CN112812112B

CN112812112B - Preparation method of isoquinoline alkaloid L-corydaline

Info

Publication number: CN112812112B
Application number: CN201911129155.4A
Authority: CN
Inventors: 杨征; 魏旭东; 谢同; 刘瑞; 秦日旭
Original assignee: Individual
Current assignee: Taizhou Lize Pharmaceutical Technology Co.,Ltd.
Priority date: 2019-11-18
Filing date: 2019-11-18
Publication date: 2024-06-28
Anticipated expiration: 2039-11-18
Also published as: CN112812112A

Abstract

本发明属于医药化学领域，提供左旋紫堇达明或其药学可接受的盐的制备方法，所述方法包括在有机溶剂存在下，经氢氧化钯碳催化，使(S)‑10‑(苄氧基)‑2,3,9‑三甲氧基‑5,8,13,13a‑四氢‑6H‑异喹啉并[3,2‑a]异喹啉进行脱苄基反应等步骤。本发明的制备方法成本低，操作简单，纯度和收率较高，适于工业规模大生产。The invention belongs to the field of pharmaceutical chemistry and provides a method for preparing levorotatory corydaline or a pharmaceutically acceptable salt thereof, the method comprising the steps of debenzylation of (S)-10-(benzyloxy)-2,3,9-trimethoxy-5,8,13,13a-tetrahydro-6H-isoquinolino[3,2-a]isoquinoline under the catalysis of palladium hydroxide on carbon in the presence of an organic solvent. The preparation method of the invention has low cost, simple operation, high purity and yield, and is suitable for large-scale industrial production.

Description

Preparation method of isoquinoline alkaloid L-corydaline

Technical Field

The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of isoquinoline alkaloid L-corydaline or pharmaceutically acceptable salt thereof.

Background

L-corydamine (l-corydalmine, l-CDL) is a known compound having analgesic, drug-dropping, and anti-drug addiction effects, and having the chemical name (S) -2,3,9-trimethoxy-5,8,13 a-tetrahydro-6H-isoquinolin-10-ol ((S) -2,3,9-trimethoxy-5,8,13 a-tetrahydroo-6H-isoquinolino [3,2-a ] isoquinolin-10-ol), and having the following structure:

Corydaline is one of the effective alkaloid components in the traditional Chinese medicine rhizoma corydalis, but the natural content of corydaline is extremely tiny, so that the application of corydaline in the field of pharmacy is limited. The prior art mainly uses bioconversion methods to prepare corydaline. For example, patent application CN201110125328.2 discloses a bioconversion fermentation process for producing corydaline using streptomyces. Patent application CN201310165657.9 discloses a method for separating corydaline alkaloids by alkalinized silica gel. The bioconversion method for producing corydaline has low yield and high cost.

Haifeng Sun et al describe chemical synthesis of tetrahydroprotoberberine compounds (Tetrahychroprotoberberines, THPBs) and intermediates thereof, for example, using microwave assisted conditions to obtain important intermediate compounds (Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1,D2 and serotonin 5-HT1A multi-action profile,Haifeng Sun et al, bioorganic & MEDICINAL CHEMISTRY,21 (2013), 856-868. However, the product obtained by the method is of a small scale, when the scale is enlarged to be higher than a pilot scale, the impurity is obviously increased, and the yield is greatly reduced.

Therefore, a new preparation method of the L-corydaline needs to be developed, so that the high yield and purity of finished products are obtained on the premise of ensuring that raw materials and reagents are easy to obtain, the price is low and the method is simple, and the industrialized mass production is realized.

Disclosure of Invention

It is an object of the present invention to provide a process for the preparation of L-corydaline or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a process for the preparation of an intermediate compound of L-corydaline or a pharmaceutically acceptable salt thereof.

The preparation method of the L-corydaline or the pharmaceutically acceptable salt thereof comprises the following steps:

Subjecting (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline of the formula TLZ-16-13 to debenzylation in the presence of an organic solvent under the catalysis of palladium-carbon hydroxide, as shown in the following formula:

Wherein, when debenzylation is carried out in the presence of an alcohol solvent and hydrochloric acid or in the presence of a Lewis acid, the three methyl groups on TLZ-16-13 are partially removed, a large amount of alkali neutralization reaction is needed for post-treatment, a large amount of products are lost in purification, and the yield is lower than 70%. The inventor of the present invention has found that the product with the yield of more than 85% and the purity of more than 99.5% can be obtained by carrying out the debenzylation reaction under the catalysis of palladium carbon hydroxide in the presence of an organic solvent, and the impurity generation is less, and the crystallization can be directly carried out in the reaction solvent after the catalyst is filtered out by post-treatment.

In some preferred embodiments, the debenzylation of (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolo [3,2-a ] isoquinoline of formula TLZ-16-13 is carried out in the presence of an organic solvent, such as ethyl acetate, toluene, tetrahydrofuran, DMF, 1, 4-dioxane, an alcoholic solvent, 2-methyltetrahydrofuran, or a mixed solvent thereof, catalyzed by 5% to 30% (w/w, palladium hydroxide carbon to compound of formula TLZ-16-13), preferably 5% to 20% (w/w), more preferably 10% to 20% (w/w), still more preferably 10% to 15% (w/w) palladium hydroxide carbon.

In some specific embodiments, the method of preparation according to the present invention, wherein the organic solvent is a mixed solvent of ethyl acetate and an alcoholic solvent.

Preferably, in the preparation method of the present invention, the alcohol solvent is a C1 to C4 alcohol solvent. In some embodiments, the alcoholic solvent is methanol or ethanol. Preferably, in the process for the preparation of levamisole or a pharmaceutically acceptable salt thereof according to the present invention, (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolo [3,2-a ] isoquinoline of formula TLZ-16-13 is debenzylated with 5% to 30% (w/w, weight ratio of palladium hydroxide on carbon to the compound of formula TLZ-16-13), preferably 5% to 20% (w/w), more preferably 10% to 20% (w/w), still more preferably 10% to 15% (w/w), palladium hydroxide on carbon, using hydrogen, formic acid, ammonium formate or a mixture thereof as hydrogen source, in the presence of ethyl acetate and methanol under nitrogen. In a specific embodiment, the palladium on carbon hydroxide is aqueous palladium on carbon hydroxide (Pd (OH) ₂/C).

The invention provides an intermediate compound acetic acid 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydro-isoquinolin-1-yl) methyl) -2-methoxybenzyl ester trifluoro-methanesulfonate used for synthesizing L-corydaline or pharmaceutically acceptable salt thereof, which has a structural formula shown in the following formula TLZ-16-9:

in some embodiments, the present invention provides a process for preparing L-corydaline or a pharmaceutically acceptable salt thereof, comprising the step of using an intermediate compound of formula TLZ-16-9.

The present invention provides a process for the preparation of an intermediate compound of formula TLZ-16-9, comprising the steps of:

in the presence of trifluoromethanesulfonic anhydride and a base reagent, carrying out cyclization reaction on 3- (benzyloxy) -6- (2- ((3, 4-dimethoxy phenethyl) amino) -2-oxo-ethyl) -2-methoxybenzyl acetate of a formula TLZ-16-8,

The inventors of the present invention found that the use of phosphorus oxychloride as the cyclization agent resulted in about 20% of side reaction products and was not easy to handle in a large scale, while the post-treatment quenched a large amount of phosphorus oxychloride. Through researches, the inventor changes the cyclization reagent into trifluoro methanesulfonic anhydride, and simultaneously adds the alkali reagent, so that the reaction temperature can be reduced, the reaction time is shortened, the byproducts are obviously reduced, the post-treatment is simple, and the crystallization is easy, thereby obtaining the product with high yield.

In some embodiments, in the process for preparing the intermediate compounds of formulas TLZ-16-9 of the present invention, the base reagent may be an inorganic base or an organic base. Preferably, the base reagent is selected from the group consisting of pyridine substituents, triethylamine, pyridine, DMAP (4-dimethylaminopyridine), DIPEA (N, N-diisopropylethylamine) and DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene). In a preferred embodiment, the pyridine substituent is 2-chloropyridine. Preferably, in the process for preparing an intermediate compound represented by formula TLZ-16-9 of the present invention, 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate of formula TLZ-16-8 is subjected to a cyclization reaction in the presence of trifluoromethanesulfonic anhydride and 2-chloropyridine at a temperature of about-15℃to about 20℃under the protection of nitrogen. Preferably, the reaction temperature is a temperature in the range of-10 ℃ to 10 ℃. More preferably, the reaction temperature is a temperature between-5 ℃ and 5 ℃. In some embodiments, according to the process for the preparation of intermediate compounds of formula TLZ-16-9 of the present invention, the molar ratio of 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate to trifluoromethanesulfonic anhydride of formula TLZ-16-8 is about 1:1-2, preferably about 1:1-1.5, more preferably about 1:1-1.2.

In some embodiments, the present invention provides a process for preparing the levamisole of the invention, or a pharmaceutically acceptable salt thereof, comprising the step of using an intermediate compound of formula TLZ-16-9, wherein the compound of formula TLZ-16-9 is synthesized by:

The invention provides a preparation method of 7- (benzyloxy) -8-hydroxy isochroman-3-ketone shown in a formula TLZ-16-5, which comprises the following steps:

1) Reacting 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid represented by formula TLZ-16-4 with phenylboronic acid in toluene; and

2) Directly adding paraformaldehyde into the reactant obtained in the step 1,

The inventors of the present invention found that a high purity product having a yield of more than 70% can be obtained by refluxing 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid represented by formula TLZ-16-4 with phenylboronic acid in toluene, then directly adding paraformaldehyde for reaction, and hydrolyzing the intermediate after the compound represented by formula TLZ-16-4 is completely converted.

In some embodiments, a process for preparing 7- (benzyloxy) -8-hydroxyisochroman-3-one of formula TLZ according to the invention, wherein after the conversion of the compound of formula TLZ-16-4 is complete, the intermediate is hydrolyzed and recrystallized in toluene to obtain the compound of formula TLZ-16-5 in high purity.

In some embodiments, the present invention provides a process for preparing L-corydaline or a pharmaceutically acceptable salt thereof according to the present invention, comprising the step of using 7- (benzyloxy) -8-hydroxyisochroman-3-one of formula TLZ-16-5, wherein the compound of formula TLZ-16-5 is obtained by the process for preparing a compound of formula TLZ-16-5 described above.

The invention provides a preparation method of 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid shown in a formula TLZ-16-4, which comprises the following steps:

reacting 2- (4- (benzyloxy) -3-bromophenyl) acetic acid represented by formula TLZ-16-3 with 1% -15% (w/w) alkali metal hydroxide in the presence of 1% -15% (mol/mol) copper catalyst,

The inventors of the present invention found that 2- (4- (benzyloxy) -3-bromophenyl) acetic acid represented by formula TLZ-16-3 was reacted with an alkali metal hydroxide in the presence of a copper catalyst in an aqueous solution in an amount of 1% -15% (w/w) of the alkali metal hydroxide, and the copper catalyst was used in an amount of 1% -15% (mol/mol), and a product having a yield of more than 80% could be obtained. Preferably, in some embodiments, the alkali metal hydroxide is sodium hydroxide or potassium hydroxide and the copper catalyst is selected from at least one or more of copper powder, copper sulfate, copper oxide, cuprous oxide, copper halide (e.g., cupric chloride, cuprous chloride), 8-hydroxyquinolinone. More preferably, in some embodiments, the alkali metal hydroxide is sodium hydroxide and the copper catalyst is 8-hydroxyquinolinone. In some specific embodiments, according to the process for preparing 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid represented by formula TLZ-16-4 of the present invention, 2- (4- (benzyloxy) -3-bromophenyl) acetic acid represented by formula TLZ-16-3 is reacted with sodium hydroxide in the presence of 8-hydroxyquinolinone in an amount of 1% to 10% (mol/mol), sodium hydroxide in an amount of 1% to 10% (w/w, concentration of sodium hydroxide aqueous solution).

In some embodiments, the present invention provides a process for preparing L-corydaline or a pharmaceutically acceptable salt thereof according to the present invention, comprising the step of using 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid represented by formula TLZ-16-4, wherein the compound of formula TLZ-16-4 is obtained by the process for preparing the compound of formula TLZ-16-4 described above.

The process for the preparation of levcorydaline or a pharmaceutically acceptable salt thereof according to the above invention, wherein the process further comprises the step of using an intermediate compound of formula TLZ-16-9. In some preferred embodiments, wherein the intermediate compound of formula TLZ-16-9 is prepared by cyclization of 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate of formula TLZ-16-8 in the presence of a triflic anhydride and a base reagent.

In some preferred embodiments, the method of preparing levamisole or a pharmaceutically acceptable salt thereof according to the present invention comprises the steps of:

1) Cyclizing 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate of formula TLZ-16-8 in the presence of trifluoromethanesulfonic anhydride and a base reagent to obtain 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate of formula TLZ-16-9;

2) Preparing (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline of formula TLZ-16-13 using the compound of formula TLZ-16-9 obtained in step 1; and

3) In the presence of ethyl acetate and alcohol solvent, the compound shown in the formula TLZ-16-13 is subjected to debenzylation reaction under the catalysis of palladium-carbon hydroxide to prepare the L-corydaline or pharmaceutically acceptable salt thereof.

1) Reacting 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid of formula TLZ-16-4 with phenylboronic acid in toluene, then directly adding paraformaldehyde to obtain 7- (benzyloxy) -8-hydroxyisochroman-3-one of formula TLZ-16-5;

2) Preparing 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate of formula TLZ-16-8 using a compound of formula TLZ-16-5;

3) Cyclizing a compound of formula TLZ-16-8 in the presence of trifluoromethanesulfonic anhydride and a base reagent to produce 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate of formula TLZ-16-9;

4) Preparing (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline of formula TLZ-16-13 using the compound of formula TLZ-16-9 obtained in step 1; and

5) The compounds of formulas TLZ-16-13 are debenzylated in the presence of an organic solvent to produce levant corydalimine or a pharmaceutically acceptable salt thereof, by catalytic reaction with 5% -30% (w/w, weight ratio of palladium carbon hydroxide to the compound of formula TLZ-16-13), preferably 5% -20% (w/w), more preferably 10% -20% (w/w), still more preferably 10% -15% (w/w) palladium carbon hydroxide.

3) Cyclizing a compound of formula TLZ-16-8 in the presence of trifluoromethanesulfonic anhydride and 2-chloropyridine to produce 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate of formula TLZ-16-9;

5) The compounds of formula TLZ-16-13 are debenzylated in the presence of ethyl acetate and an alcoholic solvent, with the palladium carbon hydroxide being catalyzed by 5% -30% (w/w, weight ratio of palladium carbon hydroxide to the compound of formula TLZ-16-13), preferably 5% -20% (w/w), more preferably 10% -20% (w/w), still more preferably 10% -15% (w/w), to produce levant corydaline or a pharmaceutically acceptable salt thereof.

1) Reacting 2- (4- (benzyloxy) -3-bromophenyl) acetic acid of formula TLZ-16-3 with 1% -15% (w/w) alkali metal hydroxide in the presence of 1% -15% (mol/mol) copper catalyst to produce 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid of formula TLZ-16-4 and phenylboronic acid;

2) Reacting a compound of formula TLZ-16-4 with phenylboronic acid in toluene, and then directly adding paraformaldehyde to prepare 7- (benzyloxy) -8-hydroxyisochroman-3-one of formula TLZ-16-5;

3) Preparing 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate of formula TLZ-16-8 using a compound of formula TLZ-16-5;

4) Cyclizing a compound of formula TLZ-16-8 in the presence of trifluoromethanesulfonic anhydride and a base reagent to produce 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate of formula TLZ-16-9;

5) Preparing (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline of formula TLZ-16-13 using the compound of formula TLZ-16-9 obtained in step 1;

6) The compounds of formula TLZ-16-13 are debenzylated in the presence of ethyl acetate and an alcoholic solvent, with the palladium carbon hydroxide being catalyzed by 5% -30% (w/w, weight ratio of palladium carbon hydroxide to the compound of formula TLZ-16-13), preferably 5% -20% (w/w), more preferably 10% -20% (w/w), still more preferably 10% -15% (w/w), to produce levant corydaline or a pharmaceutically acceptable salt thereof.

4) Cyclizing a compound of formula TLZ-16-8 in the presence of trifluoromethanesulfonic anhydride and 2-chloropyridine to produce 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate of formula TLZ-16-9;

In some embodiments, the levo-corydaline prepared according to the preparation method of the present invention is reacted with an organic acid or an inorganic acid corresponding to the pharmaceutically acceptable salt to prepare the pharmaceutically acceptable salt of levo-corydaline.

In some preferred embodiments, the invention provides pharmaceutically acceptable salts of levamisole, wherein the salts are pharmaceutically acceptable salts of the compounds with acids including, but not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, nitric acid, citric acid, maleic acid, hydroxymaleic acid, propionic acid, glycolic acid, stearic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, lactic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, glutamic acid, malic acid, tartaric acid, ascorbic acid, pamoic acid, benzoic acid, phenylacetic acid, glutamic acid, salicylic acid, oxalic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, and the like.

Preferably, the preparation method according to the present invention further comprises a step of recrystallizing the levamisole, the intermediate compound thereof, or the pharmaceutically acceptable salt thereof. Further preferably, according to the production method of the present invention, the recrystallization is performed in one or more solvents selected from the group consisting of water, tetrahydrofuran, methanol, acetone, isopropyl alcohol, acetonitrile, toluene, methylene chloride, n-heptane, butanone, ethanol, butanol, ethyl acetate, methyl t-butyl ether.

In a preferred embodiment, the method of preparation according to the present invention, the L-corydaline or a pharmaceutically acceptable salt thereof is L-corydaline hydrochloride. In another preferred embodiment, according to the preparation method of the present invention, the levocorydaline or a pharmaceutically acceptable salt thereof is a sulfate salt of levocorydaline.

In some specific embodiments, the present invention provides a process for preparing the levamisole of the invention or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

a) Reacting a compound of formula TLZ-16-3 with 1% -15% (w/w, concentration of alkali metal aqueous solution) alkali metal hydroxide in the presence of 1% -15% (mol/mol) copper catalyst to obtain a compound of formula TLZ-16-4;

b) Directly adding paraformaldehyde to prepare a compound of formula TLZ-16-5 after reacting the compound of formula TLZ-16-4 with phenylboronic acid in toluene;

c) Alkylation reaction is carried out on the compound shown in the formula TLZ-16-5 to obtain a compound shown in the formula TLZ-16-6, and then amine transesterification reaction is directly carried out on the compound shown in the formula TLZ-16-SM2 to obtain a compound shown in the formula TLZ-16-7;

d) Esterifying the compound of formula TLZ-16-7 to obtain a compound of formula TLZ-16-8;

e) The compound shown in the formula TLZ-16-8 is prepared into a compound shown in the formula TLZ-16-9 through cyclization reaction in the presence of trifluoromethanesulfonic anhydride and a base reagent;

f) Reacting a compound of formula TLZ-16-9 in the presence of a catalyst to produce a compound of formula TLZ-16-10;

g) The compound shown in the formula TLZ-16-10 is subjected to hydrolysis reaction to prepare a compound shown in the formula TLZ-16-11;

h) The compound shown in the formula TLZ-16-11 is subjected to hydroxyl activation and then substitution reaction to prepare a compound shown in the formula TLZ-16-13;

i) The compound of formula TLZ-16-13 is catalyzed by 5% -30% (w/w, weight ratio of palladium hydroxide carbon to the compound of formula TLZ-16-13), preferably 5% -20% (w/w), more preferably 10% -20% (w/w), still more preferably 10% -15% (w/w) palladium hydroxide carbon in the presence of ethyl acetate and an alcoholic solvent to produce L-corydaline of formula TLZ-16-0,

Or further reacting the L-corydaline of formula TLZ-16-0 with an acid to obtain a pharmaceutically acceptable salt of L-corydaline.

In other specific embodiments, the present invention provides a process for preparing the levamisole of the invention or a pharmaceutically acceptable salt thereof, comprising the steps of:

a) Bromination of a compound of formula TLZ-16-SM1 in the presence of DCM and liquid bromine to obtain a compound TLZ-16-1, and then benzyl protecting the hydroxyl group to obtain TLZ-16-2;

b) Reacting a compound of formula TLZ-16-2 with 1% -15% (w/w, concentration of alkali metal hydroxide) alkali metal hydroxide in the presence of 1% -15% (mol/mol) copper catalyst to obtain a compound of formula TLZ-16-4;

c) Directly adding paraformaldehyde to prepare a compound of formula TLZ-16-5 after reacting the compound of formula TLZ-16-4 with phenylboronic acid in toluene;

d) Alkylation reaction is carried out on a compound shown in a formula TLZ-16-5 to obtain a compound TLZ-16-6, and then amine transesterification reaction is directly carried out on the compound shown in a formula TLZ-16-SM2 to obtain a compound shown in a formula TLZ-16-7;

e) Esterifying the compound of formula TLZ-16-7 to obtain a compound of formula TLZ-16-8;

f) The compound shown in the formula TLZ-16-8 is prepared into a compound shown in the formula TLZ-16-9 through cyclization reaction in the presence of trifluoromethanesulfonic anhydride and a base reagent;

g) Reacting a compound of formula TLZ-16-9 in the presence of a catalyst to produce a compound of formula TLZ-16-10;

h) The compound shown in the formula TLZ-16-10 is subjected to hydrolysis reaction to prepare a compound shown in the formula TLZ-16-11;

i) The compound shown in the formula TLZ-16-11 is activated by hydroxyl to obtain a compound shown in the formula TLZ-16-12, and then substitution reaction is carried out to obtain a compound shown in the formula TLZ-16-13;

j) The compound of formula TLZ-16-13 is catalyzed by 5% -30% (w/w, weight ratio of palladium hydroxide carbon to the compound of formula TLZ-16-13), preferably 5% -20% (w/w), more preferably 10% -20% (w/w), still more preferably 10% -15% (w/w) palladium hydroxide carbon in the presence of ethyl acetate and an alcoholic solvent to produce L-corydaline of formula TLZ-16-0,

a) Brominating a compound shown in a formula TLZ-16-SM1 in the presence of acetic acid and liquid bromine to obtain a compound TLZ-16-1, and then protecting hydroxyl by benzyl under the conditions of K ₂CO₃ and BnBr to obtain TLZ-16-2;

b) The compound shown in the formula TLZ-16-2 is reacted in the presence of sodium hydroxide and methanol to prepare a TLZ-16-3 compound, and then the TLZ-16-3 compound is reacted with 1% -15% (w/w, concentration of sodium hydroxide aqueous solution) sodium hydroxide in the presence of 1% -15% (mol/mol) copper catalyst to obtain a compound shown in the formula TLZ-16-4;

d) Alkylation of a compound of formula TLZ-16-5 in the presence of DMS, K ₂CO₃ and ACN to give a compound of formula TLZ-16-6, followed by direct transesterification with a compound of formula TLZ-16-SM2 to give a compound of formula TLZ-16-7;

e) Esterifying a compound of formula TLZ-16-7 in the presence of AcCl and DMAP to obtain a compound of formula TLZ-16-8;

f) The compound shown in the formula TLZ-16-8 is prepared into a compound shown in the formula TLZ-16-9 through cyclization reaction in the presence of trifluoromethanesulfonic anhydride and alkali reagent 2-chloropyridine;

g) Reacting a compound of formula TLZ-16-9 in the presence of a catalyst RuCl [ (R, R-Tsdpen) ] (p-cymene) to produce a compound of formula TLZ-16-10;

h) The compound shown in the formula TLZ-16-10 is subjected to hydrolysis reaction in the presence of sodium hydroxide and ethanol to obtain a compound shown in the formula TLZ-16-11;

i) The compound of formula TLZ-16-11 is hydroxy activated in the presence of DCM and SOCl ₂ to obtain a compound of formula TLZ-16-12, which is then substitution reacted in the presence of Na ₂CO₃ and DCM to obtain a compound of formula TLZ-16-13;

In some embodiments, the levocorydaline or pharmaceutically acceptable salt thereof of the invention is in the form of a substantially pure isomer having an isomer purity of at least 90% ee. In another specific embodiment, the isomer purity of the levcorydaline or pharmaceutically acceptable salt thereof of the present invention is at least 98% ee. In a preferred embodiment, the isomer purity of the compounds of the invention of L-corydaline or a pharmaceutically acceptable salt thereof is at least 99% EE. The isomer excess provides a quantitative measure of the percentage of the major isomer over the percentage of the minor isomer co-present therewith, which can be readily measured by suitable methods established and well known in the art, such as chiral High Pressure Liquid Chromatography (HPLC), chiral Gas Chromatography (GC), nuclear Magnetic Resonance (NMR) using chiral shift reagents, and the like.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

As used herein, the levocorydaline or pharmaceutically acceptable salts thereof include crystalline forms, hydrates, solvates and prodrugs thereof.

The term "pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable salts of the compounds of the present invention with certain acids selected from the group consisting of inorganic acids such as phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, organic acids such as citric acid, maleic acid, hydroxymaleic acid, propionic acid, glycolic acid, stearic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, lactic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, glutamic acid, malic acid, tartaric acid, ascorbic acid, pamoic acid, benzoic acid, phenylacetic acid, glutamic acid, salicylic acid, oxalic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, and the like, which are safe and effective for use in mammals.

The terms "hydrogen", "carbon", "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers, for example isotopes of hydrogen include protium, tritium, and deuterium, isotopes of carbon include ¹²C、¹³ C and ¹⁴ C, isotopes of oxygen include ¹⁶ O and ¹⁸ O, and the like.

The L-corydaline or the pharmaceutically acceptable salt thereof prepared by the method has higher yield and purity, and can meet the production and application of industrial scale.

The embodiments of the present invention may be used alone or in combination.

Detailed Description

The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. Unless otherwise indicated, the starting materials and reagents of the invention are commercially available.

Example 1 preparation of (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinolin-10-ol (Compound TLZ-16-0)

Step 1 preparation of methyl 2- (3-bromo-4-hydroxyphenyl) acetate (Compound TLZ-16-1)

DCM (21L, 5V) and methyl 2- (4-hydroxyphenyl) acetate (4.2 kg,1.0 eq.) were added to the reaction vessel at-2℃followed by dropwise addition of liquid bromine (4.08 kg,1.01 eq.). The reaction solution was stirred for 4h at 0 ℃. The reaction solution was quenched with 5% na ₂S₂O₃ (3V). The resulting mixture was separated and the aqueous phase extracted with DCM (2V). The combined organic phases were washed with water (2V) and concentrated to give 6.2Kg of yellow oil with HPLC purity 96％.MS(ESI)245.0,247.0[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)10.15(s,1H),7.39(d,J＝2.1Hz,1H),7.07(dd,J＝2.1,8.4Hz,1H),6.91(d,J＝8.1Hz,1H),3.61(s,3H),3.57(s,2H).

Step2: preparation of methyl 2- (4- (benzyloxy) -3-bromophenyl) acetate (Compound TLZ-16-2)

Methyl 2- (3-bromo-4-hydroxyphenyl) acetate (6.2 kg,1.0 eq.) and K ₂CO₃ (3.85 kg,1.0 eq.) were dispersed in acetone (31 l,5 v) and then BnBr (4.76 kg,1.1 eq.) was added dropwise with stirring at 7 ℃. The mixture was stirred at 60 ℃ for 23h, the reaction mixture was cooled to 20 ℃, K ₂CO₃ was filtered off, and the filtrate was concentrated to 2V. N-heptane (5V) was added and concentrated to 5V. Stirring for 2h, collecting the solid by filtration, drying the filter cake to give the desired product as an off-white solid (7.64 Kg, 90% yield), HPLC purity 97.9％.MS(ESI)335.0,337.0[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)7.53–7.45(m,6H),7.22(d,J＝2.1,8.4Hz,1H),7.13(d,J＝8.4Hz,1H),5.19(s,2H),3.64(s,2H),3.61(s,3H).

Step 3 preparation of 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid (Compound TLZ-16-4)

Method 1: to a solution of NaOH (2.70 kg,4.01 eq.) in water (25.36 l,5 v) at 20 ℃ was added methyl 2- (4- (benzyloxy) -3-bromophenyl) acetate (5.64 kg,1.0 eq.). 2- (4- (benzyloxy) -3-bromophenyl) acetic acid methyl ester was dissolved at 50℃with stirring. 8-hydroxyquinolinone (592 g,0.1 eq.) was added at 50deg.C under nitrogen. The reaction mixture was refluxed for 48 hours. After cooling to room temperature, the solids were removed by filtration and the pH of the filtrate was adjusted to 2-3 by concentrated HCl. The solids were collected by centrifugation, the filter cake was transferred to the reactor, and toluene (4V) was added. The mixture was stirred at 70 ℃ until the filter cake dissolved. Stirring was stopped, and the mixture was allowed to stand to separate layers. The organic phase was cooled to 15℃and stirred for 10h. The resulting solid was collected by centrifugation and the filter cake was dried to give the desired product (3.38 Kg, yellow solid). (yield 78%, HPLC purity) 85％).MS(ESI)259.1[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)12.20(s,1H),9.00(s,1H),7.49–7.28(m,5H),6.88(d,J＝8.1Hz,1H),6.75(d,J＝2.1Hz,1H),6.58(dd,J＝2.1,8.1Hz,1H),5.08(s,2H),3.39(s,2H).

Method 2: water (67.5L, 4.5V), naOH (7.5 kg,4.01 eq.) and 2- (4- (benzyloxy) -3-bromophenyl) acetic acid (15 kg,1.0eq., supplied by the medical technology Co., ltd.) were charged to a 50 liter reaction vessel, stirred at 40.+ -. 5 ℃ until dissolved, and bis (8-hydroxyquinoline) ketone (II) (1.64 kg,0.1 eq.) was added under nitrogen. The reaction mixture was reacted at 100.+ -. 5 ℃ for 16 hours, and the reaction was terminated when 2- (4- (benzyloxy) -3-bromophenyl) acetic acid was 2.0% or less as detected by HPLC. The reaction mixture was cooled to 15.+ -. 5 ℃ and water (2.5V) and celite (10% wt) were added to the reaction mixture, stirred for 1 hour and filtered. The pH of the filtrate was adjusted to 2 with concentrated hydrochloric acid. The filtrate was collected by filtration, the filter cake was washed 2 times with water (2 x 2 v), the filter cake was placed in toluene and warmed to 70±5 ℃ to dissolve completely, stirring was stopped, and the aqueous layer was separated. The organic phase was cooled to 15℃and stirred for 10 hours, and the solid product was collected by centrifugation .MS(ESI)259.1[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)12.20(s,1H),9.00(s,1H),7.49–7.28(m,5H),6.88(d,J＝8.1Hz,1H),6.75(d,J＝2.1Hz,1H),6.58(dd,J＝2.1,8.1Hz,1H),5.08(s,2H),3.39(s,2H).

The preparation of 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid was carried out using the method of Haifeng Sun et al (see Bioorganic & MEDICINAL CHEMISTRY,21 (2013), 856-868, p.865, 5.1.6.8b synthesis), with only kg scale up, the yield of 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid obtained was less than 50% and the purity of the product was low.

Step 4: preparation of 7- (benzyloxy) -8-hydroxyisochroman-3-one (Compound TLZ-16-5)

TLZ-16-4 (9.0 kg,1.0 eq.) toluene (54L, 6V) and phenylboronic acid (5.10 kg,1.2 eq.) were added to a 100 liter reaction vessel under nitrogen, the reaction mixture was heated to 90.+ -. 5 ℃ and then paraformaldehyde (6.75 kg,9.0 eq.) was added in 2 portions over 4 hours, and the reaction was continued at 90.+ -. 5 ℃ for 20 hours. After HPLC detection TLZ-16-4 (2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid). Ltoreq.2.0%, the reaction mixture was cooled to 85.+ -. 5 ℃ and water (3V) was added dropwise from the dropping funnel, and the reaction mixture was stirred for 16 hours at 85.+ -. 5 ℃. Samples were taken for HPLC analysis.

The reaction mixture was cooled to 70.+ -. 5 ℃, stirring stopped, the aqueous phase was separated, water (1.5V) was added to the organic phase, and stirring was carried out at 70.+ -. 5 ℃ for 1.5 hours. The aqueous phase was separated off and the organic phase was concentrated to 3V volume under reduced pressure, the reaction mixture was cooled to 15±5 ℃ and stirred at this temperature for 16 hours, the solid was collected by filtration and dried under vacuum at 50±5 ℃ to give the desired product (5.9 kg, brown solid). (yield 63%, HPLC purity 97%, kf=0.090%)

MS(ESI)270.9[(M+H)⁺].¹H NMR(DMSO-d₆,400MHz)9.16(s,1H),7.50(d,J＝7.2Hz,2H),7.37(t,J＝7.2Hz,2H),7.32–7.28(m,1H),6.96(d,J＝8.0Hz,1H),6.65(d,J＝8.4Hz,1H),5.33(s,2H),5.17(s,2H),3.64(s,2H).

The preparation of 7- (benzyloxy) -8-hydroxyisochroman-3-one was carried out using the method of Haifeng Sun et al (see Bioorganic & MEDICINAL CHEMISTRY,21 (2013), 856-868, page 865, 5.1.8.9c synthesis), with only kilogram scale up of the starting materials in the reaction, the yield of 7- (benzyloxy) -8-hydroxyisochroman-3-one was less than 10% and the purity of the product was very low.

Step 5: preparation of 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (3, 4-dimethoxyphenethyl) acetamide (compound TLZ-16-7)

7- (Benzyloxy) -8-hydroxyisochroman-3-one (5.0 kg,1.0 eq.) was added to acetonitrile (30L, 6V) under nitrogen protection at 15.+ -. 5 ℃ and K ₂CO₃ (3.84 kg,1.5 eq.) was added. To the reaction mixture was added dropwise dimethyl sulfate (3.27 kg,1.4 eq.) under nitrogen blanket at a temperature of 10.+ -. 5 ℃ while cooling to 10.+ -. 5 ℃. The reaction mixture was warmed to 50.+ -. 5 ℃ and stirred for 16 hours. Samples were taken for HPLC analysis, standard: 7- (benzyloxy) -8-hydroxy isochroman-3-one is less than or equal to 2.0%.

After the reaction was completed, 3, 4-dimethoxyphenethylamine (5.03 kg,1.5 eq.) was added to the reaction mixture at a temperature of 50±5 ℃. After the addition was completed, the reaction mixture was warmed to 80.+ -. 5 ℃ and stirred for 16 hours. Samples were taken for HPLC analysis, with a standard of 7- (benzyloxy) -8-methoxyisochroman-3-one of 4.0% or less. The reaction mixture was cooled to 15.+ -. 5 ℃, filtered, the filter cake washed twice with acetonitrile (2 x 2.5V), the filtrates combined and transferred to a kettle, a pre-formulated HCl solution (0.6 eq in 4V water) was added, and then concentrated to 5-6V at a temperature below 45.+ -. 5 ℃. The reaction mixture was cooled to 15.+ -. 5 ℃, centrifuged and the filter cake was washed twice with water (2X 2V). The filter cake was dried at 50±5 ℃ to give the desired product (8.2 Kg, yellow solid) (yield 95%, HPLC purity 96%, kf=0.055%)

MS(ESI)488.2[(M+Na)⁺].¹H NMR(DMSO-d₆,300MHz)8.20(t,J＝5.7Hz,1H),7.50–7.30(m,5H),6.99(d,J＝8.4Hz,1H),6.90(d,J＝8.4Hz,1H),6.83(d,J＝8.1Hz,1H),6.78(d,J＝1.8Hz,1H),6.67(dd,J＝2.1,8.4Hz,1H),5.12(s,2H),4.53(s,2H),3.78(s,3H),3.72(s,3H),3.71(s,3H),3.50(s,2H),3.30–3.22(m,2H),2.64(t,J＝7.2Hz,2H).

Step 6: preparation of 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate (compound TLZ-16-8)

2- (4- (Benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (3, 4-dimethoxyphenethyl) acetamide (10.0 kg,1.0 eq.) was added to dichloromethane (50L, 5V) under nitrogen at 0.+ -. 5 ℃ C.) followed by DMAP (3.94 kg,1.5 eq.). The reaction mixture was cooled to-10±5 ℃ and AcCl (2.53 kg,1.5 eq.) was added dropwise to the reaction mixture under nitrogen protection at a temperature of-10±5 ℃. After the addition was completed, the reaction mixture was stirred at a temperature of-10.+ -. 5 ℃ for 1 hour. Samples were taken for HPLC analysis, with a standard of 1.0% or less of 2- (4- (benzyloxy) -2- (hydroxymethyl) -3-methoxyphenyl) -N- (3, 4-dimethoxyphenethyl) acetamide. To the reaction mixture was added dropwise a pre-prepared aqueous HCl (1N, 3V) solution at-10±5 ℃. After the addition was complete, the reaction mixture was warmed to 15.+ -. 5 ℃ and allowed to stand until the two phases separated. The lower organic phase is washed once with water (2V) and concentrated in vacuo to 2.0V-3.0V at a temperature below 40 ℃. N-heptane (4V) was added to the mixture, stirred for 0.5-1 hour and filtered, and the filter cake was washed twice with DCM/n-heptane=1/10 (2×1v). The filter cake was dried at 55.+ -. 5 ℃ to give the desired product (9.93 Kg, yellow solid, 91% yield, 97% HPLC purity)

MS(ESI)530.2[(M+Na)⁺].¹H NMR(DMSO-d₆,300MHz)8.96(t,J＝5.4Hz,1H),7.51–7.31(m,5H),7.09(d,J＝8.7Hz,1H),6.93(d,J＝8.4Hz,1H),6.83(d,J＝8.1Hz,1H),6.78(d,J＝2.1Hz,1H),6.67(dd,J＝1.8,8.1Hz,1H),5.15(s,2H),5.12(s,2H),3.77(s,3H),3.72(s,6H),3.44(s,2H),3.28–3.21(m,2H),2.63(t,J＝7.2Hz,2H).

Step 7: preparation of 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate (compound TLZ-16-9)

Dichloromethane (50 l,5 v) and 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate (10.0 kg,1.0 eq.) were added under nitrogen at 15±5 ℃ and then 2-chloropyridine (2.68 kg,1.2 eq.) was added. The reaction mixture was cooled to-10.+ -. 5 ℃ and trifluoromethanesulfonic anhydride (6.11 kg,1.1 eq.) was added dropwise under nitrogen protection at a temperature of-10.+ -. 5 ℃. After the addition was completed, the reaction mixture was stirred at a temperature of-10.+ -. 5 ℃ for 1 hour. Samples were taken for HPLC analysis, with the standard 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate +.ltoreq.0.5%. Saturated sodium bicarbonate solution (3V) was added dropwise at-10±5 ℃, the reaction mixture was warmed to 15±5 ℃, left to stand until the two phases separated, the lower organic phase was washed twice with water (2 x 2V), concentrated to 2.0V-3.0V in vacuo at a temperature below 40 ℃, isopropanol (6V) was added to the mixture, and concentration continued to 6.0V-7.0V. The temperature in the kettle is regulated to 15+/-5 ℃ and stirred for at least 1 hour. The filter cake was washed once with isopropanol (1V). The filter cake was dried to give the desired product (10.18 Kg, yellow solid) (yield 81%, HPLC purity 99%).

MS(ESI)490.2[(M+H-TfOH)⁺].¹H NMR(DMSO-d₆,300MHz)11.79(s,1H),7.51–7.32(m,6H),7.21–7.18(m,2H),6.98(d,J＝8.4Hz,1H),5.18(s,2H),5.17(s,2H),4.61(s,2H),3.93(s,3H),3.82–3.78(m,5H),3.76(s,3H),3.06(t,J＝8.1Hz,2H),1.96(s,3H).

Step 8: preparation of (S) -3- (benzyloxy) -6- ((6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxybenzyl acetate (Compound TLZ-16-10)

Preparing a formic acid/triethylamine (5:2) solution: triethylamine (1L, 0.1V) was added dropwise to formic acid (2.5L, 0.25V) under nitrogen at 0.+ -. 5 ℃ and prepared for use.

To DMF (30L, 3V) was added acetic acid 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate (10 kg,1.0 eq.) under nitrogen protection and at a temperature of 0.+ -. 5 ℃ and RuCl [ (R, R-Tsdpen) ] (p-cymene) (99.2 g,0.01 eq.). To the reaction mixture was added dropwise a solution of formic acid/triethylamine (5:2) (0.3V) prepared in advance, and the mixture was reacted at a temperature of 10.+ -. 5 ℃ for 16 hours. Samples were taken for HPLC analysis, with the standard 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate ∈1.0%. N-acetyl-L-cysteine (509 g,0.2 eq.) was added to the reaction mixture and stirred for 3 hours. To the resulting mixture was added DCM (50 l, 5V) and cooled to 0±5 ℃, PH was adjusted to 7 with saturated sodium bicarbonate solution, and purified water (5V) was added. After stirring for half an hour, the mixture was allowed to stand until the two phases separated. The lower organic phase was washed twice with purified water (2V) and the organic phase was concentrated to 2.0V-3.0V at a temperature below 40 ℃. EtOH (6V) was added to the mixture and concentration continued to 5.0V-6.0V at a temperature below 40 ℃. The obtained solution was used directly in the next step.

Step 9: preparation of (S) - (3- (benzyloxy) -6- ((6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyphenyl) methanol (compound TLZ-16-11)

The reaction solution of the previous step was cooled to 10.+ -. 5 ℃ and a solution of sodium hydroxide (1.25 kg,2.0 eq.) in water (2.5V) was slowly added to the solution at a temperature of 10.+ -. 5 ℃. The reaction mixture was stirred for 2 hours and sampled for HPLC analysis, with the standard of (S) -3- (benzyloxy) -6- ((6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxybenzyl acetate ∈1.0%. Purified water (5.5V) was added to the reaction mixture, and stirred for 1 hour. The filter cake was washed twice with ethanol: purified water=1:2 (2x1.5v). The filter cake was dried to give the desired product (6.12 Kg, yellow solid) (yield 87%, purity 99%).

MS(ESI)450.1[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)7.51–7.30(m,5H),7.08–7.01(m,2H),6.79(s,1H),6.63(s,1H),5.13(s,2H),4.59(d,J＝11.1Hz,1H),4.41(d,J＝11.1Hz,1H),3.96–3.91(m,1H),3.79(s,3H),3.72(s,3H),3.71(s,3H),3.12–2.76(m,4H),2.58(t,J＝5.7Hz,2H).

Step 10: preparation of (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (compound TLZ-16-13)

Preparing 10% sodium carbonate solution: softened water (16.5 kg,5.5 v) was added to the plastic tank under nitrogen protection and stirring, sodium carbonate (1.83 kg,2.6 eq.) was added to the plastic tank under stirring, and after stirring to fully dissolve the sodium carbonate, the product was ready for use.

Preparing isopropanol: n-heptane=1:1 solution: n-heptane (9.0L, 3V) was added to reactor B under nitrogen blanket and stirring, then isopropanol (9.0L, 3V) was added to reactor B under stirring, and stirring was continued for at least 30 minutes until it was miscible, and stored for use.

Dichloromethane (24 l,8 v) was added to reaction vessel a under nitrogen protection, stirring was turned on, and (S) - (3- (benzyloxy) -6- ((6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyphenyl) methanol (3.0 kg,1.0 eq.) was added. The temperature in the kettle is controlled to be 20+/-5 ℃, and (S) - (3- (benzyloxy) -6- ((6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyphenyl) methanol is stirred until the methanol is completely dissolved, and the temperature in the kettle is reduced to be-10+/-5 ℃. To the reaction vessel A was added thionyl chloride (0.95 Kg,1.2 eq.) dropwise and stirred at-10.+ -. 5 ℃ for at least 1 hour. Samples were taken for HPLC analysis, standard: the peak area percentage of (S) - (3- (benzyloxy) -6- ((6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinolin-1-yl) methyl) -2-methoxyphenyl) methanol is less than or equal to 0.5%. If the temperature in the reaction kettle is not in accordance with the requirements, the temperature in the reaction kettle is controlled to be minus 10+/-5 ℃, sulfoxide chloride (79.4 g,0.1 eq.) is added into the reaction kettle A, stirring is continued for at least 1 hour, and sampling is carried out for HPLC analysis until the requirements are met.

The temperature in the reactor is controlled to be 0+/-5 ℃, and the prepared 10% sodium carbonate aqueous solution is dripped into the reaction reactor A. After the addition, the temperature in the kettle is controlled to be 5+/-5 ℃ and stirred for at least 10 hours. Samples were taken for HPLC analysis, standard: the peak area percentage of the (S) -1- (4- (benzyloxy) -2- (chloromethyl) -3-methoxybenzyl) -6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline is less than or equal to 1.0 percent. After the reaction is finished, the temperature in the kettle is raised to 15+/-5 ℃, stirring is stopped, and the kettle is kept stand for at least 30 minutes until the two phases are thoroughly separated. The lower organic phase is put into a clean barrel, and the upper water phase is put into a water phase barrel for temporary storage. Transferring the lower organic phase to a reaction kettle A, adding softened water (2V), controlling the temperature in the kettle to be 15+/-5 ℃ and stirring for at least 10 minutes, standing for at least 30 minutes until the two phases are completely separated, putting the lower organic phase into a clean barrel, and putting the upper aqueous phase into an aqueous phase barrel for temporary storage. Transferring the lower organic phase to a reaction kettle A, adding softened water (2V), controlling the temperature in the kettle to be 15+/-5 ℃ and stirring for at least 10 minutes, standing for at least 30 minutes until the two phases are completely separated, putting the lower organic phase into a clean barrel, and putting the upper aqueous phase into an aqueous phase barrel for temporary storage. The organic phase is concentrated under reduced pressure to 2.0-3.0V under vacuum at a temperature below 40 ℃, isopropanol (6V) is added, and the concentration under reduced pressure is continued to 6.0-7.0V. The temperature in the kettle is reduced to 15+/-5 ℃ and stirred for at least 1 hour. Centrifuging, and using isopropanol for the centrifugal sediment: n-heptane=1:1 washed twice. The centrifugal sediment was collected. The centrifuged sediment was transferred to a vacuum oven and dried in vacuo at a temperature of 50.+ -. 5 ℃ for at least 12 hours. Samples were taken for LOD analysis until the standard was met, which was LOD 2.0% or less. Stopping drying, reducing the temperature of the oven to below 30 ℃, and keeping the temperature of the water tank below 30 ℃ for at least 1 hour. And (3) receiving materials, packaging the product by using a double-layer low-density polyethylene inner bag, sealing by using a binding belt, heat-sealing in an aluminum foil bag, and filling nitrogen between the two layers for protection. Finally, a yellow solid (2.4 Kg, yield 83%, purity 99%)

MS(ESI)432.2[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)7.50–7.30(m,5H),6.97(d,J＝8.4Hz,1H),6.87(s,1H),6.86(d,J＝8.1Hz,1H),6.68(s,1H),5.11(s,2H),4.09(d,J＝15.9Hz,1H),3.79(s,3H),3.75(s,3H),3.73(s,3H),3.44–3.34(m,3H),3.15–3.09(m,1H),3.00–2.88(m,1H),2.65–2.55(m,2H),2.49–2.43(m,1H).

Step 11: preparation of (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolin-10-ol (Compound TLZ-16-0)

Preparing ethyl acetate: n-heptane=1:2 solution: under the protection of nitrogen, ethyl acetate (4L, 2V) is added into the reaction kettle B, and stirring is started. N-heptane (8L, 4V) is added into the reaction kettle B, and the mixture is uniformly mixed and then stored for standby.

Ethyl acetate (16L, 8V) was added to autoclave A under nitrogen atmosphere and stirring, and (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (2.0 Kg,1.0 eq.) and aqueous palladium hydroxide carbon (Pd (OH) ₂/C, 240g, water content 54% and palladium content 20%,12% wt) and methanol (4L, 2V) were added to autoclave A under stirring at a temperature of 20.+ -. 5 ℃. Autoclave a was purged three times with nitrogen and then with 5 times with hydrogen. Controlling the temperature in the reactor at 20+/-5 ℃, controlling the pressure in the reactor at 0.1-0.6MPa, and stirring for at least 15 hours. Samples were taken for HPLC analysis, with the standard of (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline peak area fraction of 1.0% or less. After the reaction, the temperature in the autoclave was controlled to 20.+ -. 5 ℃, the hydrogen in the autoclave was replaced with nitrogen, ethyl acetate (5V) was added to autoclave A, and the mixture was stirred for at least 10 minutes. The reaction mixture was transferred to a plastic tank, and autoclave a was flushed with ethyl acetate (5V), and then the flush was transferred to the plastic tank containing the reaction mixture. The reaction mixture was filtered through celite (100% wt) and the filter cake was washed twice with ethyl acetate (2.5V) (total 5V, 10-20 minutes each). The combined filtrates were filtered through a microporous filter and transferred to reaction vessel C. Concentrating the filtrate under reduced pressure to 5.0-7.0V at a temperature below 40+ -5deg.C. N-heptane (5V) was added to the reaction vessel C, the temperature in the vessel was adjusted to 20.+ -. 5 ℃ and stirred for at least 30min. Centrifuging, and using ethyl acetate for a centrifugal filter cake: n-heptane=1:2 was rinsed twice, 1V each time, and the centrifugal filter cake was collected. The temperature in the reaction kettle is controlled at 20+/-5 ℃, ethyl acetate (30V) is added into the reaction kettle C, and stirring is started. Transferring the centrifugal filter cake into a reaction kettle C, regulating the temperature in the kettle to 45+/-5 ℃ and stirring until the centrifugal filter cake is completely dissolved. Controlling the external temperature of the reaction kettle C to be 40+/-5 ℃ and concentrating the mixture under reduced pressure to 5.0-7.0V; regulating the temperature in the kettle to 20+/-5 ℃, stirring for at least 0.5 hour, centrifuging, and centrifuging a filter cake by using ethyl acetate: n-heptane=1:2 was rinsed twice, 1V each time, and the centrifugal filter cake was collected. The centrifugal filter cake was dried in a vacuum oven at a temperature of 45.+ -. 5 ℃ for at least 12 hours and sampled for loss on drying analysis (LOD) until standard was met, which was 2.0% or less. Stopping drying, and reducing the temperature of the oven water tank to below 30 ℃. And (3) receiving materials, packaging by using a double-layer low-density polyethylene inner bag, sealing by using a binding belt, and sleeving the double-layer low-density polyethylene inner bag into a nitrogen-protected heat-seal aluminum foil composite outer bag. The title compound was obtained as a yellow solid (1.3 kg, yield greater than 85%, purity 99.5%).

MS(ESI)342.0[(M+H)⁺].¹H NMR(DMSO-d₆,400MHz)9.06(s,1H),6.86(s,1H),6.74–6.67(m,3H),4.05(d,J＝15.6Hz,1H),3.74(s,3H),3.73(s,3H),3.40–3.29(m,3H),3.12–3.08(m,1H),2.97–2.88(m,1H),2.63–2.43(m,2H).

Example 2 preparation of (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinolin-10-ol hydrochloride (Compound TLZ-16-CL)

Butanone (23.3L, 23V) was added to reaction vessel A under nitrogen protection and stirring, and (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolin-10-ol (1015.0 g,1.0 eq.) was added to reaction vessel A at 20.+ -. 5 ℃ in the vessel with stirring to dissolve (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolin-3, 2-a ] isoquinolin-10-ol completely. The solution in the reaction kettle A is filtered by a microporous filter and then transferred to a reaction kettle B under the protection of nitrogen, stirring is started, the internal temperature of the reaction kettle B is regulated to 20+/-5 ℃, seed crystal (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline-10-alkoxide (50.8 g, 5%wt) is added into the reaction kettle B, and stirring is carried out for at least 0.5 hours. The internal temperature of the reaction vessel was controlled at 20.+ -. 5 ℃ and concentrated hydrochloric acid (323.4 g,1.1 eq.) was added dropwise to the reaction vessel B through a microporous filter. After the addition is completed, the temperature in the kettle is regulated to 25+/-5 ℃ and stirring is continued for at least 5 hours. Samples were taken for XRPD detection until standard was met, standard: XRPD retention times were consistent with the reference standard pattern. Filtering, leaching the filter cake twice with butanone (1V) respectively, and collecting the filter cake. The filter cake was transferred to a vacuum oven and dried in vacuo at a water tank temperature of 45.+ -. 5 ℃ for at least 12 hours. Sampling and sending the samples to KF and GC to detect until the samples meet the standard, wherein the standard is as follows: KF is less than or equal to 0.3 percent, and butanone solvent residue is less than or equal to 5000ppm. Stopping drying, and reducing the temperature of the oven water tank to below 30 ℃. And (3) receiving materials, packaging the product by using an inner belt of low-density polyethylene, wrapping and sealing the product by using a nylon rope, sleeving the product in a heat-seal aluminum foil composite outer bag protected by nitrogen, and finally placing the product in a fiber (or high-density polyethylene) barrel. Finally, yellow solid (1.1 kg, yield 98%, purity 99%)

MS(ESI)342.0[(M+H-HCl)⁺].¹H NMR(DMSO-d₆,300MHz)11.58(s,1H),9.67(s,1H),7.03(s,1H),6.95–6.83(m,3H),4.69–4.55(m,2H),4.44–4.35(m,1H),3.84–3.75(m,11H),3.43–3.34(m,2H),3.09–2.80(m,2H).

Example 3 comparison of preparation of 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate salt of acetic acid under different conditions

The experiment was performed according to a method similar to that of example 1, step 7 above, using the cyclization reagent, base reagent and different temperatures as given in table 1 below.

Table 1:

N/A indicates that no alkaline agent is added

Experimental results show that 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydro-isoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate of acetic acid can be obtained in high yield in the presence of trifluoromethanesulfonic anhydride and a base reagent.

EXAMPLE 4 comparison of preparation of L-corydaline under different conditions

The experiments were performed according to a similar method to example 1, step 11 above, using the catalysts, solvents and different temperatures given in table 2 below.

TABLE 2

Experimental results show that 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydro-isoquinolin-1-yl) methyl) -2-methoxybenzyl ester triflate with high yield and high ee value can be obtained in a short time under the catalysis of 5% -30% (w/w), especially 10% -20% (w/w) palladium hydroxide carbon in the presence of an organic solvent such as toluene, tetrahydrofuran, DMF, 1, 4-dioxane, ethyl acetate, alcohol solvents, 2-methyltetrahydrofuran or a mixed solvent thereof. In particular, 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydro-isoquinolin-1-yl) methyl) -2-methoxybenzyl acetate triflate with high yield and high ee value can be obtained in a very short time, such as 10 hours, in the presence of ethyl acetate and an alcohol solvent, and the reaction time is greatly saved.

Comparative example 1: preparation of 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid (Compound TLZ-16-4)

2- (4- (Benzyloxy) -3-bromophenyl) acetic acid (20.0 g,1.0 eq.) was added to the reaction flask, after nitrogen substitution, 30% aqueous sodium hydroxide solution and bis (8-hydroxyquinoline) copper (ii) (2.2 g,0.1 eq.) were added, the mixture was heated to 110 ℃ and refluxed, and after 20 hours of reaction, samples were taken, and the reaction was completed. Cooled to room temperature, filtered, and the filtrate was adjusted to neutral pH with concentrated hydrochloric acid (65 ml) and filtered with suction to give a solid product. The yield is less than 50 percent, the purity is lower, and a large amount of bis (8-hydroxyquinoline) copper exists in the product (∏).MS(ESI)259.1[(M+H)⁺].¹H NMR(DMSO-d₆,300MHz)12.20(s,1H),9.00(s,1H),7.49–7.28(m,5H),6.88(d,J＝8.1Hz,1H),6.75(d,J＝2.1Hz,1H),6.58(dd,J＝2.1,8.1Hz,1H),5.08(s,2H),3.39(s,2H).

Comparative example 2: preparation of 7- (benzyloxy) -8-hydroxyisochroman-3-one (Compound TLZ-16-5)

Toluene (250 ml, 50V), 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid (5.0 g,1.0 eq.) and phenylboronic acid (4.7 g,2.0 eq.) were added to the reaction flask, after nitrogen substitution, the mixture was heated to 110℃and subjected to reflux water separation treatment, after water separation was completed, paraformaldehyde (3.5 g,6.0 eq.) was added in portions, and after 12 hours of reaction, the mixture was monitored. If the reaction is not finished, the reaction is continued after phenylboronic acid (1.2 g,0.5 eq.) is added until the reaction is completed. Concentrating the reaction solution to dryness, adding water (50 ml, 10V) for refluxing until the intermediate becomes a product, sampling to find the reaction very miscellaneous, extracting with dichloromethane for post-treatment, drying with anhydrous sodium sulfate, concentrating to obtain the product with very low purity and yield <10％.MS(ESI)270.9[(M+H)⁺].¹H NMR(DMSO-d₆,400MHz)9.16(s,1H),7.50(d,J＝7.2Hz,2H),7.37(t,J＝7.2Hz,2H),7.32–7.28(m,1H),6.96(d,J＝8.0Hz,1H),6.65(d,J＝8.4Hz,1H),5.33(s,2H),5.17(s,2H),3.64(s,2H).

Comparative example 3: preparation of 3- (benzyloxy) -6- ((6, 7-dimethoxy-3, 4-dihydroisoquinolin-1-yl) methyl) -2-methoxybenzyl acetate (Compound TLZ-16-9)

After nitrogen displacement, acetic acid 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl ester (10 g,1.0 eq.) and acetonitrile (100 ml,10 v) were added dropwise, phosphorus oxychloride (10 ml,1 v) was added, and then warmed to 85 ℃ and refluxed. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and then added with methylene chloride (50 ml, 5V), followed by washing with a saturated sodium bicarbonate solution (100 ml, 10V) and a saturated brine (50 ml, 5V). Dried over anhydrous sodium sulfate and concentrated to give a solid. The purity of the solid was lower and the yield was lower <30%.

Comparative example 4: preparation of (S) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolin-10-ol (Compound TLZ-16-0)

(S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline (2.0 g,1.0 eq.) was added, ethanol (10 ml, 5V) was added to dissolve, concentrated hydrochloric acid (8 ml, 4V) was added dropwise under ice bath conditions, the temperature was raised to 80℃for reflux, and after the reaction was completed, the temperature was lowered to 0 ℃. The pH was adjusted to neutral with concentrated ammonia, DCM (10 ml, 5V) was added for extraction, the DCM layer was concentrated to 2V, isopropanol (12 ml, 6V) was added for displacement, continued concentration to 2V, and filtration was performed to give a solid. The ee value of the product is about 77%. The yield is lower <35％.MS(ESI)342.0[(M+H)⁺].¹H NMR(DMSO-d₆,400MHz)9.06(s,1H),6.86(s,1H),6.74–6.67(m,3H),4.05(d,J＝15.6Hz,1H),3.74(s,3H),3.73(s,3H),3.40–3.29(m,3H),3.12–3.08(m,1H),2.97–2.88(m,1H),2.63–2.43(m,2H).

Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.

Claims

1. A process for the preparation of levamisole represented by formula TLZ-16-0 or a pharmaceutically acceptable salt thereof, said process comprising the steps of:

under the protection of nitrogen, under the catalysis of palladium hydroxide carbon and at the temperature of 15-30 ℃, adopting a hydrogen source to make (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline in the formula TLZ-16-13 perform debenzylation reaction,

2. The process according to claim 1, wherein the weight ratio of palladium on carbon hydroxide to the compound of formula TLZ-16-13 is 10% to 20%.

3. The production method according to claim 1, wherein the organic solvent is selected from the group consisting of ethyl acetate and toluene or a mixed solvent of ethyl acetate and methanol.

4. A production process according to any one of claims 1 to3, wherein the process further comprises the step of producing (S) -10- (benzyloxy) -2,3, 9-trimethoxy-5, 8,13 a-tetrahydro-6H-isoquinolino [3,2-a ] isoquinoline of formula TLZ-16-13 using the intermediate compound of formula TLZ-16-9:

5. The process according to claim 4, wherein the intermediate compound of formula TLZ-16-9 is prepared by:

6. The production process according to claim 5, wherein the process further comprises the step of producing 3- (benzyloxy) -6- (2- ((3, 4-dimethoxyphenethyl) amino) -2-oxoethyl) -2-methoxybenzyl acetate of formula TLZ-16-8 using the compound 7- (benzyloxy) -8-hydroxyisochroman-3-one represented by formula TLZ-16-5

7. The production process according to claim 6, wherein the process further comprises the step of producing 7- (benzyloxy) -8-hydroxyisochroman-3-one of the formula TLZ-16-5 by reacting 2- (4- (benzyloxy) -3-hydroxyphenyl) acetic acid, which is a compound represented by the formula TLZ-16-4, with phenylboronic acid in toluene, followed by directly adding paraformaldehyde