阅读说明：本技术 布瓦西坦中间体及其制备方法和纯化方法 (Buvalracetam intermediate, preparation method and purification method thereof ) 是由 裘鹏程 张司韬 郭珩 吴海波 刘力铭 陈港生 杨丹琦 李承明 张福利 于 2021-09-09 设计创作，主要内容包括：本发明公开了一种布瓦西坦中间体及其制备方法和纯化方法。本发明的布瓦西坦中间体的纯化方法包括如下步骤：将如式C所示的化合物和如式C’所示的化合物的混合物在溶剂中进行结晶,得到所述的如式C所示的化合物或所述的如式C’所示的化合物；采用该方法制备得到的布瓦西坦中间体的de值高,具有较好的应用前景。(The invention discloses a brivaracetam intermediate, a preparation method and a purification method thereof. The purification method of the intermediate of the brivaracetam comprises the following steps: crystallizing a mixture of a compound shown as a formula C and a compound shown as a formula C 'in a solvent to obtain the compound shown as the formula C or the compound shown as the formula C'; the prepared intermediate of the Buvalsartan has high de value and good application prospect.)

1. A method of purifying a compound of formula C or formula C', comprising the steps of: crystallizing a mixture of a compound shown as a formula C and a compound shown as a formula C 'in a solvent to obtain the compound shown as the formula C or the compound shown as the formula C';

wherein R is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

2. A process according to claim 1 for the purification of a compound of formula C or formula C', wherein the purification process satisfies one or more of the following conditions:

(1) the solvent is ester solvent, ketone solvent and C_1-4One or more of alcoholic solvents; the ester solvent is preferably ethyl acetate; the ketone solvent is preferably acetone; said C_1-4The alcohol solvent is preferably ethanol and/or isobutanol;

(2) the crystallization mode adopts a mode of naturally cooling the hot saturated solution for crystallization;

(3) the volume mass ratio of the solvent to the mixture of the compound shown in the formula C and the compound shown in the formula C' is 1.4-3.0ml/g, such as 1.5ml/g, 1.8ml/g or 2.0 ml/g;

(4) the ratio of the compound shown in the formula C to the compound shown in the formula C 'in the mixture of the compound shown in the formula C and the compound shown in the formula C' is 1:10-10:1, such as 7: 1;

(5) the mixture of the compound shown as the formula C and the compound shown as the formula C' is prepared by the following method: carrying out a salt forming reaction shown in the specification on a compound B and a compound I in a solvent to obtain a mixture of a compound shown in a formula C and a compound shown in a formula C';

3. a process according to claim 2 for the purification of a compound of formula C or formula C', wherein the purification process satisfies one or more of the following conditions:

(1) in the salifying reaction, de% of the compound B is more than or equal to 70%;

(2) in the salt-forming reaction, the compound I is quinine, quinidine or cinchonidine, such as cinchonidine;

(3) in the salt formation reaction, the molar ratio of the compound I to the compound B is 0.5:1 to 2:1, such as 1.0: 1;

(4) in the salt-forming reaction, the solvent is an ether solvent, a nitrile solvent, an ester solvent and C_1-4One or more of an alcohol solvent, a ketone solvent and water, preferably one or more of an ester solvent, an alcohol solvent and a ketone solvent; the ester solvent is preferably ethyl acetate; the alcohol solvent is preferably methanol, ethanol, n-propanol or isobutanol; the ketone solvent is preferably acetone;

(5) in the salt forming reaction, the volume mass ratio of the solvent to the compound B is 1:1-30:1, preferably 2:1-15:1, such as 2.8:1 or 3: 1;

(6) the reaction temperature is 1-110 ℃, for example, 25-80 ℃;

(7) the compound B is prepared by the following method: in the presence of hydrogen and a metal catalyst, carrying out reduction reaction on the compound A in an organic solvent as shown in the specification to obtain a compound B;

4. a process according to claim 3 for the purification of a compound of formula C or formula C', wherein the purification process satisfies one or more of the following conditions:

(1) in the reduction reaction, the metal catalyst is palladium carbon, platinum carbon, ruthenium carbon, rhodium carbon or Raney nickel, preferably palladium carbon;

(2) in the reduction reaction, the mass ratio of the metal catalyst to the compound is 1:15-1:5, such as 1: 10;

(3) in the reduction reaction, the organic solvent is one or more of an alcohol solvent, a ketone solvent, a chlorohydrocarbon solvent, an ether solvent, a nitrile solvent, an ester solvent and water, preferably the alcohol solvent or the ester solvent, and more preferably methanol or ethyl acetate;

the temperature of the reduction reaction is-50 ℃ to 50 ℃, preferably-10 ℃ to 20 ℃.

5. A preparation method of a brivaracetam intermediate is characterized by comprising the following steps: in a solvent, carrying out a free reaction of the compound C and acid as shown in the following formula to obtain a compound D;

r is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

6. The preparation method of the intermediate of the busulfame as claimed in claim 5, wherein the preparation method of the intermediate of the busulfame satisfies 1 or more of the following conditions:

(1) in the free reaction, the solvent is a water-ether solvent, preferably water-methyl tert-butyl ether; the volume ratio of water to the ether solvent in the water-ether solvent may be 1:8 to 1:1, for example, 1: 4;

(2) in the free reaction, the acid is an inorganic acid, such as hydrochloric acid;

(3) in the free reaction, the molar concentration of hydrogen ions in the acid is 0.01-0.1M;

(4) the compound C is One or more of;

the compound C is preferably prepared according to the purification method of the compound shown in the formula C or the formula C' as claimed in any one of claims 1 to 4.

7. A method for preparing a mixture of a compound of formula C and a compound of formula C', comprising the steps of: carrying out a salt forming reaction shown in the specification on a compound B and a compound I in a solvent to obtain a mixture of the compound shown in the formula C and the compound shown in the formula C';

r is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

the conditions and operation of the salt-forming reaction are as defined in claim 2 or 3.

8. A preparation method of brivaracetam comprises the following steps:

step 1: in a solvent, carrying out a free reaction of the compound C and an acid as shown in the following formula to obtain a compound D;

step 2: carrying out condensation reaction on the compound D obtained in the step 1 to obtain the brivaracetam;

in step 1, the compound C is obtained according to the purification method of the compound shown as the formula C or the formula C' in any one of claims 1 to 4; the conditions and operation of the free reaction are as defined in claim 5 or 6.

9. A preparation method of a compound shown as a formula C ' or D ', which is characterized in that the preparation method of the compound shown as the formula C ' comprises the following steps: carrying out salt-forming reaction on the compound B and the compound I 'in a solvent as shown in the specification to obtain a compound C';

the preparation method of the compound shown in the formula D' comprises the following steps: in a solvent, carrying out a free reaction of the compound C 'and acid as shown in the following formula to obtain a compound D';

wherein R' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

the conditions and operation of the salt-forming reaction are as defined in claim 2 or 3;

the conditions and operation of the free reaction are the same as those of the free reaction described in claim 5 or 6.

10. A compound of formula C, a compound of formula C ', a mixture of a compound of formula C and a compound of formula C', or a compound of formula C ″:

wherein R and R' are independently H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

the compound shown in the formula C is preferably

The compound shown as the formula C' is preferably

The mixture of the compound shown in the formula C and the compound shown in the formula C' is preferably the compound shown in the formula CThe mixture of (A) and (B), Wherein, the ratio of C-1 to C ' -1, the ratio of C-2 to C ' -2 and the ratio of C-3 to C ' -3 are preferably 7: 1;

the compound shown in the formula C' is preferably the following compound:

Technical Field

The invention relates to a brivaracetam intermediate, a preparation method and a purification method thereof.

Background

Brivaracetam (Biravavetam), trade name:the new third-generation epilepsy therapeutic drug designed and developed by Belgium-superior-time ratio (UCB Pharm) company is marketed in Europe and America at 2016, 1, 14 and 2, 18 and is suitable for adjuvant therapy of young and adult partial seizure patients over 16 years old.

The mechanism of action of the bravaracetam is the same as that of levetiracetam, and the bravaracetam plays an anti-epileptic role by being combined with an intracerebral protruding vesicular protein (SV2A) to influence synaptic function and regulate neurotransmitter release. However, clinical test data show that the curative effect of the brivaracetam is obviously superior to that of levetiracetam, and the brivaracetam has good tolerance and small adverse reaction.

Because two chiral centers exist in the structure of the bravaracetam, wherein the chiral center at the 2-position of the side chain can be directly introduced from the derivative of natural amino acid, the construction difficulty of the chiral center is the construction of the chiral carbon at the 4-position of the lactam ring. At present, the synthesis routes of the brivaracetam are more, and the synthesis routes mainly comprise methods of chiral chromatographic column preparation, chiral resolving agent resolution, asymmetric synthesis and the like. Chiral column chromatography preparation methods have more reports in documents, but have high separation and preparation cost and limited production scale, and cannot meet the requirements of industrial production; in recent years, more and more asymmetric synthetic methods are reported, and although the use of chiral column chromatography is abolished in the existing asymmetric synthetic methods, the defects of long route, low yield, need of column chromatography purification and the like exist.

CN106748950A reports a process for the preparation of the intermediate (S) -2-3-propylpyrrolidin-1-ylbutanoic acid, as shown in the following formula. The method uses R-phenylethylamine as a resolving agent and isopropanol as a resolving solvent, resolves (S) -2-3-propyl pyrrolidine-1-butyric acid to obtain an intermediate with high chiral purity, and then performs ammoniation and purification steps to obtain the high-purity bravaracetam.

CN111333563A also reports a method for preparing a brivaracetam intermediate, as shown in the following formula. In the patent, 1S, 2S-diphenylethylenediamine is used as a resolving agent to resolve (S) -2-3-propylpyrrolidine-1-ylbutanoic acid to obtain the intermediate with high chiral purity, and the high-purity brivaracetam is synthesized by using a method reported in CN106748950A for reference.

However, the inventor repeats the above two patent examples to find that neither of the above two resolution systems has resolution and purification effects, and no solid crystal is precipitated, and the patent reproducibility is yet to be investigated.

In addition, CN107513031A reports a method for preparing a brivaracetam intermediate, which is shown in the following formula. According to the method, the compound A can be directly reduced and converted into the excess isomer B under the low-temperature condition through heavy metal catalytic hydrogen by asymmetric reduction, and the high chiral purity intermediate D of the brivaracetam can be obtained through recrystallization. However, after the experimental personnel repeat the patent examples, the direct hydrogenation reduction can not reach the de value described in the patent, and the de value of the product of the recrystallization system can not reach the height reported by the patent under the conditions described in the patent, and the patent reproducibility is to be investigated.

In view of the problems of high cost, limited production scale, long route and the like of the conventional preparation method of the brivaracetam, the research and development of a more convenient preparation method of the brivaracetam with low cost for industrial production are needed.

Disclosure of Invention

The invention aims to overcome the defects of low de value or low yield of a brivaracetam intermediate in the prior art, and provides a brivaracetam intermediate, and a preparation method and a purification method thereof. The method provided by the invention has the advantages that the de value of the intermediate of the Buvalsartan is high, and the yield is high.

The invention overcomes the technical problems through the following technical scheme.

The invention provides a method for purifying a compound shown as a formula C or a formula C', which comprises the following steps: crystallizing a mixture of a compound shown as a formula C and a compound shown as a formula C 'in a solvent to obtain the compound shown as the formula C or the compound shown as the formula C';

wherein R is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The operations and conditions of the crystallization can be those conventional in the art for such purification processes, and the following are particularly preferred in the present invention:

in the present invention, the solvent is preferably an ester solvent, a ketone solvent and C_1-4One or more of alcoholic solvents. The ester solvent is preferably ethyl acetate. The ketone solvent is acetone. Said C_1-4The alcoholic solvent is preferably ethanol and/or isobutanol.

In the present invention, the crystallization is preferably performed by naturally cooling the hot saturated solution.

In the present invention, the volume-to-mass ratio of the solvent to the mixture of the compound represented by the formula C and the compound represented by the formula C' is preferably 1.4 to 3.0ml/g, for example, 1.5ml/g, 1.8ml/g or 2.0 ml/g.

In the invention, the crystallization preferably comprises suction filtration and drying.

In the invention, the ratio of the compound shown in the formula C to the compound shown in the formula C 'in the mixture of the compound shown in the formula C and the compound shown in the formula C' is preferably 1:10-10:1, for example 7: 1.

In the present invention, the mixture of the compound represented by the formula C and the compound represented by C' is preferably prepared by the following method: carrying out a salt forming reaction shown in the specification on a compound B and a compound I in a solvent to obtain a mixture of a compound shown in a formula C and a compound shown in a formula C';

the salt-forming reaction may be a reaction conventional in such reactions in the art, and the following conditions and operations are particularly preferred in the present invention:

in the salt-forming reaction, the compound B isAnd (4) mixing. The de% of the compound B is preferably more than or equal to 70%.

In the salt-forming reaction, the compound I is preferably quinine, quinidine or cinchonidine, such as cinchonidine.

In the salt formation reaction, the molar ratio of the compound I to the compound B is preferably 0.5:1 to 2:1, for example, 1.0: 1.

In the salt forming reaction, the solvent is preferably one or more of an ether solvent, a nitrile solvent, an ester solvent, an alcohol solvent, a ketone solvent and water, and is preferably one or more of an ester solvent, an alcohol solvent and a ketone solvent.

Wherein, the ether solvent is preferably one or more of methyl tert-butyl ether, isopropyl ether, tetrahydrofuran and 2-methyltetrahydrofuran.

Among them, the nitrile solvent is preferably acetonitrile.

Among them, the ester solvent is preferably ethyl acetate and/or isopropyl acetate, and more preferably ethyl acetate.

Wherein, the alcohol solvent is preferably methanol, ethanol, n-propanol or isobutanol.

Among them, the ketone solvent is preferably acetone.

In the salt formation reaction, the volume-to-mass ratio of the solvent to the compound B is preferably 1:1 to 30:1, more preferably 2:1 to 15:1, for example 2.8:1 or 3: 1.

The temperature of the salt-forming reaction may be a temperature conventional in the art. The salt formation reaction is preferably carried out under reflux of the solvent used. The reaction temperature is, for example, 1 to 110 ℃ such as 55 ℃, 70 ℃, 78 ℃ or 108 ℃, and, for example, 25 to 80 ℃.

The progress of the salt-forming reaction can be monitored by methods conventional in the art (e.g., TLC), and the end point of the reaction is generally determined as the point at which compound B is no longer reacted or disappears. The time for the salt-forming reaction is, for example, 20 to 30 hours.

The compound B is preferably prepared by the following method: in the presence of hydrogen and a metal catalyst, carrying out reduction reaction on the compound A in an organic solvent as shown in the specification to obtain a compound B;

the reduction is preferably carried out under pressure, preferably at a pressure of 1-2 bar.

In the reduction reaction, the metal catalyst may be a metal catalyst conventional in such reactions in the art, preferably palladium on carbon, platinum on carbon, ruthenium on carbon, rhodium on carbon, or raney nickel, and more preferably palladium on carbon (e.g., 10% palladium on carbon).

In the reduction reaction, the mass ratio of the metal catalyst to the compound is preferably 1:15 to 1:5, for example, 1: 10.

In the reduction reaction, the organic solvent may be an organic solvent conventional in the art, preferably one or more of an alcohol solvent (e.g., methanol, ethanol, isopropanol or propanol), a ketone solvent (e.g., acetone), a chlorinated hydrocarbon solvent (e.g., dichloromethane), an ether solvent (e.g., methyl t-butyl ether, isopropyl ether, tetrahydrofuran or 2-methyl tetrahydrofuran), a nitrile solvent (e.g., acetonitrile), an ester solvent (e.g., ethyl acetate or isopropyl acetate), and water, more preferably an alcohol solvent.

The temperature of the reduction reaction may be a matter of routine in the art for such reactions, and is preferably from-50 ℃ to 50 ℃, more preferably from-10 ℃ to 20 ℃.

The progress of the reduction can be monitored by methods conventional in the art (e.g., TLC), and the end point of the reaction is generally determined as the point at which Compound A no longer reacts or disappears. The time of the reduction reaction is, for example, 17 to 72 hours.

The invention also provides a preparation method of the mixture of the compound shown in the formula C and the compound shown in the formula C', which comprises the following steps: carrying out a salt forming reaction shown in the specification on a compound B and a compound I in a solvent to obtain a mixture of the compound shown in the formula C and the compound shown in the formula C';

the conditions and operation of the salt-forming reaction are the same as those described above.

The invention also provides a preparation method of the intermediate of the brivaracetam, which comprises the following steps: in a solvent, carrying out a free reaction of the compound C and acid as shown in the following formula to obtain a compound D (namely a brivaracetam intermediate);

r is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In said compound CExists in dominant configuration (optical purity is up to more than 96%).

The free reaction may be a reaction conventional in such reactions in the art, and the following conditions and operations are particularly preferred in the present invention:

in the dissociation reaction, the solvent may be a water-ether solvent (e.g., water-methyl t-butyl ether). The volume ratio of water to the ether solvent in the water-ether solvent may be 1:8 to 1:1, for example (1: 4).

In the free reaction, the acid may be more acidic than compound D, and may form a salt with compound I, for example hydrochloric acid (concentrated hydrochloric acid).

In the dissociation reaction, the molar concentration of hydrogen ions in the acid may be 0.01 to 0.1M.

The compound C is preferably One or more of (a).

The compound C is preferably prepared according to the preparation method of the compound shown in the formula C.

The post-treatment step after the completion of the reaction may be extraction (for example, the extraction solvent is methyl t-butyl ether) and concentration (for example, concentration under reduced pressure).

The invention also provides the compound shown in the formula C, the compound shown in the formula C ', or a mixture of the compound shown in the formula C and the compound shown in the formula C';

wherein R is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The ratio of the compound shown in the formula C to the compound shown in the formula C 'in the mixture of the compound shown in the formula C and the compound shown in the formula C' is preferably 1:10-10:1, for example 7: 1.

The compound shown in the formula C and the mixture of the compounds shown in the formula C' are preferably used for preparing the intermediate of the brivaracetam.

The compound shown in the formula C, the compound shown in the formula C 'or the mixture of the compound shown in the formula C and the compound shown in the formula C' is preferably the following compound:

the compound shown as the formula C is

The compound shown as the formula C' is

The mixture of the compound shown in the formula C and the compound shown in the formula C' is preferably the compound shown in the formula CA mixture of (e.g. a ratio of C-1 to C' -1 of 7:1),(e.g., a ratio of C-2 to C' -2 of 7:1) or,(e.g., a ratio of C-3 to C' -3 of 7: 1).

The invention also provides a preparation method of the mixture of the compound shown in the formula C and the compound shown in the formula C', which comprises the following steps:

carrying out a salt forming reaction shown in the specification on a compound B and a compound I in a solvent to obtain a mixture of a compound shown in a formula C and a compound shown in a formula';

the operation and conditions of the salt-forming reaction are the same as those described above.

The invention also provides an application of the compound C in preparation of the brivaracetam.

In the application, the preparation method of the brivaracetam comprises the following steps:

step 1: in a solvent, carrying out a free reaction of the compound C and an acid as shown in the following formula to obtain a compound D;

step 2: carrying out condensation reaction on the compound D obtained in the step 1 to obtain the brivaracetam;

in step 1, the conditions and operation of the dissociation reaction are the same as described above.

In step 2, the conditions and operations of the condensation reaction may be those conventional in the art for such reactions, for example, the condensation of ammonium chloride and compound D in a solvent (tetrahydrofuran) with a condensing agent (HATU) and a base (DIEA) to give bwaitam.

The invention also provides a preparation method of the brivaracetam, which comprises the following steps:

step 1: in a solvent, carrying out a free reaction of the compound C and an acid as shown in the following formula to obtain a compound D;

step 2: carrying out condensation reaction on the compound D obtained in the step 1 to obtain the brivaracetam;

wherein the conditions and operations in steps 1 and 2 are the same as described above

In step 1, the compound C is preferably prepared according to the above-mentioned preparation method of the compound represented by the formula C.

The invention also provides a preparation method of the compound shown as the formula C '(namely the compound C'), which comprises the following steps: carrying out salt-forming reaction on the compound B and the compound I 'in a solvent as shown in the specification to obtain a compound C';

r' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The conditions and operations in the process for the preparation of compound C "are the same as those in the process for the preparation of compound C.

The invention also provides a preparation method of the compound shown as the formula D '(namely the compound D'), which comprises the following steps: in a solvent, carrying out a free reaction of the compound C 'and acid as shown in the following formula to obtain a compound D';

r' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In R', the C_1-4The alkoxy group is preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group, and more preferably a methoxy group.

The conditions and operation of the dissociation reaction are the same as those in the dissociation reaction described above.

The preparation method of the compound shown in the formula D ' can further comprise the preparation method of the compound shown in the formula C ', and the preparation method of the compound shown in the formula C ' is the same as that described above.

The invention also provides a compound shown as the formula C':

wherein R' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

The compound shown in the formula C' is preferably the following compound:

the above-mentioned preparation methods of the compounds can be combined at will to obtain a compound represented by formula C, C' or C ", a compound represented by formula D or D" (i.e., a intermediate of brivaracetam), or a synthetic route of brivaracetam (e.g., A → B → C → D → brivaracetam, A → B → C → D, B → C → D, A → B → C, etc.).

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the intermediate of the invention has the advantages that the de value of the intermediate of the invention is high, the yield is high, the reacted materials can be recycled for a plurality of times and repeatedly split, and the optimization of material utilization is achieved.

Detailed Description

In the document J.org.chem.1996,61,215-222, a carboxylic acid substrate containing a six-membered cyclic lactam structure is chemically resolved using cinchonidine. The yield of the carboxylic acid substrate for resolving the six-membered cyclic lactam structure by the inventor through cinchonidine is 45%, and the ee value is 98%. Compared with the resolution effect in the document, the resolution method of the invention using the quinine resolving agent has higher yield (> 65%) and higher chiral purity (> 98%).

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

de% normal phase HPLC detection method:

a chromatographic column: IC-3; flow rate: 1 mL/min; wavelength: 210 nm; mobile phase: n-hexane: isopropanol 85: 15; isocratic elution for 30 min; column temperature: at 30 ℃.

Purity (reverse phase HPLC) detection method:

a chromatographic column: c18; flow rate: 0.8 mL/min; wavelength: 210 nm; column temperature: 30 ℃; mobile phase: a-1% phosphoric acid in water, B-acetonitrile; gradient: 0 min-A90% and B10%; 20 min-A10%, B90%; 30 min-A10%, B90%; 30.1 min-A90%, B10%; 45 min-A90% and B10%.

EXAMPLE 1 preparation of Compound B

Adding the compound A (40g) and methanol (200mL) into a 500mL three-neck flask, stirring for dissolving, adding 4g of 10% palladium carbon, stirring, replacing with hydrogen, controlling the hydrogen pressure to be 1-2bar, stirring at room temperature for reaction for 72 hours, controlling the raw materials in LCMS until the raw materials disappear completely and a single compound B peak appears, stopping the reaction, filtering, and performing rotary evaporation at 45 ℃ to obtain 37.58g of light yellow solid, wherein the yield is 93.3%, the HPLC (high performance liquid chromatography) is 99.1%, and the de% is 75%.

EXAMPLE 2 preparation of Compound B

Adding the compound A (1g) into a 25mL three-neck flask, stirring and dissolving ethyl acetate (5mL), adding 0.1g of 10% palladium carbon, stirring, replacing with hydrogen, stirring at room temperature for reaction for 17 hours, controlling the raw materials to disappear completely and generating a single compound D peak in LCMS, stopping the reaction, filtering, and performing rotary evaporation at 45 ℃ to obtain 95.9mg of a light yellow solid, wherein the yield is 95%, the HPLC 99% and the de% are 70%.

EXAMPLE 3 preparation of Compound C-1 (quinidine salt)

Adding the compound B (15.68g), 45mL of ethyl acetate and quinidine (1 equivalent) into a 10mL three-neck flask, heating to about 70 ℃, dissolving, naturally cooling to-18 ℃, stirring for 31 hours, and then carrying out suction filtration to obtain 31.66g of wet product, directly adding the 45mL of ethyl acetate into the wet product, heating to 70 ℃ for dissolution, naturally cooling to 10 +/-5 ℃, carrying out suction filtration to obtain 25.33g of compound C wet product, and drying to obtain 25g of white solid. Yield: 63.16%, purity: 98% and de% is 99%.

EXAMPLE 4 preparation of Compound C-2 (quinic salt)

Adding the compound B (5g), 15mL of ethyl acetate and quinine (1 equivalent weight) into a 10mL three-neck flask, heating to about 70 ℃, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, and performing suction filtration to obtain 10g of wet product, directly adding 15mL of ethyl acetate into the wet product, heating to 70 ℃ for dissolution, naturally cooling to 10 +/-5 ℃, performing suction filtration to obtain 7g of compound C wet product, and drying to obtain 6.7g of white solid. Yield: 67%, purity: 95% and de% is 96%.

EXAMPLE 5 preparation of Compound C-1 (quinidine salt)

Adding a compound B (5g), 15mL of acetone and 1 equivalent of quinidine into a 10mL three-neck flask, heating to reflux, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, carrying out suction filtration to obtain 7.5g of wet product, directly adding 15mL of acetone into the wet product, heating to 70 ℃ for dissolution, naturally cooling to 10 +/-5 ℃, carrying out suction filtration to obtain 7g of compound C wet product, and drying to obtain 6.7g of white solid. Yield: 67%, purity: 95% and de% is 96%.

EXAMPLE 6 preparation of Compound C-3 (Octocranidine salt)

Adding compound B (5g), isobutanol 15mL and cinchonidine (1 equivalent) into a 10mL three-neck flask, heating to reflux, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, carrying out suction filtration to obtain 8g of wet product, directly adding 15mL of isobutanol into the wet product, heating to 110 ℃ for dissolution, naturally cooling to 10 +/-5 ℃, carrying out suction filtration to obtain 7.3g of compound C wet product, and drying to obtain 7g of white solid. Yield: 70%, purity: 96% and de% is 98%.

EXAMPLE 7 preparation of Compound C-1 (quinidine salt)

Adding the compound B (5g), 15mL of ethanol and quinidine (1 equivalent) into a 10mL three-neck flask, heating to reflux, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, carrying out suction filtration to obtain 11g of wet product, directly adding 15mL of ethanol into the wet product, heating to 80 ℃ for dissolution, naturally cooling to 10 +/-5 ℃, carrying out suction filtration to obtain 6.5g of compound C wet product, and drying to obtain 6.0g of white solid. Yield: 60%, purity: 96% and de% is 98%.

EXAMPLE 8 preparation of Compound D

A50 mL three-necked flask was charged with C-314 g of the above-mentioned compound (cinchonidine salt), 5mL of water and 20mL of methyl t-butyl ether were added, the pH was adjusted to 1-2 with concentrated hydrochloric acid, the organic phase was separated after standing and layering, the aqueous phase was extracted with 20mL of methyl t-butyl ether, the organic phases were combined and concentrated under reduced pressure to give compound D as a white solid (5.12 g), yield 65.1%, purity 99%, de% 98.01%, retention time 8.725min (consistent with the time of peak appearance of standard compound D).