CN109776646B

CN109776646B - Method for preparing high-purity cholesterol by continuous countercurrent micro-channel extraction

Info

Publication number: CN109776646B
Application number: CN201910160334.8A
Authority: CN
Inventors: 李中贤; 刘小培; 余学军; 王俊伟; 董学亮
Original assignee: High and New Technology Research Center of Henan Academy of Sciences
Current assignee: High and New Technology Research Center of Henan Academy of Sciences
Priority date: 2019-03-04
Filing date: 2019-03-04
Publication date: 2021-06-04
Anticipated expiration: 2039-03-04
Also published as: CN109776646A

Abstract

The invention discloses a method for preparing high-purity cholesterol by continuous countercurrent micro-channel extraction, belonging to the technical field of chemical engineering. Which comprises the following steps: (1) mixing n-heptane, ethyl acetate, methanol and water according to the volume ratio of 0.9-1.2:1.1-1.3:0.8-1.0:1, standing, separating an upper phase solution and a lower phase solution, dissolving a cholesterol crude product by using the upper phase solution, and adjusting the pH of the lower phase solution to be 3.7-4.5 by using acetic acid as an extracting agent; (2) the extractant carries out continuous countercurrent micro-channel extraction on the cholesterol crude product solution; (3) the cholesterol solution obtained by countercurrent microchannel extraction was evaporated and the cholesterol recrystallized from ethanol. The invention adopts a continuous countercurrent micro-channel extraction technology to separate and purify a crude product of cholesterol to obtain high-purity medical cholesterol, and is a method for efficiently and quickly preparing the high-purity medical cholesterol.

Description

Method for preparing high-purity cholesterol by continuous countercurrent micro-channel extraction

Technical Field

The invention relates to a separation and purification method of a compound, belongs to the technical field of chemical engineering, and particularly relates to a method for preparing high-purity cholesterol by purifying a cholesterol crude product by adopting a continuous countercurrent micro-channel extraction technology.

Background

Cholesterol is an important medical intermediate, is mainly used for the production of vitamins D2 and D3, artificial bezoar, synthetic hormone, anticancer drugs and the like, and can also be used as ecdysone of shrimps, an additive of breeding feed and photochemical and electronic liquid crystal materials. The purity requirement of cholesterol required by vitamin D3 production is more than 95%, which corresponds to NF-grade cholesterol in United states pharmacopoeia, but when the vitamin D3 is used for producing medicines and liquid crystal materials, the purity of the cholesterol is required to be more than 99%, and the 41 th edition of United states pharmacopoeia which takes effect 5, 1 and 2018 puts forward more strict requirements on the impurity content of pharmaceutical-grade cholesterol. At present, cholesterol is extracted from lanolin, animal brainstem and fish oil, and contains more impurities such as 24-dehydrocholesterol, 7-ene cholesterol alcohol, dihydro cholesterol and the like, so that the quality requirements of medicine production are difficult to meet. The impurities, especially 24-dehydrocholesterol, have similar properties to cholesterol, are difficult to remove by the traditional recrystallization purification method, and are required to be recrystallized for multiple times to reach the cholesterol content of the pharmaceutical grade, so the yield is low. Chinese patent 201310510069.4 discloses a method for preparing high-purity lanolin cholesterol, which uses NF grade lanolin cholesterol with purity of more than 95.0% as raw material, and adopts a method of combining melt crystallization and solvent recrystallization to obtain high-purity lanolin cholesterol with content of more than 99.0%, but the yield is only 60-75%, and continuous industrial production is difficult to realize.

Disclosure of Invention

The invention aims to provide a method for purifying and preparing high-purity medical cholesterol by taking a crude cholesterol product as a raw material, and the method meets the industrial production requirement of high recovery rate.

In order to realize the purpose, the invention adopts a continuous countercurrent micro-channel extraction method, and the specific technical scheme is as follows:

(A) mixing n-heptane, ethyl acetate, methanol and water according to the volume ratio of 0.9-1.2:1.1-1.3:0.8-1.0:1, standing, separating an upper phase solution and a lower phase solution, dissolving a cholesterol crude product by using the upper phase solution, and adjusting the pH of the lower phase solution to be 3.7-4.5 by using acetic acid as an extracting agent;

(B) pumping an extractant into a microchannel extraction system, wherein the microchannel extraction system comprises n mixing modules M and n separation modules S, the mixing modules and the separation modules are sequentially spaced, a lower phase solution outlet of each separation module is connected with an inlet of a previous stage of mixing module, an upper phase solution outlet is connected with an inlet of a next stage of mixing module, the lower phase solution outlet and the upper phase solution outlet are repeatedly connected in this way, the extracting agent and a cholesterol crude product solution storage tank are respectively connected by a feeding pump, and a lower phase outlet of each separation module is connected with a feeding pump to control the flow rate; the extractant sequentially enters the mixing module Mn and the separation module Sn, when the extractant occupies about one-half of the volume of the separation module Sn, a Sn lower phase solution discharge port is opened, and the extractant enters the upper-stage mixing module M through a feed pump_n-1Operating in turn, step-by-step counter-current to the microchannel mixing module M₁At this point, the mixing module M begins₁Pumping the crude cholesterol solution into the mixing module M₁Fully mixed and extracted, and enters a separation module S₁Layering, feeding the upper phase solution into a micro-channel mixing module M₂The lower phase solution enters a recovery tank to be evaporated and recovered, and the flow rate of the lower phase solution is the same as that of the extractant; such step-by-step continuous countercurrent extraction separation is carried out by using gas chromatography for each stepAnd analyzing the purity of the cholesterol on the phase separation module until the purity is more than or equal to 99.0%, collecting the phase solution on the phase separation module, distilling to recover the solvent, and recrystallizing the remainder with ethanol to obtain the target product.

The mass percentage of the cholesterol in the raw material cholesterol crude product in the step (A) is more than or equal to 85.0 percent; the weight volume concentration of cholesterol in the prepared cholesterol crude product solution is 5.0-10.0% (g/mL).

The stage number of the fractional countercurrent extraction in the step (B) is 1 to 5; the flow ratio of the extracting agent to the cholesterol crude product solution is 1: 1-2.

The mixing module in the extraction system in the step (B) is a microchannel reaction/mixing module of various types. Such as: corning Advanced-Flow^TMMicrochannel heart-shaped reaction modules, Bayer microreactor mixing modules, and the like.

In the step (B), the separation module of the extraction system is designed to have larger volume and height-diameter ratio according to the flow of the cholesterol crude product solution and the extractant, so as to ensure the stable separation effect of two phases.

The invention has the beneficial effects that: 1. the recovery rate of cholesterol by adopting the method reaches more than 80 percent. 2. The purity of the cholesterol product is more than or equal to 99.0 percent, and the requirements of medicine and liquid crystal material production are met. 3. Continuous operation, convenience, high efficiency, rapidness and stable quality, is a method suitable for rapidly preparing high-purity medical cholesterol in large quantities, and has good application and development prospects.

Drawings

FIG. 1 is a schematic process diagram of a continuous countercurrent extraction system according to the present invention.

Detailed Description

To better illustrate the invention, the following examples are given:

example 1

Mixing n-heptane, ethyl acetate, methanol and water according to a volume ratio of 1.2: 1: 1.0:1, standing, separating an upper phase solution from a lower phase solution, and dissolving a crude cholesterol product (crude cholesterol with a mass percentage of 85.8%) by using an upper phase solution to obtain a crude cholesterol solution with a weight volume concentration of 5.0% (g/mL); adjusting pH of the lower phase solution with acetic acid = 4.5 as an extractant;

under normal temperature, pump into microchannel extraction system with extractant, as shown in fig. 1, microchannel extraction system includes n mixing module M (corning G1 heart type reaction module) and n separation module S (diameter 10cm, cylindrical container of height 60 cm), mixing module and separation module are interval in proper order, the import of preceding one-level mixing module of phase solution exit linkage under the separation module, the import of last phase mixing module of phase solution exit linkage, the connection is repeated so, connect extractant and cholesterol solution liquid storage pot respectively with the charge pump, and the phase exit linkage feed pump control velocity of flow under every separation module. Firstly, the extractant of the embodiment is sequentially pumped into the micro-channel mixing module Mn and the separation module Sn at 80mL/min, when the extractant occupies about one-half of the volume of the separation module Sn, a discharge port of a lower phase solution of the separation module Sn is opened, and the extractant enters the upper-stage mixing module M at the same flow rate of 80mL/min controlled by a feed pump_n-1In this manner of operation, the extractant flows to the microchannel mixing module M₁At this point, the mixing module M begins₁Pumping 80mL/min of crude cholesterol solution, mixing the two solutions in a mixing module M₁Fully mixed and extracted, and enters a separation module S₁Layering until the solution is full of S₁When the flow control valve at the lower phase of S1 is opened, the solution enters a recovery tank at the flow rate of 80mL/min, and the upper phase of the solution enters a micro-channel mixing module M₂And (3) allowing the lower phase of the solution to enter a recovery tank for evaporation and recovery, performing step-by-step countercurrent extraction and separation as shown in figure 1, analyzing the cholesterol purity of the upper phase solution of each separation module by using gas chromatography until the purity is more than or equal to 99.0%, collecting the upper phase solution of the separation module, distilling and recovering the solvent, and recrystallizing the remainder with ethanol to obtain the high-purity cholesterol. The results show that: in this example, the number of counter-current extraction stages was 2, and the purity of the obtained high-quality cholesterol was 99.38%, and the yield was 81.1%.

Different conditions were used for the continuous countercurrent extraction, examples 2-5 are summarized in the following table and the results show: according to the quality of crude cholesterol and different extraction operation parameters, the number of stages of countercurrent extraction in the examples is 1 to 5, the purity of the obtained high-quality cholesterol is 99.08 to 99.53 percent, and the yield is 81.6 to 86.3 percent.

Claims

1. A method for extracting cholesterol by a continuous countercurrent micro-channel is characterized by comprising the following steps:

(B) pumping an extractant into a microchannel extraction system, wherein the microchannel extraction system comprises n mixing modules M and n separation modules S, the mixing modules and the separation modules are sequentially spaced, a lower phase solution outlet of each separation module is connected with an inlet of a previous stage of mixing module, an upper phase solution outlet is connected with an inlet of a next stage of mixing module, the lower phase solution outlet and the upper phase solution outlet are repeatedly connected in this way, the extracting agent and a cholesterol crude product solution storage tank are respectively connected by a feeding pump, and a lower phase outlet of each separation module is connected with a feeding pump to control the flow rate; the extractant sequentially enters the mixing module Mn and the separation module Sn, when the extractant occupies about one-half of the volume of the separation module Sn, a Sn lower phase solution discharge port is opened, and the extractant enters the upper-stage mixing module M through a feed pump_n-1Operating in turn, step-by-step counter-current to the microchannel mixing module M₁At this point, the mixing module M begins₁Pumping the crude cholesterol solution into the mixing module M₁Fully mixed and extracted, and enters a separation module S₁Layering, feeding the upper phase solution into a micro-channel mixing module M₂The lower phase solution enters a recovery tank to be evaporated and recovered, and the flow rate of the lower phase solution is the same as that of the extractant; performing continuous countercurrent extraction and separation step by step, analyzing the purity of cholesterol on the phase of each separation module by using gas chromatography until the purity is more than or equal to 99.0%, collecting the phase solution on the separation module, distilling to recover the solvent, and recrystallizing the remainder with ethanol to obtain a target product;

the stage number of the graded continuous countercurrent micro-channel extraction in the step (B) is 1-5, and the volume ratio of the extractant to the cholesterol crude product solution is 1: 1-2;

the mass percentage of the cholesterol in the crude cholesterol product in the step (A) is more than or equal to 85.0 percent, and the weight volume concentration of the cholesterol in the prepared crude cholesterol product solution is 5.0 to 10.0 percent;

in the step (B), the separation module of the extraction system is designed to have larger volume and height-diameter ratio according to the flow of the cholesterol crude product solution and the extractant, so as to ensure the stable separation of two phases.

2. The continuous countercurrent microchannel cholesterol extraction process of claim 1, wherein the mixing module in the extraction system of step (B) is a microchannel reaction/mixing module of various types.