ alkyl, such as methyl, ethyl, isopropyl, n-propyl, and third butyl;

In a more preferred embodiment, R ^x is tertiary butyl.

In another embodiment, R ^x is a substituted or unsubstituted aryl group of halogen.

In a preferred embodiment, R ^x is an unsubstituted aryl group.

In another preferred embodiment, R ^x is an aryl group substituted with halogen.

The preferred embodiments of steps (A), (B), (C) and (D) of the present invention are described below.

In general, the reaction steps carried out in steps (A), (B), (C) and (D), as described in detail below, are carried out in reaction vessels customary for such reactions. Semi-continuous or batch mode.

In general, certain reactions will be carried out at atmospheric pressure. However, the reaction can also be carried out under reduced pressure.

In general, the product obtained by any of the reaction steps (A), (B), (C) or (D) results in an enantiomeric excess. However, during the separation, purification (eg, crystallization) of the enantiomers, and during or after use of the product, the enantiomeric excess can be further increased.

Those skilled in the art know from similar reactions that the temperature and duration of the reaction can vary within a wide range. The temperature usually depends on the reflux temperature of the solvent. The other reactions are preferably carried out at room temperature, that is, at about 25°C, or under ice cooling, that is, at about 0°C. The end of the reaction can be monitored by methods known to those skilled in the art, such as thin layer chromatography or HPLC or GC.

If not otherwise specified, the molar ratio of the reactants used in the reaction is in the range of 0.2:1 to 1:0.2, preferably 0.5:1 to 1:0.5, more preferably 0.8:1 to 1:0.8. It is preferable to use an equivalent molar amount.

If not specified otherwise, the reactants can in principle be contacted with each other in any desired order.

Those skilled in the art know when the reactants or reagents are sensitive to humidity, so the reaction should be performed under an inert gas, such as a nitrogen atmosphere, and a dry solvent should be used.

Those skilled in the art also know the best treatment of the reaction mixture after the reaction is over.

In the following, preferred embodiments regarding step (A) of the present invention are provided. It should be understood that the above-mentioned preferred embodiments and the preferred embodiments still described in step (A) of the invention below should be understood as preferably alone or in combination with each other.

In one embodiment, the hydrogen source is a hydrogen source selected from the group consisting of: b) a mixture of N(R) ₃ and HCOOH, where R is H or C ₁ -C ₆ alkyl, c) HCOONa and d) isopropanol Mixture with t- BuOK or t- BuONa or t- BuOLi;

In one embodiment, the hydrogen source is hydrogen gas;

In one embodiment, the hydrogen source is a mixture of N(R) ₃ and HCOOH.

In one embodiment, R is H;

In another embodiment, R is C ₁ -C ₆ alkyl

In another embodiment, R is C ₁ -C ₄ alkyl, such as methyl, ethyl, isopropyl, n-propyl, and tert-butyl.

In a preferred embodiment, R is H, ethyl, isopropyl or tertiary butyl.

In a more preferred embodiment, R is H or ethyl.

In a preferred embodiment, R is ethyl.

In one embodiment, the volume ratio of N(R) ₃ to HCOOH is in the range of 1:2 to 1:10.

In a preferred embodiment, the volume ratio of N(R) ₃ to HCOOH is in the range of 1:1 to 1:4.

In a more preferred embodiment, the volume ratio of N(R) ₃ to HCOOH is in the range of 1:1 to 1:3.

In another embodiment, the hydrogen source is HCOONa.

In another embodiment, the hydrogen source is HCOOK.

In another embodiment, the hydrogen source is a mixture of isopropyl alcohol and t- BuOK.

In another embodiment, the hydrogen source is a mixture of isopropyl alcohol and t- BuONa.

In one embodiment, m is 0;

In one embodiment, m is 1;

In one embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon is an unsubstituted or C ₁ -C ₄ alkyl substituted aryl ring.

In one embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon series is selected from benzene, p-isopropyltoluene, mesitylene, 2,4,6-triethylbenzene , Hexatoluene, anisole, 1,5-cyclooctadiene, cyclopentadienyl (Cp), norbornadiene and pentamethylcyclopentadienyl (Cp*).

In one embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon series is selected from benzene, p-isopropyltoluene, mesitylene, 2,4,6-triethylbenzene , Hexatoluene, anisole, 1,5-cyclooctadiene, cyclopentadienyl (Cp) and pentamethylcyclopentadienyl (Cp*).

In another embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon is selected from cyclopentadienyl (Cp) and pentamethylcyclopentadienyl (Cp*) .

In another embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon is cyclopentadienyl (Cp).

In another embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon is pentamethylcyclopentadienyl (Cp*).

In another embodiment, the hydrogenation catalyst is MXLn (ƞ-aromatic hydrocarbon) _m , where m is 1 and the ƞ-aromatic hydrocarbon series is selected from benzene, p-isopropyltoluene, mesitylene, 2,4,6-triethyl Benzene, hexatoluene, anisole and 1,5-cyclooctadiene.

In one embodiment, X is an anion, which is formed by reacting M or MLn with the acid of the corresponding anion, preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, tetrafluoroboric acid, or hexafluorophosphoric acid.

In another embodiment, X is an anion selected from halide, hexafluorosilicate, hexafluorophosphate, benzoate, sulfonate and C ₁ -C ₆ alkanoic acid, preferably formate, acetate, propionate Acid and butyrate.

In another embodiment, X is a halide ion selected from chloride ion, bromide ion and iodide ion.

In another embodiment, X is chloride or bromide.

In another embodiment, X is chloride ion.

In another embodiment, X is tetrafluoroborate.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ and wherein R ¹² and R ^{11 are} independently unsubstituted or substituted aryl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ and wherein R ¹² and R ^{11 are} independently substituted aryl groups.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ and wherein R ¹² and R ^{11 are} independently unsubstituted aryl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ , wherein R ¹¹ is a substituted aryl group and R ¹² is C ₆ -C ₁₀ cycloalkyl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ ; wherein R ¹¹ is a substituted aryl group and R ¹² is an unsubstituted aryl group.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ ; wherein R ¹¹ is an unsubstituted aryl group and R ¹² is a substituted aryl group.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is NH-SO ₂ -R ¹¹ , wherein R ¹¹ is unsubstituted or substituted aryl and two R ^{12 are} joined together to form 3 to 6 Member carbocyclic ring or 5 to 10 member partially unsaturated carbocyclic ring.

In another embodiment, MXLn(ƞ-aromatic hydrocarbon) _m is MXLn1(ƞ-aromatic hydrocarbon) _m , where R ¹⁰ is NH-SO ₂ -R ¹¹ ; and R ¹² and R ^{11 are} independently phenyl, which is not Substitution or substitution by 1 or 2 substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, SO ₃ H, and SO ₃ Na.

In another embodiment, MXLn(ƞ-aromatic hydrocarbon) _m is MXLn1(ƞ-aromatic hydrocarbon) _m , where X is a halide ion; R ^{12 is} independently phenyl, 2-methylphenyl, 3-methylphenyl , 4-methylphenyl or 4-methoxyphenyl; R ¹⁰ is NH-SO ₂ -R ¹¹ and -SO ₂ -R ¹¹ is p-toluenesulfonyl, methanesulfonyl, 4-benzenesulfonyl Group, 4-trifluoromethylphenyl-sulfonyl or pentafluorophenyl-sulfonyl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is OH and R ¹² is unsubstituted or substituted aryl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is OH and R ¹² is substituted aryl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is OH and R ¹² is unsubstituted aryl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is OH and R ¹² is C ₆ -C ₁₀ cycloalkyl.

In another embodiment, Ln is Ln1, wherein R ¹⁰ is OH and two R ^{12 are} joined together to form a 3 to 6 member carbocyclic ring or 5 to 10 member partially unsaturated carbocyclic ring.

In another embodiment, Ln1 is supported on silicone, dendrimer, polystyrene, or mesoporous silica foam, such as Haraguchi, N., Tsuru, K., Arakawa, Y., Isuno, S. Org. Biomol. Chem. 2009 , 7 , 69.

In one embodiment, M is rhodium, ruthenium, iridium, platinum, palladium, iron, or nickel.

In another embodiment, M is rhodium, ruthenium, iridium or platinum.

In another embodiment, M is rhodium, ruthenium or platinum.

In another embodiment, M is rhodium, iridium or platinum.

In another embodiment, M is rhodium, ruthenium or iridium.

In another embodiment, M is rhodium or ruthenium.

In another embodiment, M is rhodium or iridium.

In another embodiment, M is ruthenium or iridium.

In another embodiment, M is palladium, iron, or nickel.

In another embodiment, M is palladium or nickel.

In another embodiment, M is iron or nickel.

In another embodiment, M is palladium or iron.

In a preferred embodiment, M is rhodium.

In another preferred embodiment, M is ruthenium.

In another preferred embodiment, M is iridium.

In another preferred embodiment, M is palladium.

In another preferred embodiment, M is iron.

In another preferred embodiment, M is nickel.

In another preferred embodiment, M is platinum.

In another embodiment, m is 1 and MXLn (ƞ-aromatic hydrocarbon) _m has the formula MXLnCp*, where M is rhodium, ruthenium, iridium, platinum, palladium, iron, or nickel.

In another embodiment, Ln is Ln2, which is a palmitate phosphorus ligand.

In another embodiment, the para-palmitophosphorus ligand Ln2 is selected from para-palate monodentate or bidentate phosphine or phosphite ligands.

In another embodiment, the palmitic phosphorus ligand Ln2 is selected from the ligands listed in Table A below or from their corresponding enantiomers. Table A: where Cy = cyclohexyl and Ph = phenyl.

In another embodiment, the palmitic phosphorus coordination system is selected from ( R )-BINAP, ( S )-BINAP, ( R ) TolBINAP, (S)-TolBINAP, ( R,R )-DIPAMP, (S,S ) -DIPAMP, (1 R ,2 S) -( R )- (S) -Josiphos, or selected from their corresponding enantiomers.

In one embodiment, the molar ratio of the compound of formula III to MXLn (ƞ-aromatic hydrocarbon) _m is in the range of 1:0.0001 to 1:0.001.

In a preferred embodiment, the molar ratio of the compound of formula III to MXLn (ƞ-aromatic hydrocarbon) _m is in the range of 1:0.001 to 1:0.01.

In a more preferred embodiment, the molar ratio of the compound of formula III to MXLn (ƞ-aromatic hydrocarbon) _m is in the range of 1:0.001 to 1:0.05.

In one embodiment, the temperature of the hydrogenation reaction in step (A) is maintained in the range of 0 to 120°C, preferably in the range of 0 to 85°C, preferably in the range of 20 to 85°C, more preferably in It is also in the range of 20 to 50°C, more preferably in the range of 0 to 30°C, and even more preferably at 0°C.

In one embodiment, the hydrogenation reaction in step (A) is carried out at a temperature below 0°C.

In one embodiment, the hydrogenation in step (A) is carried out in the absence of a solvent.

In another embodiment, the hydrogenation in step (A) is carried out in a solvent.

Suitable solvents include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; halogenated hydrocarbons such as methylene chloride , Chloroform, 1,2-dichloroethane and chlorobenzene; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and third butanol; ketones, such as acetone, 2-butanone; C ₂ -C ₄ alkanediols, such as ethylene glycol or propylene glycol; an ether alcohol, such as diethylene glycol; carboxylic esters, such as ethyl acetate; N-methyl pyrrolidone; dimethylformamide; two Methylacetamide; and ethers, including open chain ethers and cyclic ethers, especially ether, methyl tertiary butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether , 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of these solvents can also be used.

In a preferred embodiment, the solvent is selected from water, C ₂ -C ₆ alkanediol, C ₁ -C ₆ haloalkane, halobenzene, carboxylic acid ester, N-methylpyrrolidone; dimethyl methyl Acetamide; dimethylacetamide and ethers, including open chain ethers and cyclic ethers, or mixtures of two or more thereof.

In another preferred embodiment, the solvent is selected from water, dimethylformamide, toluene, tetrahydrofuran, N-methylpyrrolidone, dimethylacetamide, or a mixture of two or more thereof .

In one embodiment, the volume ratio of the compound of formula V to the solvent is in the range of 1:40 to 1:0.

In another embodiment, the volume ratio of the compound of formula V to the solvent is in the range of 1:30 to 1:5.

In a preferred embodiment, the volume ratio of the compound of formula V to the solvent is in the range of 1:20 to 1:10, preferably 1:1.

The reaction time in step (A) can vary within a wide range. The preferred reaction time is 5 minutes to 1 day, preferably 15 minutes to 6 hours, more preferably 15 minutes to 3 hours, for example 1 to 2 hours.

In one embodiment, step (A) can be performed in the presence of surfactant N(R ^s ) ₄ X ^a , where R ^{s is} independently C ₁ -C ₂₂ alkyl, C ₁ -C ₂₂ cycloalkyl or Aryl, which is unsubstituted or substituted with halogen, and X ^a is chlorine, bromine, iodine, hydrogen sulfate, hexafluorophosphate, acetate, benzoate, or tetrafluoroborate.

It is further preferred that the reaction is carried out in a protective or inert gas atmosphere, for example under nitrogen or argon.

It is further preferred that the reaction is carried out under reduced pressure.

In another embodiment, the reaction is carried out in a hydrogen atmosphere.

In a preferred embodiment, the enantiomeric excess of the compound of formula VI obtained by step (A) is >80%.

In the following, preferred embodiments regarding step (B) of the present invention are provided. It should be understood that the above-described preferred embodiments and the preferred embodiments still described in step (B) of the invention below should be understood as preferably alone or in combination with each other.

In one embodiment, step (B) is performed in the presence of an acid;

In one embodiment, suitable acids are generally inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, or a mixture of one or more thereof.

In a preferred embodiment, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, hydroiodic acid, or a mixture of one or more thereof.

In another embodiment, suitable acids are Lewis acids such as boron trifluoride, aluminum trichloride, iron (III) chloride, tin (IV) chloride, titanium (IV) chloride, and zinc chloride ( II).

In another embodiment, suitable acids are generally organic acids, such as formic acid, C ₁ -C ₈ alkyl-(COOH) _y or C ₁ -C ₈ haloalkyl-(COOH) _y , where y is 1 or 2; CH ₃ SO ₃ H, citric acid, oxalic acid, p-toluenesulfonic acid acetic acid, propionic acid, oxalic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid and trifluoroacetic acid or a mixture of one or more thereof.

In a preferred embodiment, the acid is C ₁ -C ₈ alkyl-(COOH) _y , C ₁ -C ₈ haloalkyl-(COOH) _y , where y is 1 or 2; CH ₃ SO ₃ H, Citric acid, oxalic acid, p-toluenesulfonic acid or a mixture of two or more thereof.

In another embodiment, the acid in step (B) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, hydroiodic acid, C ₁ -C ₈ alkyl-(COOH) _y , C ₁ -C ₈ haloalkane -(COOH)y, CH ₃ SO ₃ H, citric acid, oxalic acid, p-toluenesulfonic acid, or a mixture of two or more thereof;

In a particularly preferred embodiment, the acid in step (B) is hydrochloric acid.

In a preferred embodiment, when R ^A in the compound of formula VI is S(=O) ₂ R ^x , step (B) is performed in the presence of an acid.

The acid is usually used in equal molar amounts; however, it can also be used in catalytic amounts, in excess or, if appropriate, as a solvent.

In another embodiment, step (B) is performed in the presence of acid and buffer.

The buffering agent includes aqueous and non-aqueous buffering agents, and is preferably a non-aqueous buffering agent. Preferred buffers include buffers based on acetate, phosphate or formate, such as sodium acetate, potassium hydrogen phosphate, potassium dihydrogen phosphate or ammonium formate.

In another embodiment, wherein step (B) performed in the presence of an acid further comprises a metal, such as palladium or platinum, preferably palladium, and hydrogen. In one embodiment, step (B) is performed in the presence of a base.

Suitable bases are usually inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide,

Alkali and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide,

Alkali and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate, and calcium carbonate.

In a particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydroxides, especially selected from the group consisting of lithium hydroxide, sodium hydroxide, magnesium hydroxide, potassium hydroxide and calcium hydroxide.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal oxides, especially selected from the group consisting of lithium oxide, sodium oxide, calcium oxide and magnesium oxide.

The base is usually used in equal molar amounts; however, it can also be used in catalytic amounts or in excess.

In one embodiment, the reaction temperature in step (B) is maintained in the range of 0 to 120°C, preferably in the range of 20 to 100°C, and more preferably in the range of 20 to 60°C.

In one embodiment, the hydrolysis in step (B) is carried out in the absence of a solvent.

In another embodiment, the hydrolysis in step (B) is carried out in a solvent.

Suitable solvents include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; halogenated hydrocarbons such as methylene chloride , Chloroform, 1,2-dichloroethane and chlorobenzene; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and third butanol; ketones, such as acetone, 2-butanone; C ₂ -C ₄ alkanediols, such as ethylene glycol or propylene glycol; an ether alcohol, such as diethylene glycol; carboxylic esters, such as ethyl acetate; N-methyl pyrrolidone; dimethylformamide; and Ethers, including open chain ethers and cyclic ethers, especially ether, methyl tertiary butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether, 1,4-dioxane Alkanes, tetrahydrofuran and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of these solvents can also be used.

In another embodiment, the solvent is selected from the group consisting of C ₁ -C ₆ alcohol, water, C ₂ -C ₆ alkanediol, carboxylic acid ester, N-methylpyrrolidone, dimethylformamide and including Chain ether and cyclic ether ether, or a mixture of two or more thereof.

In another embodiment, the solvent is selected from water, dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether, methanol, ethanol, isopropanol, or two or more thereof Kind of mixture.

The preferred solvent is a protic solvent, preferably an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, and tertiary butanol.

In a preferred embodiment, the solvent is a C ₁ -C ₄ alcohol, especially methanol.

In one embodiment, the volume ratio of the compound of formula VI to the solvent is in the range of 1:30 to 1:0.

In another embodiment, the volume ratio of the compound of formula VI to the solvent is in the range of 1:20 to 1:10.

In a preferred embodiment, the volume ratio of the compound of formula VI to the solvent is in the range of 1:10 to 1:0.

In a preferred embodiment, the enantiomeric excess of the compound of formula VII obtained by step (B) is >80%.

In the following, preferred embodiments regarding step (C) of the present invention are provided. It should be understood that the above-mentioned preferred embodiments and the preferred embodiments still described in step (C) of the invention below should be understood as preferably alone or in combination with each other.

In one embodiment, step (C) is performed in the presence of a base;

Suitable bases are usually inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide,

Alkali and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide,

Alkali and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride,

Alkali and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and

Alkali metal bicarbonate, such as sodium bicarbonate,

In addition, organic bases such as tertiary amines such as trimethylamine, triethylamine, triisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as trimethylpyridine, lutidine and 4-Dimethylaminopyridine, and bicyclic amines.

In a particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydroxides, especially selected from the group consisting of lithium hydroxide, sodium hydroxide, magnesium hydroxide, potassium hydroxide and calcium hydroxide.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal oxides, especially selected from the group consisting of lithium oxide, sodium oxide, calcium oxide and magnesium oxide.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydrides, especially selected from the group consisting of lithium hydride, sodium hydride, potassium hydride and calcium hydride.

In another particularly preferred embodiment, the base is selected from alkali metal amides, especially selected from the group consisting of lithium amide, sodium amide and potassium amide.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal carbonates, especially from the group consisting of lithium carbonate and calcium carbonate.

In another particularly preferred embodiment, the base is selected from alkali metal bicarbonates and is preferably sodium bicarbonate.

In another particularly preferred embodiment, the base is selected from the group consisting of alkyl alkali metals, especially selected from the group consisting of methyl lithium, butyl lithium and phenyl lithium.

In another particularly preferred embodiment, the base is selected from alkylmagnesium halides and is preferably isopropylmagnesium chloride.

In another particularly preferred embodiment, the base is selected from trimethylamine, triethylamine, triisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridine, such as trimethylpyridine, dimethyl Pyridine and 4-dimethylaminopyridine, and bicyclic amines.

In a more particularly preferred embodiment, the base is trimethylamine or triethylamine.

The base is usually used in equal molar amounts; however, it can also be used in catalytic amounts, in excess or, if appropriate, as a solvent.

In one embodiment, the hydrolysis reaction temperature in step (C) is maintained in the range of 0 to 130°C, preferably in the range of 20 to 85°C, and more preferably in the range of 20 to 60°C.

In one embodiment, step (C) is carried out in the absence of a solvent.

In another embodiment, step (C) is performed in a solvent.

Suitable solvents include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; halogenated hydrocarbons such as methylene chloride , Chloroform, 1,2-dichloroethane and chlorobenzene; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and third butanol; ketones, such as acetone or 2-butanone; C ₂ -C ₄ alkanediols, such as ethylene glycol or propylene glycol; an ether alcohol, such as diethylene glycol; carboxylic esters, such as ethyl acetate; N-methyl pyrrolidone; dimethylformamide; and Ethers, including open chain ethers and cyclic ethers, especially ether, methyl tertiary butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether, 1,4-dioxane Alkanes, tetrahydrofuran and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of these solvents can also be used.

In another embodiment, the solvent is selected from the group consisting of C ₁ -C ₆ alcohol, water, C ₂ -C ₆ alkanediol, carboxylic acid ester, N-methylpyrrolidone, dimethylformamide and including Chain ether and cyclic ether ether, or a mixture of two or more thereof.

In another embodiment, the solvent is selected from water, dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether, methanol, ethanol, isopropanol, or two or more thereof Kind of mixture.

The preferred solvent is a protic solvent, preferably an alcohol selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, and tertiary butanol.

In a preferred embodiment, the solvent is a C ₁ -C ₄ alcohol, especially ethanol.

In one embodiment, the volume ratio of the compound of formula VII to the solvent is in the range of 1:30 to 1:0.

In another embodiment, the volume ratio of the compound of formula VII to the solvent is in the range of 1:20 to 1:5.

In a preferred embodiment, the volume ratio of the compound of formula VII to the solvent is in the range of 1:20 to 1:10.

In a preferred embodiment, the enantiomeric excess of the compound of formula VIII obtained by step (C) is >80%.

In the following, preferred embodiments regarding step (D) of the present invention are provided. It should be understood that the above-mentioned preferred embodiments and the preferred embodiments still described in step (D) of the invention below should be understood as preferably alone or in combination with each other.

In one embodiment, LG is OR ^u ;

In another embodiment, LG is SR ^u ;

In one embodiment, R ^u is unsubstituted C ₁ -C ₆ alkyl;

In another embodiment, R ^u is C ₁ -C ₆ alkyl substituted with halogen;

In another embodiment, ^Ru is unsubstituted aryl;

In another embodiment, R ^u is substituted with halogen or an aryl group;

In one embodiment, the reaction temperature in step (D) is maintained in the range of 0 to 130°C, preferably in the range of 20 to 100°C, and more preferably in the range of 70 to 110°C.

In one embodiment, step (D) is carried out in the absence of a solvent.

In another embodiment, step (D) is performed in a solvent.

Suitable solvents include aliphatic hydrocarbons such as hexane, heptane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene; halogenated hydrocarbons such as methylene chloride and chloroform , 1,2-dichloroethane and chlorobenzene; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and third butanol; ketones, such as acetone or 2-butanone; C _2- C ₄ alkyl glycols, such as ethylene glycol or propylene glycol; ether alkanols, such as diethylene glycol; carboxylic acid esters, such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, Including open chain ethers and cyclic ethers, especially ether, methyl tertiary butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether, 1,4-dioxane, Tetrahydrofuran and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of these solvents can also be used.

In another embodiment, the solvent is selected from dimethylformamide, N-methylpyrrolidone, toluene, xylene, monochlorobenzene, or a mixture of two or more thereof.

The preferred solvents are aromatic hydrocarbons, preferably toluene, o-xylene, m-xylene, p-xylene and monochlorobenzene. In a preferred embodiment, the solvent is toluene.

In one embodiment, the volume ratio of reactant to solvent is in the range of 1:40 to 1:0.

In another embodiment, the volume ratio of reactants to solvent is in the range of 1:40 to 1:5.

In a preferred embodiment, the volume ratio of reactants to solvent is in the range of 1:30 to 1:10.

In a preferred embodiment, the volume ratio of the reactants to the solvent is in the range of 1:20 to 1:10, preferably 1:5.

In a preferred embodiment, the enantiomeric excess of the compound of formula X obtained by step (D) is >80%.

In a more preferred embodiment, the enantiomeric excess of the compound of formula X obtained by step (D) is >95%.

其中Het、R¹ 及R² 係如本文所定義； 包含至少以下步驟， (A) 式V化合物，

其中Het、R^A 及W係如本文所定義； 在氫化催化劑MXLnCp*，其中M為銠、釕、銥、鈀、鐵、鉑或鎳，

及選自以下之氫源存在下氫化：a)氫氣；b) N(R)₃ 與HCOOH之混合物，其中R為H或C₁ -C₆ 烷基；c) HCOONa或HCOOK；d) C₁ -C₈ 醇及t-BuOK、t-BuONa或t-BuOLi之混合物；及e) a)至d)中之兩者或更多者之組合； 以獲得具有以下如式VI-S中之立體化學的式VI化合物，

其中Het、R^A 及W係如式V化合物中所定義； (B) 在酸或鹼存在下，水解如本文所定義之式VI-S化合物， 以獲得具有以下如式VII-S中之立體化學的式VII化合物，其中Het及W係如式VI-S化合物中所定義；

(C) 使式VII-S化合物與R¹ NCS在鹼存在下反應，其中R¹ 係如本文所定義， 以獲得具有以下如式VIII-R中之立體化學的式VIII化合物，

其中Het及W係如式VII-S化合物中所定義； (D) 使式VIII-R化合物與式IX化合物反應，

其中LG及R² 係如本文所定義， 以獲得式X-R化合物。In another embodiment of the present invention, a method for preparing a compound of formula X having the following stereochemistry as in formula XR, or for preparing an R-enantiomer with an enantiomeric excess (i.e. Compound XR) of the compound of formula X,

Wherein Het, R ¹ and R ² are as defined herein; comprising at least the following steps, (A) a compound of formula V,

Wherein Het, R ^A and W-based as defined herein; in the hydrogenation catalyst MXLnCp *, wherein M is rhodium, ruthenium, iridium, palladium, iron, platinum or nickel,

And hydrogenation in the presence of a hydrogen source selected from: a) hydrogen; b) a mixture of N(R) ₃ and HCOOH, where R is H or C ₁ -C ₆ alkyl; c) HCOONa or HCOOK; d) C ₁ -A mixture of C ₈ alcohol and t-BuOK, t-BuONa or t-BuOLi; and a combination of two or more of e) a) to d); to obtain a stereo having the following formula VI-S Chemical compounds of formula VI,

Where Het, R ^A and W are as defined in the compound of formula V; (B) in the presence of an acid or base, hydrolyze the compound of formula VI-S as defined herein to obtain the following stereo as in formula VII-S The chemical compound of formula VII, wherein Het and W are as defined in the compound of formula VI-S;

(C) reacting the compound of formula VII-S with R ¹ NCS in the presence of a base, where R ¹ is as defined herein, to obtain a compound of formula VIII having the following stereochemistry as in formula VIII-R,

Wherein Het and W are as defined in the compound of formula VII-S; (D) reacting the compound of formula VIII-R with the compound of formula IX,

Wherein LG and R ² are as defined herein to obtain the compound of formula XR.

Example: Characterization can be performed by coupled high-performance liquid chromatography/mass spectrometry (HPLC/MS), gas chromatography (GC), by NMR or by its melting point. HPLC method 1: Agilent Eclipse Plus C18, 150mmx4.6mm IDx5um Gradient A=0.1% TFA/water, B=0.1% TFA/acetonitrile. Flow rate = 1.4 ml/min., column oven temperature = 30℃, gradient program = 10% B-100% B-5min, hold for 2min, 3min-10% B. Run time = 10 min LCMS method 1: C18 column (50 mm × 3.0 mm × 3µ) gradient A = 10 Mm ammonium formate/water, B = 0.1% formic acid/acetonitrile flow rate = 1.2 ml/min., column oven temperature = 40°C gradient program = 10% B to 100% B in 1.5 min, hold for 1 min 100% B, 1 min-10% B Run time: 3.75 min For palm HPLC method 1: ChiralPak IA column, 150 mm ×4.6 mm× 5µ mobile phase A = heptane, B = isopropanol, flow rate = 1.0 ml/min, column oven temperature = 40 °C gradient program = 5% B isocratic; running time: 20 min for palm HPLC Method 2: ChiralPak IC column, 150 mm × 4.6 mm × 5 µ mobile phase A = 0.1% diethylamine/heptane, B = 0.1% diethylamine/isopropanol, flow rate = 1.0 ml/min, column oven Temperature = 40°C Gradient formula = 15% B isocratic; Run time: 20 min Palm HPLC Method 3: ChiralPak IA column, 150 mm×4.6 mm× 5µ Mobile phase A=heptane, B=isopropanol, Flow rate = 1.0 ml/min, column oven temperature = 40°C Gradient program = 40% B isocratic; running time: 20 min ¹ H-NMR: signal is obtained by chemical shift (ppm) relative to tetramethylsilane It is characterized by its multiplicity and its integral (given the relative number of hydrogen atoms). The following abbreviations are used to characterize the multiplicity of the signal: m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

The abbreviations used are: h for hours, min for minutes, rt for residence time, ee for enantiomeric excess and ambient temperature for 22-27°C.

The present invention will now be described in further detail by the following examples without imposing any restrictions on it.

By appropriately modifying the starting materials, other compounds of formula VI, VII, VIII, or X can be obtained using the procedures described in the following examples.

Example 1: Preparation of (3 R )-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2 -a] Pyrimidine-4-ium-5-alkoxide: Step 1: Preparation of 2-chloro-N-methoxy-N-methyl-acetamide:

A 3-L four-necked flask equipped with a Teflon blade stirrer, reflux condenser and heat bag was fed with N-methoxymethylamine hydrochloride (345 g), water (1.6 L), and The resulting reaction mixture was cooled to 0 to -5°C. Then potassium carbonate (1466 g) was added to the above reaction mixture in portions, followed by methyl tert-butyl ether (1.4 L). Chloroacetyl chloride (400 g) was dissolved in tert-butyl methyl ether (0.2 L) and added dropwise to the above maintained reaction mixture at -5°C to 0°C, and the reaction mixture was stirred at 0°C 2 hours. The reaction mixture was brought to ambient temperature and the two phases were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-N-methoxy-N-methyl-acetamide as a white solid (440 g, 90% yield, HPLC purity 98.0 area %).

Step 2: Preparation of 2-chloro-1-(2-chlorothiazol-5-yl)ketene: A 5-L four-necked flask equipped with a Teflon blade stirrer, reflux condenser and hot bag was fed with 2-chlorothiazole (250 g), THF (0.75 L), and the resulting reaction mixture was cooled to 0 to- 5℃. Subsequently, lithium isopropylmagnesium chloride (1.929 L, 1.3 M THF solution) was added to the reaction mixture maintained above at 0.5 to -5°C for 0.5 hour. The reaction mixture was then heated to 40°C and the reaction was continued at 40°C for 2 hours. Chlorine was confirmed by quenching a small aliquot of the reaction mixture with iodine and monitoring the formation of 2-chloro-5-iodo-thiazole by GC analysis (96% conversion observed by GC analysis). (Chlorothiazol-5-yl) magnesium species formation. The reaction mixture was cooled to 0 to -5°C, and a solution of 2-chloro-N-methoxy-N-methyl-acetamide (343 g) in THF (0.25 L) was added dropwise. The reaction was continued at -5 to 0°C for 1 hour, and the progress of the reaction was monitored by HPLC. The reaction mixture was quenched with 1.5 N aqueous HCl (1 L) at -5 to 0°C and then warmed to ambient temperature. The two phases were separated and the aqueous phase was extracted with methyl tert-butyl ether (2 x 300 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to obtain a crude residue. The crude product was dissolved in methyl tert-butyl ether (0.7 L) at ambient temperature, and activated carbon (4 g) and silica (80 g, 60-120 mesh) were added. The slurry was stirred for 0.5 hours, filtered through a Buchner funnel (Buchner funnel) and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain 2-chloro-1-(2-chlorothiazol-5-yl)ethanone as a light brown oil (409 g, HPLC purity 46 area%)

Step 3: Preparation of N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylene]-2-methyl-propane-2-sulfenamide: A 5-L four-necked flask equipped with a Teflon blade stirrer, reflux condenser and heat bag was fed with 2-chloro-1-(2-chlorothiazol-5-yl) at ambient temperature under a nitrogen atmosphere Acetone (409 g, HPLC purity 46 area%), THF (1.2 L), 2-methylpropane-2-sulfenamide (252.4 g) and titanium (IV) ethoxide (485 mL). The resulting mixture was heated to 50°C and stirred for 2 hours. The progress of the reaction was monitored by HPLC (conversion rate determined by HPLC>95%). The reaction was fed with methyl tert-butyl ether (2.4 L), cooled to 0 to 10° C., slowly quenched with 1 N aqueous HCl (3.6 L) and stirred for 10 minutes. The two phases were separated, and the organic phase was washed with water (2 × 800 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain a crude residue. The crude product was dissolved in methyl tert-butyl ether (1 L) at ambient temperature, and activated carbon (5.5 g) and silica (100 g, 60-120 mesh) were added. The slurry was stirred for 0.5 hour, filtered through a Buchner funnel and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylene]-2-methyl-propane-2-sulfenamide (510 g) as a light brown oil , HPLC purity is 68 area%).

Step 4: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide: a) Preparation of rhodium catalyst -RhCl[(R,R)-TsDPEN]Cp*:

Under a nitrogen atmosphere, feed [RhCl ₂ Cp*] ₂ (2.0 g), (1R, 2R)-N-pair to a 250 mL three-necked flask equipped with a Teflon blade stirrer, nitrogen inlet, and hot bag Tosyl-1,2-diphenylethylenediamine (2.38 g), dichloromethane (68 mL) and TEA (1.72 ml). The resulting slurry was stirred at 22-27°C for 0.5 hour, and distilled water (40 mL) was added. The two phases were separated, and the organic phase was washed with water (40 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to give a brown solid residue. The brown residue was triturated with n-heptane (20 mL), filtered and dried under a nitrogen atmosphere to obtain RhCl [(R, R)-TsDPEN]Cp* (3.4 g) as a red solid. b) Preparation of HCOOH-NEt ₃ mixture:

Formic acid (275 mL, >= 99% w/w) was added to a 2 L 3-neck round bottom flask and cooled to 0°C. At 0°C, triethylamine (250 mL, >=99% w/w) was slowly added thereto and used immediately for the reaction.

c) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide: To be equipped with a magnetic stirrer , A nitrogen inlet and a hot-bag 5 L four-necked flask were fed with dimethylformamide (2.9 L) and degassed with nitrogen for 10 minutes. Subsequently, under a nitrogen atmosphere, RhCl[(R,R)-TsDPEN]Cp* (3.63 g) was added at 22 to 27°C. At 22 to 27°C, N-[2-chloro-1-(2-chlorothiazole-5-) dissolved in dimethylformamide (0.51 L) was added to the above-mentioned holding solution over a period of 0.5 hours. Group) ethylene]-2-methyl-propane-2-sulfonamide (170 g) and HCOOH-NEt ₃ (425 mL, ratio: 1.1:1) solution, and the resulting mixture was at 22-27 ℃ Stir for 2 hours. HPLC showed >97% conversion. The reaction mixture was quenched with water (3.4 L) and extracted with methyl tert-butyl ether (3×1500 mL). The combined organic phase was evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide (180 g , 80% HPLC purity (rt = 4.48 and 4.52 min.))

Step 5: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine: At ambient temperature, N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethane was fed into a 1 L three-necked flask equipped with a magnetic stirrer, nitrogen inlet and hot bag Group]-2-methyl-propane-2-sulfenamide (180 g) and MeOH (540 mL) containing 1 N HCl, and the reaction mixture was stirred at 22-27°C for 14 hours. The progress of the reaction was monitored by HPLC. The organic volatiles were removed in vacuo, the residue was triturated with methyl tert-butyl ether (3×300 mL) and the organic phase containing methyl tert-butyl ether was separated from the pale yellow oily residue. The pale yellow residue containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine hydrochloride was neutralized with 1 N NaOH aqueous solution and extracted with MTBE (3 × 300 ml). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine as a brown residue (51 g; by palm HPLC Method 1, HPLC purity was 93 area% (rt = 2.646 min.) and 72% ee).

Step 6: Preparation of (4 R )-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine: To 500 equipped with magnetic stirrer, reflux condenser and hot bag The mL three-necked flask was fed with (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine (51 g, 72% ee), ethanol (200 ml), methyl isothiocyanate (28.53 g) and triethylamine (70 ml). The resulting mixture was stirred at 22-27°C for 14 hours. HPLC analysis showed >99% conversion, forming (4 R )-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine. The organic volatiles were then removed in vacuo, and sodium hydroxide (26 g) and water (200 mL) were added to the reaction flask. The reaction mixture was heated to 100°C and stirred for 2 hours. The reaction was diluted with water (200 mL) and extracted with methyl tert-butyl ether (2×500 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo to give (4 R )-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine as a brown oil [53 g, 98 area% HPLC purity (rt = 2.506 min.), m/z = 234 amu (M+H ⁺ )].

Step 7: Preparation of (3 R )-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2 -a] Pyrimidine-4-ium-5-alkoxide: Under a nitrogen atmosphere, feed (4 R )-4-(2 to a 500 mL three-necked flask equipped with a magnetic stirrer, reflux condenser and hot bag -Chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (53 g, 98% HPLC purity), toluene (160 mL) and heated to 110°C. Subsequently, bis(4-chlorophenyl) 2-phenylmalonate (109 g) was added in three portions to the reaction mass maintained at 110°C. After stirring at 110°C for 2 hours, HPLC showed >99% conversion. The reaction was cooled between 45 and 50°C, the precipitated light yellow solid was filtered through a sintered funnel, washed with methyl tert-butyl ether (480 mL) and dried in vacuo to give (3 R )-3-(2- (Chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alcoholate[ 54 g, by palm HPLC method 3, 98.8 area% HPLC purity (rt = 3.86 min.), m/z = 378 amu (M+H ⁺ ) and 99% enantiomeric excess).

¹ H NMR (300 MHz, DMSO-d6): 3.42(s, 3H), 3.94(d, J = 12 Hz, 1H), 4.25-4.32(m, 1H), 6.48 (d, J=8.1 Hz, 1H ), 7.06-7.11(m, 1H), 7.21-7.26(m, 2H), 7.6(d, J = 7.5 Hz, 1H), 7.96(s, 1H)

Example 2: Preparation of (3 R )-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2 -a] Pyrimidine-4-ium-5-alkoxide: Step 1: Preparation of N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylene]-2-methyl-propane-2 -Sulfasamide:

To a 0.5 L three-necked flask equipped with a Teflon blade stirrer, reflux condenser and heat bag was fed 2-chloro-1-(2-chlorothiazol-5-yl) at ambient temperature under a nitrogen atmosphere Acetone (60 g, 97 area% HPLC purity), THF (180 ml), 2-methylpropane-2-sulfenamide (44 g) and titanium (IV) ethoxide (77 mL). The resulting mixture was heated to 50°C and stirred for 2 hours. The progress of the reaction was monitored by HPLC (conversion rate determined by HPLC>95%). The reaction was fed with methyl tert-butyl ether (360 ml), cooled to 0 to 10° C., slowly quenched with 1 N HCl aqueous solution (540 ml) and stirred for 10 minutes. The two phases were separated, and the organic phase was washed with water (2 × 300 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain a crude residue. At ambient temperature, the crude product was dissolved in methyl tert-butyl ether (100 ml), and activated carbon (1.8 g) and silica (5 g, 60-120 mesh) were added. The slurry was stirred for 0.5 hour, filtered through a Buchner funnel and washed with methyl tert-butyl ether (0.3 L). The filtrate was evaporated to obtain N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylene]-2-methyl-propane-2-sulfenamide (88 g) as a light brown oil , By HPLC method 1, 84 area% purity).

Step 2: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide: a) Preparation of rhodium catalyst-RhCl[(R,R)-TsDPEN]Cp*: The catalyst was prepared as described in step 4 of Example 1.

b) Preparation of HCOOH-NEt ₃ mixture: prepared as described in step 4 of Example 1.

c) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide: Xiang equipped with magnetic stirrer , A nitrogen inlet and a hot bag of 3 L four-necked flask was fed with dimethylformamide (1.5 L) and degassed with nitrogen for 10 minutes. Subsequently, under a nitrogen atmosphere, RhCl[(R,R)-TsDPEN]Cp* (1.87 g) was added at 22 to 27°C. At 22 to 27°C, N-[2-chloro-1-(2-chlorothiazole-5-, which was dissolved in dimethylformamide (260 ml), was simultaneously added to the above-mentioned holding solution over a period of 0.5 hours. Group) ethylene]-2-methyl-propane-2-sulfinamide (88 g) and HCOOH-NEt ₃ (220 mL, ratio: 1.1:1) solution, and the resulting mixture was at 22-27°C Stir for 2 hours. HPLC showed >97% conversion. The reaction mixture was quenched with water (1700 ml) and extracted with methyl tert-butyl ether (3×1000 mL). The combined organic phase was evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide (95 g )

Step 3: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine: At ambient temperature, to a 1 L three-necked flask equipped with a magnetic stirrer, nitrogen inlet, and hot bag Feed N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide (95 g) and containing 1 MeOH (285 mL) of N HCl, and the reaction mixture was stirred at 22-27 °C for 14 hours. The progress of the reaction was monitored by HPLC. The organic volatiles were removed in vacuo, the residue was triturated with methyl tert-butyl ether (3×150 mL) and the organic phase containing methyl tert-butyl ether was separated from the pale yellow oily residue. The pale yellow residue containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine hydrochloride was neutralized with 1 N NaOH aqueous solution and extracted with MTBE (3×150 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine as a brown residue (35 g; by palm HPLC Method 1, 99.5 area% HPLC purity (rt = 2.64 min.), m/z = 198 amu (M+H ⁺ ) and 96.2% ee).

Step 4: Preparation of (4 R )-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine: To 250 equipped with a magnetic stirrer, reflux condenser and hot bag The mL three-necked flask was fed with (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine (35 g, 96.2% ee), ethanol (140 ml), and methyl isothiocyanate (19.58 g) and triethylamine (48 ml). The resulting mixture was stirred at 22-27°C for 14 hours. HPLC analysis showed >99% conversion, forming (4 R )-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine. Subsequently, the organic volatiles were removed in vacuo, and sodium hydroxide (17.15 g) and water (140 mL) were added to the reaction flask. The reaction mixture was heated to 100°C and stirred for 2 hours. The reaction was diluted with water (140 mL) and extracted with methyl tert-butyl ether (3×200 mL). The organic phase was dried over sodium sulfate and evaporated in vacuo to give (4 R )-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine as a brown oil [41 g, 96 area% HPLC purity (rt = 2.506 min.), m/z = 234 amu (M+H ⁺ )].

Step 5: Preparation of (3 R )-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2 -a] Pyrimidine-4-ium-5-alkoxide: Under a nitrogen atmosphere, feed (4 R )-4-(2 to a 500 mL three-necked flask equipped with a magnetic stirrer, reflux condenser and hot bag -Chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (41 g, 96% HPLC purity), toluene (125 mL) and heated to 110°C. Subsequently, bis(4-chlorophenyl) 2-phenylmalonate (85 g) was added in three portions to the reaction mass maintained at 110°C. After stirring at 110°C for 2 hours, HPLC showed >99% conversion. The reaction was cooled between 45 and 50°C, the precipitated light yellow solid was filtered through a sintered funnel, washed with methyl tert-butyl ether (480 mL) and dried in vacuo to give (3 R )-3-(2- (Chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide ( 38 g, by palm HPLC method 3, 99.3 area% HPLC purity, m/z = 378 amu (M+H ⁺ ) and 99% ee).

Example 3: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2- a] Pyrimidine-4-ium-5-alkoxide: Step 1: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide:

a) Preparation of rhodium catalyst-RhCl[(R,R)-TsDPEN]Cp*: The catalyst was prepared as described in step 4 of Example 1.

b) Preparation of HCOOH-NEt ₃ mixture: prepared as described in step 4 of Example 1.

c) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide: into a 20 L reactor Feed N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylene]-2-methyl-propane-2-sulfenamide (1275 g, 2.2 mol, 68% HPLC purity ), dimethylformamide (2550 ml) and toluene (2550 ml), and degassed with nitrogen for 10 minutes. RhCl[(R,R)-TsDPEN]Cp* (7.0 g, 0.01 mol) was then added under a nitrogen atmosphere. The resulting mixture was cooled to 0 to 5°C, a freshly prepared HCOOH-NEt ₃ (375 mL, ratio of 1.1:1) solution was added dropwise over a period of 30 minutes, and stirred for 3 hours between 0°C and 5°C. The reaction was monitored by HPLC, quenched with water (2550 mL) and extracted with toluene (2550 mL). The combined organic phase was washed with water (3 × 3750 ml) and evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane- 2-Brown residue of sulfenamide (1150 g, 68% HPLC purity (rt = 4.70 and 4.82 min)).

Step 2: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine at 25°C to 30°C to a 5 L four equipped with a magnetic stirrer, nitrogen inlet and hot bag N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide (1150 g) was fed into the neck flask, It was diluted in MTBE (3210 ml) and HCl gas was purged for 1 hour. The progress of the reaction was monitored by HPLC. The precipitated yellow hydrochloride salt was filtered, and the residue was washed with MTBE (2 × 2000 ml) to obtain a pale yellow solid (500 g). The light yellow solid containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine hydrochloride was adjusted to pH 8.5 to 9 with 2 N NaOH aqueous solution, and toluene (3 × 1000 ml) extraction. The combined organic phase was washed with water (1 L) and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine (370 g; as a brown residue) HPLC method 1, 98% HPLC purity (rt = 2.64 min.), m/z = 198 amu (M+H ⁺ ) and 93% ee).

Step 3: Preparation of (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine: At ambient temperature, (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine was fed into a 2 L three-necked flask equipped with a magnetic stirrer, reflux condenser and hot bag ( 165 g, 0.83 mol, 93% ee), methanol (400 ml), methyl isothiocyanate (91.86 g, 1.25 mol) and triethylamine (225 ml, 1.67 mol). The resulting mixture was stirred at 22-27°C for 14 hours. HPLC analysis showed >99% conversion, forming (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine. Then sodium hydroxide (67 g, 1.67 mol) and water (660 mL) were added to the reaction flask. The reaction mixture was heated to 65°C and stirred for 2 hours. The reaction mixture was extracted with toluene (3 × 660 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (198 g) as a brown oil , 94 area% HPLC purity), m/z = 234 amu (M+H+)).

Step 4: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl-2,3-dihydrothiazolo[3,2- a] Pyrimidine-4-ium-5-alkoxide: Under a nitrogen atmosphere, feed (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (2070 g, 98% HPLC purity) to a 20 L reactor ), toluene (4140 mL) and heated to 80 °C. Subsequently, bis(4-chlorophenyl) 2-phenylmalonate (3553 g, 8.8 mol) was dissolved in toluene (4140 ml) at 45°C, and added dropwise to the reaction maintained at 80°C In the material. After stirring at 100°C for 1 hour, HPLC showed >99% conversion. The reaction was cooled to below 40°C, and the precipitated light yellow solid was filtered and washed with toluene (3×2070 ml) to obtain (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7 -Pendant-6-phenyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide as the first batch (1660 g, 99 area% HPLC purity and 100 % Excess of enantiomer). The combined mother liquor was transferred to a 20 L reactor, acetone (6210 ml) was added and stirred at 22-27°C for 1 hour. The precipitated light yellow solid was filtered and washed with toluene (2070 ml × 3) to obtain (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-phenyl -2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alcoholate as the second batch (718 g, by palmiometric HPLC method 3, 99 area% HPLC purity and 100 % Excess of enantiomer).

Example 4: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine: Step 1: Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide:

a) Preparation of HCOOH-NEt ₃ mixture: prepared as described in step 4 of Example 1.

b) Preparation of N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide: To 1 L 3 neck round The bottom flask was fed with N-[2-chloro-1-(2-chlorothiazol-5-yl)ethylene]-2-methyl-propane-2-sulfenamide (50 g, 85% HPLC purity ), dimethylformamide (100 ml), toluene (100 ml) and degassed with nitrogen for 10 minutes. Subsequently, under a nitrogen atmosphere, pentamethylcyclopentadienyl rhodium dimer (150 mg) and (1R, 2R)-N-p-toluenesulfonyl-1,2-dichloromethane were added at ambient temperature. Phenylethylenediamine (170 mg). The resulting mixture was cooled to 0 to 5°C, freshly prepared HCOOH-NEt ₃ (15 mL, ratio: 1.1:1) was added and stirred for 2 hours. The reaction was monitored by HPLC, quenched with water (100 mL) and extracted with toluene (200 mL). The combined organic phase was washed with water (3 × 20 ml) and evaporated to obtain N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane- Brown residue of 2-sulfenamide (49 g, 88% HPLC purity).

Step 2: Preparation of (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine: At 25°C to 30°C, apply 5 L equipped with a magnetic stirrer, nitrogen inlet, and hot bag A four-necked flask was fed with N-[(1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethyl]-2-methyl-propane-2-sulfenamide (49 g) , Which was diluted in MTBE (147 ml) and HCl gas was purged for 15 minutes. The progress of the reaction was monitored by HPLC. The precipitated yellow hydrochloride salt was filtered, and the residue was washed with MTBE (2 × 100 ml) to obtain a pale yellow solid (35 g). The light yellow solid containing (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine hydrochloride was adjusted to pH 8.5 with 2 N NaOH aqueous solution, and toluene (3 × 80 ml) extraction. The combined organic phases were washed with water (100 ml) and evaporated to obtain (1S)-2-chloro-1-(2-chlorothiazol-5-yl)ethylamine (30 g; as a brown residue) HPLC method 1, m/z = 198 amu (M+H ⁺ ), 98.5% HPLC purity and 99% ee).

Example 5: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-6-(3,5-dichlorophenyl)-8-methyl-7-oxo-2,3-di Hydrothiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide: Follow a method similar to that described in Step 4 of Example 3. Use (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (1 g, 96% HPLC purity), toluene (3 mL) and 2-(3 ,5-dichlorophenyl)malonic acid bis(4-chlorophenyl) ester (2.8 g) was reacted to obtain (3R)-3-(2-chlorothiazol-5-yl)-6-(3, 5-dichlorophenyl)-8-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide (1.1 g and 94% Enantiomeric excess, palm HPLC method 3 (rt = 5.01min), m/z = 448 amu (M+H+))

Example 6: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-6-(4-methoxyphenyl)-8-methyl-7-oxo-2,3-dihydro Thiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide: Follow a method similar to that described in Step 4 of Example 3. (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (1 g, 96% HPLC purity), toluene (3 mL) and 2-(4 -Methoxyphenyl)malonic acid bis(4-chlorophenyl) ester (2.6 g) was reacted to obtain (3R)-3-(2-chlorothiazol-5-yl)-6-(4-methyl Oxyphenyl)-8-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alcoholate (1.1 g and 95% enantiomer Isomer excess, for handheld HPLC method 3 (rt = 3.85 min), m/z = 408 amu (M+H+)).

Example 7: Preparation of (3R)-3-(2-chlorothiazol-5-yl)-8-methyl-7-oxo-6-[3-(trifluoromethyl)phenyl]-2,3 -Dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide: Follow a method similar to that described in Step 4 of Example 3. Use (4R)-4-(2-chlorothiazol-5-yl)-N-methyl-thiazolidine-2-imine (1 g, 96% HPLC purity), toluene (3 mL) and 2-(3 -(Trifluoromethyl)phenyl)malonic acid bis(4-chlorophenyl) ester (2.7 g) was reacted to obtain (3R)-3-(2-chlorothiazol-5-yl)-8-methyl Yl-7-oxo-6-[3-(trifluoromethyl)phenyl]-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ium-5-alkoxide (1.05 g and 97% enantiomeric excess, for palmitic HPLC method 3 (rt = 4.66 min), m/z = 446 amu (M+H+)).

Claims (17)

A method for preparing an optically active pyrimidinium compound of formula X,

Where C* is S or R -configured asymmetric carbon atom; R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl or -CH ₂ -phenyl , These groups are unsubstituted or substituted with halogen or C ₁ -C ₄ alkyl; R ² is a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, where the ring system is not Substitution or substitution by R ^2a ; Het is selected from D-1, D-2 and D-3:

Where R ^{a is} independently halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio or phenyl; n is 0, 1 or 2, and # represents Bond in formula X; R ^2a is halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, OR ^c , C(=O)OR ^c , C(=O)NR ^b R ^c , Phenyl or pyridyl, these groups are unsubstituted or substituted with halogen, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ haloalkoxy; R ^b is hydrogen, C ₁ -C ₆ alkyl Group, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy; R ^c is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkane Group or C ₁ -C ₆ cycloalkyl; where two geminally bound groups R ^c R ^b together with the atoms to which they are bound can form a 3- to 7-membered saturated, partially unsaturated or aromatic group Heterocycle; it contains at least the following steps: (A) hydrogenation of the compound of formula V,

Where R ^A is S(=O) _o R ^x , P(=O)(R ^x ) ₂ , C ₁ -C ₄ alkoxy or -CH ₂ -phenyl, where phenyl is unsubstituted or halogenated , Methoxy or nitro substitution; and R ^x is C ₁ -C ₆ alkyl or aryl, which is unsubstituted or substituted with halogen; and o is 1 or 2; W is halogen, hydroxy, O-pair Tosylate, O-methanesulfonyl or O-trifluoromethanesulfonyl; Het is as defined in the compound of formula X; it is carried out in the presence of the following: hydrogenation catalyst MXLn(ƞ-aromatic) _m , Where M is a transition metal from Group VIII to Group XII of the periodic table; X is an anion; m is 0 or 1; Ln is Ln1 or Ln2, where Ln1 is a palmitic ligand of the formula Ln1

Where C* is an asymmetric carbon atom of S or R-configuration; R ¹⁰ is OH or NH-SO ₂ -R ¹¹ ; wherein R ¹¹ is unsubstituted or independently of each other via halogen, C ₁ -C ₁₀ alkyl , C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, SO ₃ H or SO ₃ Na substituted aryl or R ¹¹ is C ₁ -C ₁₀ perfluoroalkyl, or R ¹³ R ¹⁴ N , Where R ¹³ and R ¹⁴ independently represent a C ₁ -C ₁₀ alkyl group that is unsubstituted or substituted with a C ₆ -C ₁₀ aryl group, or R ¹³ and R ¹⁴ each independently represent a C ₆ -C ₁₀ cycloalkyl group ; R ¹² independently represents a C ₆ -C ₁₀ aryl ring or a C ₆ -C ₁₀ cycloalkyl ring, wherein the rings are unsubstituted or independently of each other via halogen, C ₁ -C ₁₀ alkyl, C _1- C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, SO ₃ H or SO ₃ Na substituted aryl, or two R ^{12 are} joined together to form a 3 member to 6 member carbocyclic ring or 5 member to 10 member Partially unsaturated carbocyclic ring; Ln2 is a para-phosphorous ligand; and a hydrogen source selected from the group consisting of: a) hydrogen gas; b) a mixture of N(R) ₃ and HCOOH, where R is H or C ₁ -C ₆ alkane Base; c) HCOONa or HCOOK; d) a mixture of C ₁ -C ₈ alcohol and t-BuOK, t-BuONa or t-BuOLi; and e) a combination of two or more of a) to d); To obtain the compound of formula VI,

Where C* is an asymmetric carbon atom of S or R-configuration; R ^A , Het and W are as defined in the compound of formula V. The method according to claim 1, further comprising step (B): in the presence of an acid or a base, hydrolyzing the compound of formula VI as defined in claim 1, to obtain the compound of formula VII,

Where C*, Het and W are as defined in the compound of formula VI. The method according to claim 1 or 2, further comprising the following steps: (C) reacting the compound of formula VII as defined in claim 2 with R ¹ NCS in the presence of a base, wherein R ¹ is C ₁ -C ₄ alkyl Group, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl or -CH ₂ -phenyl, these groups are unsubstituted or substituted with halogen or C ₁ -C ₄ alkyl; to obtain the formula Compound VIII,

Where C*, Het and R ¹ are as defined in the compound of formula X; (D) reacting the compound of formula VIII with the compound of formula IX

Wherein, LG is a leaving group selected from halogen, OR ^u and SR ^u ; wherein R ^u is C ₁ -C ₆ alkyl or aryl, which is unsubstituted or substituted by halogen; R ² is as claimed in item 1 As defined in the compound of formula X in; to obtain the compound of formula X as defined in claim 1. The method of claim 1, wherein in step (A), the pair of palmitic phosphorus ligands Ln2 are selected from the ligands listed in Table A below or from their corresponding enantiomers, Table A: Where Cy = cyclohexyl and Ph = phenyl

. The method of claim 1, wherein the ƞ-aromatic hydrocarbon is selected from benzene, p-isopropyltoluene, mesitylene, 1,3,5-triethylbenzene, hexatoluene, anisole, 1,5-cyclooctyl Diene, cyclopentadienyl (Cp), norbornadiene and pentamethylcyclopentadienyl (Cp*). As in the method of claim 1, wherein MXLn(ƞ-aromatic hydrocarbon) _m is MXLn1(ƞ-aromatic hydrocarbon) _m , where R ¹⁰ is NH-SO ₂ -R ¹¹ ; and R ¹² and R ^{11 are} independently phenyl, which is not Substituted or substituted with 1 or 2 substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, SO ₃ H, and SO ₃ Na. The method of any one of 5 and 6, wherein MXLn (ƞ-aromatic hydrocarbon) _m is MXLn1 (ƞ-aromatic hydrocarbon) _m , wherein X is a halide ion; R ^{12 is} independently phenyl, 2-methylphenyl, 3- Methylphenyl, 4-methylphenyl or 4-methoxyphenyl; R ¹⁰ is NH-SO ₂ -R ¹¹ and -SO ₂ -R ¹¹ is p-toluenesulfonyl, methanesulfonyl, 4 -Benzenesulfonyl or pentafluorophenyl-sulfonyl. The method of any one of 5 and 6, wherein m is 1 and MXLn (ƞ-aromatic hydrocarbon) _m has the formula MXLnCp*, where M is rhodium, ruthenium, iridium, palladium, iron, platinum or nickel

. The method of any one of 5 and 6, wherein M is rhodium, ruthenium or iridium. The method according to claim 2, wherein the acid in step (B) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, hydroiodic acid, C ₁ -C ₈ alkyl-(COOH) _y , C ₁ -C ₈ Haloalkyl-(COOH)y, CH ₃ SO ₃ H, citric acid, oxalic acid, p-toluenesulfonic acid or a mixture of two or more thereof; wherein y is 1 or 2. The method of claim 1, wherein R ¹ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or C ₂ -C ₄ alkenyl, which is unsubstituted or substituted with halogen. The method of claim 1, wherein R ² is phenyl, pyridyl, or thienyl, which is unsubstituted or substituted with R ^2a . The method of the requested item 1, wherein Het is a D-2, where n is 0 and R ^a is a halogen. A compound of formula V,

Wherein R ^A , Het and W are as defined in the compound of formula V in claim 1. An optically active compound of formula VI,

Where C* is an asymmetric carbon atom of S or R-configuration; and wherein Het, W and R ^A are as defined in the compound of formula VI in claim 1. An optically active compound of formula VII,

Wherein C* is an asymmetric carbon atom of S or R-configuration; and wherein Het is D-2 or D-3; W is as defined in the compound of formula VII in claim 2. An optically active compound of formula VIII,

Where C* is an asymmetric carbon atom of S or R-configuration; Het is as defined in the compound of formula VIII in claim 3; R ¹ is as defined in the compound of formula VIII in claim 3, or as requested As defined in item 11.