CN109694348B

CN109694348B - Racemization recovery method for recovering materials from resolution mother liquor of dextromethorphan intermediate

Info

Publication number: CN109694348B
Application number: CN201910080479.7A
Authority: CN
Inventors: 姚胜宇; 陈荣; 林楠
Original assignee: Jiangsu Baozhong Baoda Pharmaceutical Co ltd
Current assignee: Jiangsu Baozhong Baoda Pharmaceutical Co ltd
Priority date: 2018-11-12
Filing date: 2019-01-28
Publication date: 2022-07-05
Anticipated expiration: 2039-01-28
Also published as: CN109694348A

Abstract

The invention relates to a racemization recovery method for recovering materials in a resolution mother liquor of a dextromethorphan intermediate, which comprises the following steps: (1) adding a recovered material of a resolution mother liquor of a dextromethorphan intermediate into a reaction kettle, sequentially adding dimethylbenzene, caustic soda liquid and deionized water, stirring, measuring the pH value to be between 10 and 11, keeping the temperature for a period of time, and transferring the mixture into a halogenation reaction kettle for halogenation to obtain a halogenated product II; (2) adding liquid caustic soda and methanol into a reaction kettle for stirring, after nitrogen replacement, starting to dropwise add a halogenated product II at 0-5 ℃, after the addition is finished, keeping the temperature for a period of time, adding water, layering, and keeping an organic layer III for later use; (3) removing the organic layer III in the previous step, adding the mixture into an autoclave, adding a catalyst, and then slowly adding H₂And concentrating the organic solvent xylene to obtain racemic products I and IV. The invention has the advantages that: the invention has safe and high-efficiency reaction; the isomer is convenient to recycle, and the three wastes are less.

Description

Racemization recovery method for recovering materials from resolution mother liquor of dextromethorphan intermediate

Technical Field

The invention belongs to the technical field of chemical industry, and particularly relates to a racemization recovery method for recovering 1- (4-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline from a recovered material dextromethorphan intermediate splitting mother liquor.

Background

Dextromethorphan is an antitussive or antitussive drug that exerts a central antitussive effect by inhibiting the medullary cough center. The cough relieving intensity of the medicine is equal to or slightly stronger than that of codeine, and the medicine resistance and addiction are lower, so the medicine is suitable for long-term taking or high-dose use.

In the process of synthesizing the dextromethorphan, recovering a material 1- (4-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline from a dextromethorphan intermediate splitting mother liquor, wherein the structural formula of the octahydroisoquinoline is shown as a formula I:

it can be recycled so as to reduce three wastes.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a racemization recovery method for recovering materials from a dextromethorphan intermediate resolution mother liquor, which can reduce three wastes.

In order to solve the technical problems, the technical scheme of the invention is as follows: a racemization recovery method for recovering materials from a dextromethorphan intermediate splitting mother solution has the innovation points that: the recovery method specifically comprises the following steps:

(1) racemization treatment and recovery: adding a recovered material of a mother liquor obtained by splitting a dextromethorphan intermediate into a reaction kettle, sequentially adding dimethylbenzene, caustic soda liquid and deionized water, stirring, measuring the pH value to be 10-11, preserving the temperature for a period of time, transferring the mixture into a halogenation reaction kettle, and performing halogenation reaction to obtain a halogenated product II;

(2) eliminating: adding liquid caustic soda and methanol into a reaction kettle for stirring, after nitrogen replacement, beginning to dropwise add a halogenated product II at 0-5 ℃, after the addition is finished, preserving the temperature for a period of time, adding water, layering, and keeping an organic layer III for later use;

(3) reduction: removing the organic layer III, adding into an autoclave, adding catalyst, and slowly adding H₂And concentrating organic solvent xylene to obtain racemic products I and IV, wherein the specific reaction process is as follows:

wherein the content of the first and second substances,

X₂＝Cl₂、Br₂

further, the liquid alkali in (2) is one of sodium hydroxide, potassium hydroxide or lithium hydroxide.

The invention has the advantages that: the racemization recovery method for recovering materials from the resolution mother liquor of the dextromethorphan intermediate can stably obtain high-quality racemized 1- (4-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline in batches, and has safe and efficient reaction; the isomer is convenient to recycle, and the three wastes are less.

Detailed Description

The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the scope of the embodiments described herein.

Examples

The racemization recovery method for recovering 1- (4-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline from the mother liquor for resolution of dextromethorphan intermediate in this embodiment specifically includes the following steps:

a halogenation step:

adding 100g of dextromethorphan intermediate splitting mother liquor (S/R is 8.2/91.8) to be recovered into a 1L reaction kettle, then adding 400g of dimethylbenzene, 75g of caustic soda liquid and 250g of deionized water, stirring, measuring the pH value between 10 and 11, keeping the temperature at 40 ℃ for 15 minutes, and transferring to a halogenation reaction kettle. Cooling to 0-5 ℃, then adding chlorine or liquid bromine at-10-0 ℃, and finishing the addition within about 0.5 hour. The temperature is controlled not to exceed 10 ℃. The temperature is controlled to be not higher than 5 ℃, and the dropwise addition is finished within about 1 hour. After about 3 hours of reaction, sampling and controlling, and after the reaction is finished, layering. And (4) separating and removing a water layer to obtain a halogenated product, wherein the content of a HPLC (high performance liquid chromatography) controlled recovery product is less than or equal to 3%.

And (3) elimination step:

adding 100g of liquid alkali (50% of potassium hydroxide aqueous solution) and 1000g of methanol into a 2L elimination reaction kettle, stirring for 1 hour, replacing with nitrogen, starting to dropwise add a halide at 0-5 ℃, keeping the temperature at 15 ℃ for about 2 hours after finishing adding for about 1 hour, adding 1500g of water, layering, and keeping an organic layer for later use. HPLC with less than 2% of controlled halides.

A reduction step:

and (3) removing the organic layer, adding the organic layer into a 1L high-pressure kettle, adding a catalyst, slowly adding H2, keeping the pressure at 45-60 psi, controlling the temperature at 50-60 ℃, and reacting for 3 hours. Concentrating the organic solvent xylene to obtain a racemic product: 89 g. Yield: 89 percent. (chiral HPLC: S/R55.4/44.6)

The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims

1. A racemization recovery method for recovering 1- (4-methoxybenzyl) -1,2,3,4,5,6,7, 8-octahydroisoquinoline from a dextromethorphan intermediate resolution mother liquor is characterized in that: the recovery method specifically comprises the following steps:

(1) a halogenation step:

adding 100g of dextromethorphan intermediate splitting mother liquor to be recovered into a 1L reaction kettle, wherein S/R is 8.2/91.8, then adding 400g of dimethylbenzene, 75g of caustic soda liquid and 250g of deionized water, stirring, measuring the pH value between 10 and 11, keeping the temperature at 40 ℃ for 15 minutes, and transferring to a halogenation reaction kettle; cooling to 0-5 ℃, then adding chlorine or liquid bromine at the temperature of-10-0 ℃, finishing the addition within about 0.5 hour, and controlling the temperature not to exceed 10 ℃; sampling and controlling after reacting for about 3 hours, and layering after the reaction is finished; separating out the water layer to obtain a halogenated product, wherein the content of HPLC (high performance liquid chromatography) controlled recovery is less than or equal to 3%;

(2) and (3) elimination step:

adding 100g of liquid alkali and 1000g of methanol into a 2L elimination reaction kettle, and stirring for 1 hour, wherein the liquid alkali is 50% potassium hydroxide aqueous solution; after nitrogen replacement, beginning to dropwise add 0-5 ℃ halide, finishing charging for about 1 hour, then keeping the temperature at 15 ℃ for about 2 hours, adding 1500g of water, layering, and keeping an organic layer for later use; the HPLC controlled halogen is less than 2 percent;

(3) a reduction step:

removing the organic layer, adding the organic layer into a 1L high-pressure kettle, adding a catalyst, slowly introducing H2, keeping the pressure at 45-60 psi, controlling the temperature at 50-60 ℃, and reacting for 3 hours; concentrating the organic solvent xylene to obtain a racemic product: 89g, yield: 89% of chiral HPLC, wherein S/R is 55.4/44.6;

the specific reaction process is as follows:

wherein, X2 ═ Cl2 and Br2

。