WO2012097471A1 - PREPARATION METHOD OF β-METHYL CARBAPENEM COMPOUND - Google Patents

Abstract

Provided is a preparation method of compound shown by formula (I), which comprises the following steps: in the presence of alkali, reacting compound of formula (III) with compound of formula (IV) in organic solvents to obtain compound of formula (II), then washing the obtained materials with aqueous solution of an acid and separating the organic layer which contains the compound of formula (II); adding alkali, catalysts and hydrogen to the obtained organic solution which contains the compound of formula (II), and crystallizing the obtained materials after reaction to give compound of formula (I). During the process for preparing the solution which contains compound of formula (II) from the compound of formula (III), the obtained solution only need to be washed several times with acid-containing aqueous solution, and no other post-treatment process is needed for the reaction of the next step. The said compounds of formulas (I) ~ (IV) are shown in the specification.

Description

 Method for preparing β-methyl carbapenem compound

 The present invention relates to a method for preparing a β-mercaptocarbamene compound, and in particular,

(4R,5S,6S) -3-[[(3S,5S)-5-(didecylaminocarbonyl)-3-pyrrolidinyl]thio]-6-[(1R)hydroxyethyl]- A process for the preparation of 4-mercapto-7-oxo- 1 -azahan ring [3.2.0]hept-2-en-2-indole acid trihydrate. Background technique

 A compound of the formula (I), ie (4R,5S,6S)-3-[[(3S,5S)-5-(didecylaminocarbonyl)-3-pyrrolidinyl]thio]-6- [(1R)-1-Hydroxyethyl]-4-indolyl-7-oxo-1-azabicyclo[3.2. 0]hept-2-en-2-indoleic acid trihydrate is an antibiotic in the pharmaceutical industry An important raw material for production. Chinese Patent Application CN101410398A discloses a process for preparing a compound of the formula (I): a compound of the formula (III) is reacted with a compound of the formula (IV) in the presence of a base to synthesize a compound of the formula (II).

(II)

 (III) (IV) The reaction solution containing the compound of the formula (Π) is subjected to extraction/brine washing/water washing to obtain a water-saturated ethyl acetate solution containing the compound of the formula (Π). To a water-saturated ethyl acetate solution containing a compound of the formula (Π), a palladium carbon catalyst is added to carry out a hydrodeprotection reaction, and after completion of the reaction, palladium carbon is removed by filtration, and the reaction liquid containing the compound represented by the formula (I) is used. Acid adjustment pH / concentration under reduced pressure / addition of activated carbon stirring / filtration / addition of solvent crystallization. In the above preparation method, the reaction liquid of the compound of the formula (II) is subjected to a series of post-treatment processes such as extraction, washing with water, washing with water, etc.; the obtained reaction liquid containing the compound of the formula (I) is also required. A series of post-treatment processes such as pH adjustment of acid, concentration under reduced pressure, addition of activated carbon and filtration, resulting in cumbersome steps, increased cost, increased raw material loss and increased environmental pollution, are not conducive to industrial production in the pharmaceutical industry and environmental protection. Claim. Summary of the invention

 Accordingly, it is an object of the present invention to find a process which is simple, environmentally friendly and can be industrially produced on a large scale to produce a compound of the formula (I).

 The technical solution for achieving the above object is as follows:

 A method for preparing a compound of the formula (I), which comprises the steps of:

 (A) reacting a compound of the formula (III) with a compound of the formula (IV) in an organic solvent in the presence of a base to form a compound of the formula (II), washing the reaction product with an aqueous acid solution and isolating the formula ( II) an organic solution layer of the compound shown;

(B) A reaction is carried out by adding a base, a catalyst and hydrogen to an organic solution containing the compound of the formula (II), followed by crystallization to give a compound of the formula (I).

 ( I ) Among them, ! ^ is an acyl group.

 Specifically, it may be an unsubstituted or substituted carbonyl group, a sulfonyl group or a phosphoryl group; preferably, the substituent of the substituted carbonyl group, sulfonyl group or phosphoryl group is an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic group, a heterocyclic group, An amino group, an aliphatic alkoxy group, an aromatic oxy group, an aliphatic hydrocarbon group substituted with an aryl group or a heterocyclic group or an amino group substituted with an aryl group or a heterocyclic group;

Further preferably, the compound is selected from alkanoyl groups having 1 to 6 carbon atoms, such as decanoyl group, acetyl group, propionyl group, butyryl group, valeryl group and hexanoyl group; acryloyl group; having 1 to 6 carbon atoms An alkylsulfonyl group such as a sulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group and a hexylsulfonyl group; an alkoxycarbonyl group having 1 to 5 carbon atoms, such as a decanoyl group, an ethoxylated group, Propoxyl, butanoyl and valeryl; propyleneoxycarbonyl; with 1 Alkoxyphosphoryl group of up to 5 carbon atoms, such as diethoxyphosphoryl; benzoyl; phenylsulfonyl, for example p-toluenesulfonyl; phenylphosphoryl; phenoxyphosphoryl, such as diphenoxyphosphoryl; Aminoamino group, N-phenylaminodecanoyl; furanoyl; thiazolylcarbonyl; phenylacetyl; phenylpropionyl; benzyloxycarbonyl; imidazolylacetyl;

 More preferably, it is a diaryloxyphosphoryl group;

 Most preferably, R is a diphenoxyphosphoryl group.

 In the step (A), the base may be an organic base such as a trialkylamine, a tridecylamine, a triethylamine, a tributylamine, a triamylamine, a trihexylamine, a trioctylamine, and an anthracene. Ν-diisopropylethylamine; dialkylamine, hydrazine, hydrazine-diisopropylamine; pyridine; pyridine having a substituent on the pyridine ring, such as 2,6-dimercaptopyridine, 3,5- Dimercaptopyridine, 2,3,5-tridecylpyridine, 2,4,6-trimercaptopyridine, 3-mercaptopyridine, 2-mercaptopyridine and 4-methylpyridine; quinoline; An alkylmorpholine; and one or more of tetrakisinium, preferably ruthenium, osmium-diisopropylethylamine, hydrazine, hydrazine-diisopropylamine or tetradecyl hydrazine;

 The organic solvent is selected from the group consisting of: fluorene-fluorenylpyrrolidone, hydrazine-ethylpyrrolidone; hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide; nitrile, such as acetonitrile; halogenated hydrocarbon, such as two Chlorodecane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as toluene; ketones, acetone and butanone; tetrahydrofuran; oxime, ethyl acetate and decyl acetate; alcohols such as decyl alcohol, ethanol, n-propanol and One or more of isopropanol, preferably dichlorodecane, tetrahydrofuran, acetonitrile, ethyl acetate, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide, hydrazine-fluorenyl One or more of pyrrolidone, hydrazine-ethylpyrrolidone and toluene;

 The aqueous acid solution is selected from the group consisting of inorganic acids such as hydrochloric acid, acid, nitric acid, phosphoric acid, potassium dihydrogen phosphate, and sodium dihydrogen phosphate; and organic acids such as one or more of citric acid, acetic acid, sulfonic acid, and trifluoroacetic acid. Kind of aqueous solution. Sodium dihydrogen phosphate is preferred.

 In the step (Α), the molar ratio of the compound of the formula (IV) to the compound of the formula (III) is 1: 0.8-3.0, preferably 1: 1.0-1.5 mol; the base and the formula (III) The molar ratio of the compound is 1: 0.8 to 5.0 moles, preferably 1: 1.0 to 3.0 moles; the temperature of the reaction is -50 ° C to 5 (TC, preferably -30 ° C to 3 (TC; The mass ratio of the organic solvent to the compound of the formula (III) is from 1 to 40:1, preferably from 2 to 20:1; the volume ratio of the aqueous acid solution to the reaction product is 1: 0.1-20, preferably 1 : 0.5-10; the concentration of the aqueous acid solution is 0.01 mol / liter to 10 mol / liter, preferably 0.01 mol / liter ~ 5 mol / liter; the washing temperature is 0 ° C ~ 40 ° C, It is preferably 20 ° C to 40 ° C, more preferably 34 ° C.

In the step (A), adding a water-immiscible organic solvent, preferably a hydrocarbon, such as dichlorosilane and chloroform, when separating the organic solution layer containing the compound of the formula (II); Esters such as ethyl acetate and methyl acetate; hydrocarbons such as petroleum ether and n-pentane; aromatic hydrocarbons such as toluene; alcohols such as n-butanol and n-pentanol; ketones such as 2-butanone and 2-pentanone; Ether, such as B One or more of the ethers.

 In the step (B), the organic solution containing the compound of the formula (II) is concentrated before the reaction, or water and/or one or more is added to the organic solution containing the compound of the formula (Π) before the reaction. Selected from N-decyl pyrrolidone, N-ethylpyrrolidone; N,N-dimercaptoamide, N,N-dimercaptoacetamide; nitrile, such as acetonitrile; 13⁄4 hydrocarbon, such as dichlorodecane, three Chlorodecane and carbon tetrachloride; aromatic hydrocarbons such as toluene; ketones such as acetone and methyl ethyl ketone; tetrahydrofuran; esters, ethyl acetate and decyl acetate; alcohols, sterols, ethanol, n-propanol and isopropanol, Preferred are dichlorodecane, tetrahydrofuran, acetonitrile, ethyl acetate, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide, hydrazine-methylpyrrolidone, hydrazine-ethylpyrrolidone and toluene. One or more organic solvents.

 In the step (Β), the base is selected from an organic base such as pyridine; a pyridine having a substituent on the pyridine ring, such as 2,6-dimercaptopyridine, 3,5-dimercaptopyridine, 2, 3,5-trimercaptopyridine, 2,4,6-trimercaptopyridine, 3-mercaptopyridine, 2-mercaptopyridine and 4-mercaptopyridine; morpholine; quinoline; pyrimidine; 4-di Aminopyridine; triethylamine, diethylamine, tributylamine, diisopropylethylamine and diisopropylamine; inorganic bases such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; one of sodium carbonate and potassium carbonate One or more; the catalyst is a catalyst containing palladium and/or platinum, preferably a palladium-containing catalyst, more preferably a palladium catalyst supported on activated carbon; the solvent of the crystallization is selected from a nitrile such as acetonitrile; For example, dichloromethane; aromatic hydrocarbons such as toluene; ketones such as acetone and methyl ethyl ketone; tetrahydrofuran; esters, ethyl acetate and decyl acetate; alcohols such as decyl alcohol, ethanol, n-propanol and isopropanol One or more, preferably dichlorosilane, tetrahydrofuran, acetonitrile, acetone and methanol One or more.

 In the step (Β), the pressure of the hydrogen gas is 0.05 to 6.0 MPa, preferably 0.1 to 4.0 MPa; the temperature of the reaction is 0 to 70 ° C, preferably 15 to 50 ° C; the solvent of the crystallization The volume ratio to the reaction product is from 0.2 to 50:1, preferably from 1 to 10:1.

 In the step (B), a seed crystal is added during the crystallization; the crystallization is stirred or not stirred.

The inventors have found through extensive studies that the reaction solution containing the compound of the formula (II) obtained by reacting the compound of the formula (III) with the compound of the formula (IV) needs to be washed only one to ten times with an aqueous solution containing an acid. It is preferably five times and can be used in the next reaction without additional post-treatment, which would otherwise affect the product quality and yield of the subsequent reaction product, ie, the compound of formula (I). The reaction solution containing the compound of the formula (II) subjected to the treatment is concentrated, and water, an organic solvent, a base, a noble metal catalyst is added, and hydrogen is deprotected in an autoclave to obtain a compound containing the compound of the formula (I). The reaction solution is filtered to remove the catalyst, and the reaction liquid at this time is directly added to the crystallizing solvent without further post-treatment, whereby a compound of the formula (I) having a good yield and high quality can be obtained. The best way to implement the invention

 The present invention is further described in detail with reference to the preferred embodiments of the present invention. Example 1

 The starting compound Ilia was obtained by the method disclosed in Chinese Patent ZL200610057578.6. Unless otherwise stated, other test materials are commercially available.

 Compound (4R,5S,6S)-3-[[(3S,5S)-l-(p-Nitrobenzyloxycarbonyl)-5-(didecylaminocarbonyl)-3-pyrrolidinyl]thio] 6-[ ( 1R ) -1-Hydroxyethyl]-4-indolyl-7-oxo-1-azabicyclo[3.2.

 ( Π)

 33.0 g of the compound ( 4R,5R,6S )-3-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-indolyl-7-oxo-1- Azabicyclo[3.2.0]hept-2-ene-2-decanoic acid p-nitrobenzyl ester (Ilia) was added to the reaction flask, and 200.0 g of acetonitrile, 10.Og of diisopropylethylamine, 19.0 g of the formula was added. The compound shown in IV was reacted at -10 °C. After completion of the reaction, 500 g of ethyl acetate was added to the reaction solution, and washed twice with 500 ml of a 6% (g/mL) aqueous solution of sodium dihydrogen phosphate, and the washing temperature was 34 ° C, and the phases were separated to obtain the formula II. An organic solution of the compound. Example 2

( 4R, 5S, 6S ) -3-[[(3S, 5S)-5-(didecylaminocarbonyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl Preparation of 4-mercapto-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-decanoic acid trihydrate (I)

 (π) (I) The compound (II) obtained in Example 1 (i.e., (4R, 5S, 6S)-3-[[(3S,5S)-l-(p-nitrobenzyloxycarbonyl)-5) - (didecylaminocarbonyl)-3-pyrrolidinyl]thio]-6-[(1R)hydroxyethyl]-4-indolyl-7-oxo-1-azabicyclo[3.2.0 The organic solution of p-nitro-2-ene-2-nonanoic acid p-nitrobenzyl ester was concentrated, and the concentrate was introduced into an autoclave, 600 g of tetrahydrofuran was added, and 20 g of palladium carbon catalyst was added to 3.5 g of dimercaptopyridine. Hydrogen was introduced, the pressure was about 0.5 MPa, and the temperature was controlled at 0 to 50 ° C. After the reaction was completed, a catalyst such as palladium carbon was removed by filtration, and the filtrate was transferred to a crystallization flask, and 1000 g of acetone was added thereto, and the mixture was stirred and crystallized at about 0 ° C. Filtration gave 18.2 g of Compound (1).

 Determination of the physical properties of the compound (I):

UV _max ^H20 nm: 297

IR ^KBr cm : 1755, 1627, 1393, 1252, 1130

NMR8 (D ₂ 0): 1.25 ( 3H, d, J = 6.4 Hz ) , 1.81-1.96 ( 1 Η m) 2.96 (3Η, s) , 3.03 (3Η, s) , 3.14-3.20 (3Η m) , 3.31- 3.41 (2Η, m) , 3.62-3.72 ( 1Η m) , 3.90-4.00 ( 1Η, m) , 4.14-4.26 (2Η m) , 4.63 ( 1Η, t, J=8.5Hz) Example 3

 This example was used to investigate the effect of different treatment methods on the preparation reaction in the post-treatment of the reaction liquid for preparing the compound of the formula (II) from the compound of the formula (III).

 The compound of the formula (I) was prepared by a method similar to that of Example 1 and Example 2, except that the following two methods were used in the post-treatment of the compound of the intermediate formula (Π):

Method 1: Wash once with water, twice with saline, and then once with water; Method 2: Wash five times with an aqueous solution of potassium dihydrogen phosphate (KH ₂ P0 ₄ ).

 According to the above two treatment methods, the following results are obtained:

 (1) It is treated by Method 1. The process is easy to emulsify, the phase separation is difficult, and the phase separation is required for a long time; the use method 2 is easy to phase separation, and the reaction speed is fast;

 (2) From the liquid phase spectrum, after the post-treatment, using the method 1 treatment, there is a phenomenon that the peak of the small impurity becomes large, that is, the impurity is significantly increased, which is likely to cause serious adverse drug reactions;

2 treatment does not have this phenomenon;

(3) The yields of the products obtained by the methods 1 and 2 were significantly different. The compound of the formula (I) was prepared by a method similar to that of Example 1 and Example 2, except that the method of the intermediate formula (Π) was used in the post-treatment of the compound (Method 1) and Method 2, respectively. Two batches of experiments were carried out, and a batch of experiments were carried out in accordance with Method 2 for comparison. The results are shown in Table 1.

 Table 1 Effect of different treatment methods on product yield

从表 1可以看出使用方法②进行处理， 得到的产物产率明显较高。 结论： 在式 （III) 所示化合物制备式 （II) 所示化合物的反应液中使 用方法②可以使得到的含有式（II) 所示化合物的有机溶液体系较纯， 因 而使式（Π) 所示化合物制备式（I)所示化合物中反应体系在反应完全后 可以通过直接析晶得到产品， 且纯度和收率较高； 而如果在式（III)所示 化合物制备式 （II) 所示化合物的反应液中使用方法②， 即食盐水洗涤， 一方面， 后处理过程中容易出现乳化现象， 会造成产品溶液中式 （II) 所 示化合物收率损失和纯度上的降低； 另一方面， 如果在式 （II) 所示化合 物制备式 （I) 所示化合物中按照本发明的直接析晶法， 得到的式 （I) 所 示化合物的产品纯度会受影响， 因而必须采用繁瑣的后处理方法来得到纯 度较高的产品， 其收率大大降低。 实施例 4

It can be seen from Table 1 that the treatment using Method 2 yields a significantly higher yield. Conclusion: The method 2 for preparing the compound of the formula (II) by using the compound of the formula (III) can be used to make the organic solution system containing the compound of the formula (II) relatively pure, thereby making the formula (Π) The compound shown in the preparation of the compound of the formula (I) can be obtained by direct crystallization after completion of the reaction, and the purity and yield are higher; and if the compound of the formula (III) is used to prepare the formula (II) In the reaction solution of the compound, the method 2 is used, that is, washing with a saline solution. On the one hand, the emulsification phenomenon is likely to occur during the post-treatment, which causes a decrease in the yield loss and purity of the compound represented by the formula (II) in the product solution; If the direct crystallization method according to the present invention is carried out in the preparation of the compound of the formula (I) in the compound of the formula (II), the purity of the product of the compound of the formula (I) obtained is affected, and cumbersome post-treatment must be employed. The method is to obtain a product with higher purity, and the yield thereof is greatly reduced. Example 4

 This example was used to investigate the effect of different kinds of washing solutions on the product yield and yield in the post-treatment of the reaction solution of the compound of the formula (ΙΠ) prepared by the compound of the formula (ΙΠ).

The compound of the formula (I) was prepared by a method similar to that of Example 1 and Example 2, except that the solution shown in Table 2 was used for the post-treatment of the compound of the formula (II), and the results were as follows. Table 2 shows. Table 2 Effect of different kinds of washing solutions on product yield and yield

由上表 2可知， 在式（III )所示化合物制备式（II )所示化合物的反应 液的后处理中， 选择洗涤溶液非常关键， 不同的洗涤溶液对最终产品的纯 度和收率影响很大， 使用酸性水溶液， 例如磷酸二氢钠或磷酸二氢钾的水 溶液, 与其他各类溶液相比， 可以使得到的式 （Π ) 所示化合物的有机溶 液体系较纯， 大大提高了式（I )所示化合物粗品产量的純度和收率。 由表 2还可以看出， 使用磷酸二氢钾的水溶液作为洗涤溶液效果更好。 实施例 5

It can be seen from the above Table 2 that in the post-treatment of the reaction solution of the compound of the formula (II) to prepare the compound of the formula (II), it is very important to select a washing solution, and different washing solutions have a great influence on the purity and yield of the final product. Large, using an acidic aqueous solution, such as sodium dihydrogen phosphate or potassium dihydrogen phosphate aqueous solution, compared with other types of solutions, can make the organic compound system of the compound of formula (Π) to be purer, greatly improved the formula ( I) The purity and yield of the crude product yield shown. It can also be seen from Table 2 that the use of an aqueous solution of potassium dihydrogen phosphate as a washing solution is more effective. Example 5

 This example was conducted to investigate the effect of different washing temperatures on the product yield in the post-treatment of the reaction solution of the compound of the formula (II) in the preparation of the compound of the formula (III).

The compound of the formula (?) was prepared in the same manner as in Example 1, except that the washing was carried out by the washing temperature shown in Table 3 in the post-treatment, and the results are shown in Table 3. Table 3 Effect of Different Washing Temperatures on Product Yield

由表 3可知， 在将式（πι)所示化合物与式（IV)所示化合物在减存 在下于有机溶剂中反应生成式（II)所示化合物的反应液中， 使用酸的水 溶液洗涤反应产物并分离出含有式（u)所示化合物的有机溶液层中， 洗 涤温度对式（Π)所示化合物的产量有很大影响， 考虑到最终产量， 洗涤 温度可以为 0°C~40°C， 优选为 20°C〜40°C, 最佳为 34°C。

It can be seen from Table 3 that the reaction solution of the compound of the formula (IV) and the compound of the formula (IV) are reacted in an organic solvent to form a compound of the formula (II), and the reaction solution is washed with an aqueous acid solution. The product is separated into an organic solution layer containing the compound of the formula (u), and the washing temperature has a great influence on the yield of the compound represented by the formula (Π), and the washing temperature may be 0 ° C to 40 ° in consideration of the final yield. C, preferably from 20 ° C to 40 ° C, most preferably 34 ° C.

Claims

Rights request  A process for the preparation of a compound of the formula (I), which comprises the steps of: (A) reacting a compound of the formula (III) with a compound of the formula (IV) in an organic solvent in the presence of a base to form a compound of the formula (II), washing the reaction product with an aqueous acid solution and isolating the formula ( II) an organic solution layer of the compound shown;  (B) A base, a catalyst and hydrogen are added to an organic solution containing the compound of the formula (II) to carry out a reaction, followed by crystallization to give a compound of the formula (I).

 (I)  Wherein 1 is an acyl group.  The method according to claim 1, wherein the compound is an unsubstituted or substituted carbonyl group, a sulfonyl group or a phosphoryl group; Preferably, the substituent of the substituted carbonyl, sulfonyl or phosphoryl group is an aliphatic hydrocarbon group, an alicyclic ring a hydrocarbon group, an aromatic group, a heterocyclic group, an amino group, an aliphatic alkoxy group, an aromatic oxy group, an aliphatic hydrocarbon group substituted with an aryl group or a heterocyclic group or an amino group substituted with an aryl group or a heterocyclic group;  Further preferably, the compound is selected from alkanoyl groups having 1 to 6 carbon atoms, such as decanoyl group, acetyl group, propionyl group, butyryl group, valeryl group and hexanoyl group; acryloyl group; having 1 to 6 carbon atoms An alkylsulfonyl group such as a sulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group and a hexylsulfonyl group; an alkoxycarbonyl group having 1 to 5 carbon atoms, such as a decanoyl group, an ethoxylated group, a propoxy acyl group, a butoxy acyl group and a pentyl acyl group; a propyleneoxycarbonyl group; an alkoxyphosphoryl group having 1 to 5 carbon atoms, such as a diethoxyphosphoryl group; a benzoyl group; a benzenesulfonyl group such as p-toluenesulfonyl; Acylphosphoryl; phenoxyphosphoryl, such as diphenoxyphosphoryl; phenylamino acyl, N-phenylaminodecanoyl; furanoyl; thiazolylcarbonyl; phenylacetyl; phenylpropionyl; Oxycarbonyl; imidazolyl acetyl;  More preferably, R is a diaryloxyphosphoryl group;  Most preferably, it is a diphenoxyphosphoryl group.  The method according to claim 1 or 2, wherein in the step (A), the base is an organic base such as a trialkylamine, a tridecylamine, a triethylamine, or a tris Butylamine, triamylamine, trihexylamine, trioctylamine and N,N-diisopropylethylamine; dialkylamine, N,N-diisopropylamine; pyridine; having a substituent on the pyridine ring Pyridine, such as 2,6-dimercaptopyridine, 3,5-dimercaptopyridine, 2,3,5-trimercaptopyridine, 2,4,6-trimercaptopyridine, 3-mercaptopyridine, 2-pyridylpyridine and 4-mercaptopyridine; quinoline; N-alkylmorpholine; and one or more of tetramethylguanidine, preferably ruthenium, osmium-diisopropylethylamine, ruthenium , Ν-diisopropylamine or tetradecyl hydrazine;  The organic solvent is selected from the group consisting of: fluorene-fluorenylpyrrolidone, hydrazine-ethylpyrrolidone; hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide; nitrile, such as acetonitrile; Chlorodecane, trichloromethane and carbon tetrachloride; aromatic hydrocarbons such as toluene; ketones, acetone and butanone; tetrahydrofuran; esters, ethyl acetate and decyl acetate; alcohols such as decyl alcohol, ethanol, n-propanol and One or more of isopropanol, preferably dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide, hydrazine-methylpyrrolidone One or more of Ν-ethylpyrrolidone and toluene;  The aqueous acid solution is selected from the group consisting of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, potassium dihydrogen phosphate, and sodium dihydrogen phosphate; and organic acids such as one or more of citric acid, acetic acid, diaphoric acid, and trifluoroacetic acid. An aqueous solution; preferably potassium dihydrogen phosphate or sodium dihydrogen phosphate. The preparation method according to any one of claims 1 to 3, wherein in the step (Α), the molar ratio of the compound of the formula (IV) to the compound of the formula (III) is 1: 0.8 to 3.0, preferably 1: 1.0 to 1.5 mole; the molar ratio of the base to the compound of the formula (III) is 1: 0.8 to 5.0 moles, preferably 1: 1.0 to 3.0 moles; -50 ° C ~ 50 ° C, preferably -3 (TC ~ 30 ° C; the quality of the organic solvent and the compound of the formula (III) The ratio of the aqueous solution of the acid to the reaction product is 1:0.1-20, preferably 1:0.5-10; 0.01 mol/L to 10 mol/L, preferably 0.01 mol/L to 5 mol/L; the washing temperature is 0 ° C to 40 ° C, preferably 20 ° C to 40 ° C, more preferably 34 °C.  The preparation method according to any one of claims 1 to 4, wherein in the step (A), adding water and water when separating the organic solution layer containing the compound of the formula (II) The immiscible organic solvent is preferably a [3⁄4 generation hydrocarbon such as dichloromethane and trichloromethane; an ester such as ethyl acetate and decyl acetate; a hydrocarbon such as petroleum ether and n-pentane; an aromatic hydrocarbon such as hydrazine; Benzene; an alcohol such as n-butanol and n-pentanol; S is the same as, for example, 2-butanone and 2-pentanone; and an ether such as one or more of diethyl ether.  The preparation method according to any one of claims 1 to 5, wherein, in the step (B), the organic solution containing the compound of the formula (II) is concentrated before the reaction, or before the reaction. To the organic solution containing the compound of the formula (II), water and/or one or more selected from the group consisting of N-decylpyrrolidone and N-ethylpyrrolidone; hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine- Dimercaptoacetamide; nitrile such as acetonitrile; halogenated hydrocarbons such as dichlorodecane, trichlorodecane and carbon tetrachloride; aromatic hydrocarbons such as toluene; ketones such as acetone and butanone; tetrahydrofuran; Ethyl acetate and decyl acetate, decyl alcohol, ethanol, n-propanol and isopropanol, preferably dichlorosilane, tetrahydrofuran, acetonitrile, ethyl acetate, hydrazine, hydrazine-dimercaptocarboxamide, hydrazine, hydrazine- An organic solvent of one or more of dimethylacetamide, fluorenyl-pyridylpyrrolidone, anthracene-ethylpyrrolidone, and toluene.  The preparation method according to any one of claims 1 to 6, wherein in the step (Β), the base is selected from an organic base such as pyridine; and a pyridine having a substituent on the pyridine ring For example, 2,6-lutidine, 3,5-lutidine, 2,3,5-trimethylpyridine, 2,4,6-trimercaptopyridine, 3-mercaptopyridine, 2- Methylpyridine and 4-methylpyridine; morpholine; quinoline; pyrimidine; 4-diaminopyridine; triethylamine, diethylamine, tributylamine, diisopropylethylamine and diisopropylamine; An inorganic base such as disodium hydrogen phosphate or dipotassium hydrogen phosphate; one or more of sodium carbonate and potassium carbonate; the catalyst is a catalyst containing palladium and/or platinum, preferably a catalyst containing palladium, more preferably a load. a palladium catalyst on activated carbon; the solvent of the crystallization is selected from a nitrile such as acetonitrile; 3⁄4 generation hydrocarbons such as dichlorodecane; aromatic hydrocarbons such as toluene; ketones such as acetone and butanone; tetrahydrofuran; esters, ethyl acetate and decyl acetate; alcohols such as decyl alcohol, ethanol, n-propanol and isopropyl One or more of the alcohols are preferably one or more of dichlorosilane, tetrahydrofuran, acetonitrile, acetone and methanol.  The preparation method according to any one of claims 1 to 3, wherein in the step (Β), the pressure of hydrogen gas is 0.05 to 6.0 MPa, preferably 0.1 to 4.0 MPa; The temperature is 0 to 70 ° C, preferably 15 to 50 ° C; the volume ratio of the solvent to the reaction product is 0.2 to 50:1, preferably 1 to 10:1. The preparation method according to any one of claims 1 to 8, characterized in that In the step (B), the seed crystal is added during the crystallization; the crystallization process is stirred or not stirred.