CN114426552A

CN114426552A - Stable artemisinin preparation method

Info

Publication number: CN114426552A
Application number: CN202111236200.3A
Authority: CN
Inventors: 郭建钊; 郭宇鹏; 王娅娟
Original assignee: Henan Tianyuan Pharmaceutical Research Co ltd
Current assignee: Henan Tianyuan Pharmaceutical Research Co ltd
Priority date: 2021-10-22
Filing date: 2021-10-22
Publication date: 2022-05-03

Abstract

The invention discloses a stable artemisinin preparation method, which comprises the following steps: dissolving sodium borohydride in the first portion of methanol solution to form a homogeneous sodium borohydride methanol solution; adding artemisinin into the second methanol solution, stirring and mixing to obtain artemisinin solution; adding the sodium borohydride methanol solution prepared in the step one into the artemisinin solution prepared in the step two, and continuously stirring for reaction; after the reaction is finished, adding a hydrochloric acid solution to decompose redundant sodium borohydride, then slowly dripping purified water, separating out white floccules, and carrying out suction filtration and drying to obtain the dihydroartemisinin. The method changes the feeding mode of sodium borohydride, completely dissolves the sodium borohydride in the methanol solution to form uniform liquid, and adds the uniform liquid into the reaction system in a liquid phase form to avoid the adverse effect of solid-liquid suspension on the reaction.

Description

Stable artemisinin preparation method

Technical Field

The invention relates to the technical field of organic drug synthesis, in particular to a stable artemisinin preparation method.

Background

Dihydroartemisinin is a derivative of artemisinin, and the antimalarial effect is 48 times that of artemisinin. Dihydroartemisinin is easily soluble in chloroform and can be dissolved in propanol, methanol or ethanol. Almost insoluble in water, because the dihydroartemisinin has good curative effect on malaria, more researches on synthesizing the dihydroartemisinin by utilizing the arteannuin at home and abroad are carried out. Regarding the preparation process of dihydroartemisinin, the prior art mainly uses artemisinin as a raw material and sodium borohydride as a reducing agent. Most of the synthesis methods use sodium borohydride solid as a reducing agent. However, from the reaction mechanism of synthesizing dihydroartemisinin from artemisinin, it is known that sodium borohydride reduces ketone, essentially by nucleophilic addition of hydride to carbonyl, BH 4-acts as a donor of a strong reducing agent H-which is irreversibly attached to the carbon atom of the carbonyl as a strong nucleophile. Solid sodium borohydride is slowly added into a reaction system in batches, but the reaction is inconvenient to operate and difficult to control because the reaction heat release is large and a large amount of gas is generated, so that the reaction liquid overflows to cause danger, and great danger is brought to experiments and production.

Disclosure of Invention

The invention aims to provide a stable artemisinin preparation method to solve the problems in the background technology.

In order to achieve the purpose, the invention provides the following technical scheme: a method for preparing stable artemisinin comprises the following steps:

step one, dissolving sodium borohydride in a first methanol solution to form a uniform methanol solution of sodium borohydride;

step two, adding artemisinin into the second methanol solution, stirring and mixing to obtain artemisinin solution;

step three, adding the sodium borohydride methanol solution prepared in the step one into the artemisinin solution in the step two, and continuously stirring for reaction;

and step four, after the reaction is finished, adding a hydrochloric acid solution to decompose redundant sodium borohydride, then slowly dropwise adding purified water, separating out white floccules, and performing suction filtration and drying to obtain the dihydroartemisinin.

Preferably, 4.5g of sodium borohydride measured in the first step is dissolved in 200ml of the first portion of methanol solution;

in step two 28g of artemisinin were measured and dissolved in 50ml of a second portion of formaldehyde solution and kept under stirring at 10 ℃ for 20min in step two.

Preferably, 11g of calcium chloride is also added in step two.

Preferably, the stirring is continued for 30min in step three at a stirring speed of 600r/min, maintaining 10 ℃.

Preferably, 45mL of 20% hydrochloric acid solution is added in the fourth step to decompose the excess sodium borohydride, and 300mL of purified water is added dropwise.

Preferably, after the sodium borohydride in the reaction system of the fourth step is decomposed, the whole system is stirred for 10min at a stirring speed of 50r/min, stands for 30min, and is centrifugally filtered to obtain purified crystals.

Preferably, the purified crystal obtained by centrifugal filtration is dried at the temperature of 55-65 ℃ for 2-4 h.

Preferably, the third step is performed in a closed stirring device, the stirring device comprises a supporting plate fixed on the bottom plate, a U-shaped frame rotatably installed on the supporting plate, and a stirring cylinder arranged on the inner side of the U-shaped frame, a second stirring paddle is rotatably installed at the bottom end inside the stirring cylinder, an upper cover is arranged above the stirring cylinder, a screw rod in threaded connection with the U-shaped frame is connected to one side of the upper cover along the vertical direction, a first motor is fixedly installed on the other side of the upper cover, and the output end of the first motor is in driving connection with the first stirring paddle.

Preferably, a second motor is fixedly installed on the end face of the outer side of the supporting plate, the output end of the second motor is in driving connection with a rotating shaft, and the rotating shaft penetrates through the supporting plate and then is fixedly connected with the middle of the U-shaped frame.

Preferably, the fixed fluted disc that has cup jointed on the pivot, the both ends that upper cover one side was kept away from to U type frame are provided with first band pulley and second band pulley respectively, the belt has been cup jointed between first band pulley and the second band pulley, the fixed head rod that has cup jointed in the middle part of first band pulley, the head rod extends to in the inside recess of U type frame along its length direction, and the terminal fixedly connected with fluted disc of head rod meshes the gear, one side fixed mounting that the upper cover was kept away from to U type frame has the base that is used for installing the churn, the center department of base rotates installs the joint piece, the center department fixedly connected with second connecting rod of second band pulley, the second connecting rod extends through behind the base along its axial with joint piece fixed connection, the outside that the bottom of second stirring rake is located the churn is formed with the spacing draw-in groove with joint piece looks adaptation.

Compared with the prior art, the invention provides a stable artemisinin preparation method, which has the following beneficial effects:

(1) the method changes the feeding mode of sodium borohydride, completely dissolves the sodium borohydride in the methanol solution to form uniform liquid, and adds the uniform liquid into the reaction system in a liquid phase form, thereby avoiding the adverse effect of solid-liquid suspension on the reaction.

(2) When the artemisinin solution is prepared, calcium chloride is added into the artemisinin and formaldehyde solution and is used as Lewis acid, so that the reaction process can be accelerated, the reaction time is shortened, the reaction stability is improved, and the reaction conversion rate is also obviously improved in a reaction system.

(3) Artemisinin solution and sodium borohydride methanol solution react in the agitating unit in reverse, and the churn is rotary motion in vertical direction for the backup pad, and meanwhile, the first stirring rake of upper cover and the second stirring rake of churn bottom stir simultaneously, and when mixed liquid and churn rotate jointly, disturbed by two stirring rakes again, consequently can make the abundant contact reaction of mixed liquid, and then improved the reaction conversion rate.

Drawings

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention without limiting the invention in which:

FIG. 1 is a schematic view of the overall structure of a stirring apparatus according to the present invention;

FIG. 2 is a schematic view of the immersion-stirring apparatus of the present invention with the stirring cylinder removed;

FIG. 3 is a schematic structural view of the U-shaped frame of FIG. 2 after being half-cut;

FIG. 4 is a schematic view of another angle of the stirring device of the present invention;

FIG. 5 is a schematic view of a half-section structure of the mixing drum;

FIG. 6 is a schematic structural view of a mixing drum;

fig. 7 is a schematic view of an assembly structure of the clamping block and the base.

In the figure: 1. a base plate; 2. a support plate; 3. a fluted disc; 4. a U-shaped frame; 5. a first pulley; 6. a belt; 7. a second pulley; 8. a base; 9. a mixing drum; 10. an upper cover; 11. a first motor; 12. a first stirring paddle; 13. a screw; 14. a rotating shaft; 15. a first connecting rod; 16. A gear; 17. a second connecting rod; 18. a groove; 19. a second motor; 20. a second stirring paddle; 21. a limiting clamping groove; 22. and a clamping block.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. The components of embodiments of the present invention generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations. Thus, the following detailed description of the embodiments of the present invention, presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention.

In the description of the embodiments of the present invention, it should be understood that the terms "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", etc. indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience in describing embodiments of the present invention and simplifying the description, but do not indicate or imply that the device or element referred to must have a particular orientation, be constructed in a particular orientation, and be operated, and thus should not be construed as limiting the embodiments of the present invention.

The embodiment discloses a stable artemisinin preparation method, which comprises the following steps:

step one, measuring 4.5g of sodium borohydride and dissolving the sodium borohydride in 200ml of first methanol solution to form a uniform sodium borohydride methanol solution.

And step two, weighing 28g of artemisinin and 11g of calcium chloride, dissolving the artemisinin and the calcium chloride in a second 50ml of formaldehyde solution, keeping the temperature at 10 ℃ and continuously stirring for 20min to obtain an artemisinin solution, wherein the calcium chloride is used as Lewis acid, so that the reaction process can be accelerated, the reaction time can be shortened, the reaction stability can be improved, and the reaction conversion rate can be obviously improved.

And step three, adding the sodium borohydride methanol solution prepared in the step one into the artemisinin solution in the step two, and keeping the temperature at 10 ℃ and continuously stirring for 30min at the stirring speed of 600 r/min.

And step four, after the reaction is finished, adding 45mL of 20% hydrochloric acid solution to decompose redundant sodium borohydride, then slowly dropwise adding 300mL of purified water, stirring the whole system at a stirring speed of 50r/min for 10min, standing for 30min, separating out white floccules, drying the white floccules obtained by centrifugal filtration at the drying temperature of 55-65 ℃ for 2-4 h, and obtaining the dihydroartemisinin.

As a preferred example, in order to make the sodium borohydride methanol solution and the artemisinin solution react sufficiently and increase the reaction conversion rate, step three in the present application is performed in a closed stirring device.

As shown in fig. 1-7, the stirring device includes a supporting plate 2 fixed on a bottom plate 1, a U-shaped frame 4 rotatably installed on the supporting plate 2, and a stirring barrel 9 disposed inside the U-shaped frame 4, a second stirring paddle 20 rotatably installed at the bottom end inside the stirring barrel 9, an upper cover 10 is disposed above the stirring barrel 9, one side of the upper cover 10 is connected with a screw 13 in threaded connection with the U-shaped frame 4 along the vertical direction, the other side is fixedly installed with a first motor 11, an output end of the first motor 11 is connected with a first stirring paddle 12 in a driving manner, after the sodium borohydride methanol solution and the artemisinin solution are mixed and loaded into the stirring barrel 9, the stirring barrel 9 is sealed by the upper cover 10, then the stirring barrel 9 makes a rotational movement in the vertical direction relative to the supporting plate 2, and at the same time, the first stirring paddle 12 on the upper cover 10 and the second stirring paddle 20 at the bottom of the stirring barrel 9 perform stirring simultaneously, the mixed liquid and the mixing drum 9 rotate together and are disturbed by the two stirring paddles, so that the mixed liquid can be in full contact reaction, and the reaction conversion rate is further improved.

The end face of the outer side of the supporting plate 2 is fixedly provided with a second motor 19, the output end of the second motor 19 is in driving connection with a rotating shaft 14, the rotating shaft 14 penetrates through the supporting plate 2 and then is fixedly connected with the middle part of the U-shaped frame 4, and the U-shaped frame 4 drives the stirring cylinder 9 to rotate on the supporting plate 2 and then is driven by the second motor 19.

Further, a fluted disc 3 is fixedly sleeved on the upper portion of the rotating shaft 14, a first belt wheel 5 and a second belt wheel 7 are respectively arranged at two ends of one side of the U-shaped frame 4, which is far away from the upper cover 10, a belt 6 is sleeved between the first belt wheel 5 and the second belt wheel 7, a first connecting rod 15 is fixedly sleeved in the middle of the first belt wheel 5, the first connecting rod 15 extends into a groove 18 in the U-shaped frame 4 along the length direction, a gear 16 meshed with the fluted disc 3 is fixedly connected to the tail end of the first connecting rod 15, a base 8 for mounting the stirring cylinder 9 is fixedly mounted at one side of the U-shaped frame 4, which is far away from the upper cover 10, a clamping block 22 is rotatably mounted at the center of the base 8, a second connecting rod 17 is fixedly connected to the center of the second belt wheel 7, the second connecting rod 17 extends through the base 8 along the axial direction thereof and then is fixedly connected with the clamping block 22, a limiting clamping groove 21 matched with the clamping block 22 is formed at the bottom of the second stirring paddle 20, which is located at the outer side of the stirring cylinder 9, after the mixing drum 9 holds the mixed liquid, the mixed liquid is placed on the base 8, the limiting clamping groove 21 at the bottom of the mixing drum 9 is aligned with the clamping block 22 and inserted into the base 8, then the screw 13 is rotated to drive the upper cover 10 to move towards the direction of the mixing drum 9 to seal the mixing drum, at the moment, the second motor 19 is started to drive the rotating shaft 14 to rotate, the rotating shaft 14 drives the U-shaped frame 4 to rotate, the fluted disc 3 that its outside cup jointed is also rotatory with it in step, fluted disc 3 meshes with gear 16 mutually and drives the rotation of head rod 15, the first band pulley 5 of the head rod 15 other end is rotatory, it is rotatory that first band pulley 5 is rotatory to drive second band pulley 7 through belt 6, it is rotatory that second band pulley 7 is rotatory to drive joint piece 22 through second connecting rod 17, joint piece 22 is owing to with the joint of second stirring rake 20, consequently can drive the rotatory stirring that realizes mixing the liquid of second stirring rake 20.

When the stirring device is used, after the sodium borohydride methanol solution and the artemisinin solution are mixed in the stirring cylinder 9, the mixing drum 9 is inserted on the base 8, the upper cover 10 is driven by the rotating screw 13 to move towards the direction of the mixing drum 9 to seal the mixing drum, at the moment, the second motor 19 is started, the second motor 19 drives the U-shaped frame 4 through the rotating shaft 14 to drive the mixing drum 9 to rotate on the supporting plate 2, meanwhile, the fluted disc 3 is meshed with the gear 16 to drive the first connecting rod 15 to rotate, the first belt wheel 5 at the other end of the first connecting rod 15 rotates, the first belt wheel 5 rotates to drive the second belt wheel 7 to rotate through the belt 6, the second belt wheel 7 rotates to drive the clamping block 22 to rotate through the second connecting rod 17, the clamping block 22 is clamped with the second stirring paddle 20, therefore, the second stirring paddle 20 is driven to rotate to stir the mixed liquid, and the first stirring paddle 12 is driven by the first motor 11 independently to work.

In the description of the present invention, the terms "first", "second", "another", and "yet" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more features. In the description of the embodiments of the present invention, "a plurality" means two or more unless specifically limited otherwise.

In the description of the present invention, it is to be noted that, unless otherwise explicitly specified or limited, the terms "connected" and "connected" are to be interpreted broadly, e.g., as being fixed or detachable or integrally connected; can be mechanically or electrically connected; may be directly connected or indirectly connected through an intermediate. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art. In addition, in the description of the present invention, "a plurality" means two or more unless otherwise specified.

While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A method for preparing stable artemisinin is characterized by comprising the following steps:

2. The method for preparing stable artemisinin according to claim 1, wherein in step one 4.5g of sodium borohydride is taken and dissolved in 200ml of the first portion of methanol solution;

3. The method of claim 2, wherein 11g of calcium chloride is added in step two.

4. The method of claim 2 or 3, wherein the temperature of 10 ℃ is maintained at 600r/min for 30 min.

5. The method of claim 4, wherein 45mL of 20% HCl solution is added to decompose excess sodium borohydride, and 300mL of purified water is added dropwise.

6. The method of claim 1 or 5, wherein after the decomposition of sodium borohydride in the reaction system of step four, the whole system is stirred at a stirring speed of 50r/min for 10min, left to stand for 30min, and centrifuged to obtain purified crystals.

7. The method for preparing stable artemisinin according to claim 6, wherein the purified crystals obtained by centrifugal filtration are dried at 55-65 ℃ for 2-4 h.

8. The stable artemisinin preparation method according to any one of claims 1-3, 5 and 7, wherein the step three is performed in a closed stirring device, the stirring device comprises a support plate (2) fixed on a bottom plate (1), a U-shaped frame (4) rotatably mounted on the support plate (2), and a stirring barrel (9) arranged on the inner side of the U-shaped frame (4), a second stirring paddle (20) is rotatably mounted at the bottom end inside the stirring barrel (9), an upper cover (10) is arranged above the stirring barrel (9), one side of the upper cover (10) is vertically connected with a screw (13) in threaded connection with the U-shaped frame (4), the other side of the upper cover is fixedly mounted with a first motor (11), and the output end of the first motor (11) is in driving connection with a first stirring paddle (12).

9. The method for preparing stable artemisinin according to claim 8, wherein a second motor (19) is fixedly mounted on the outer end face of the support plate (2), the output end of the second motor (19) is connected with a rotating shaft (14) in a driving manner, and the rotating shaft (14) penetrates through the support plate (2) and then is fixedly connected with the middle part of the U-shaped frame (4).

10. The stable artemisinin preparation method according to claim 9, wherein a fluted disc (3) is fixedly sleeved on a rotating shaft (14), a first belt wheel (5) and a second belt wheel (7) are respectively arranged at two ends of one side of a U-shaped frame (4) far away from an upper cover (10), a belt (6) is sleeved between the first belt wheel (5) and the second belt wheel (7), a first connecting rod (15) is fixedly sleeved in the middle of the first belt wheel (5), the first connecting rod (15) extends into a groove (18) inside the U-shaped frame (4) along the length direction of the first connecting rod, a gear (16) meshed with the fluted disc (3) is fixedly connected to the tail end of the first connecting rod (15), a base (8) used for mounting a stirring barrel (9) is fixedly mounted at one side of the U-shaped frame (4) far away from the upper cover (10), a clamping block (22) is rotatably mounted at the center of the base (8), fixedly connected with second connecting rod (17) is located at the center of second band pulley (7), and second connecting rod (17) extend through base (8) back and joint piece (22) fixed connection along its axial, and the bottom of second stirring rake (20) is located the outside of churn (9) and is formed with spacing draw-in groove (21) with joint piece (22) looks adaptation.