CN107021990B - The preparation method of high-purity selamectin - Google Patents
The preparation method of high-purity selamectin Download PDFInfo
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Abstract
The present invention provides a kind of improved selamectin preparation process, the techniques are as follows: (1) doractin DL is in the presence of Wilson catalyst, hydrogen reducing, obtains intermediate SL1；(2) the intermediate SL1 that step (1) obtains carries out recrystallization purifying using methanol；(3) the intermediate SL1 that step (2) obtains obtains intermediate SL2 through persulfuric acid desugar；(4) the intermediate SL2 that step (3) obtains passes through manganese dioxide, obtains intermediate SL3；(5) the intermediate SL3 that step (4) obtains passes through the oximate of hydroxylamine hydrochloride, obtains selamectin SL；(6) the crude product SL that step (5) obtains is recrystallized three times by toluene, acetone, methanol, obtains SL after purification.
Description
Technical field
The invention belongs to field of medicine production, are related to the preparation method of selamectin, in particular to high-purity selamectin
Preparation method.
Background technique
Avermectins medicine is the one group of Macrocyclolactone lactone kind medicine generated by streptomycete fermentation, can effectively prevent agriculture
Industry pest and a variety of harmful mites, the especially harmful mite to common pesticides with drug resistance and pest have excellent control efficiency.It is right
Crop is comparatively safe, and will not kill natural enemy, is conducive to the ecological balance.Meanwhile Avermectins medicine posts humans and animals
Raw nematode and arthropod class helminth have many advantages, such as to kill effect by force, and with wide spectrum, efficient and less toxic, animal with
And it is very extensive in terms of the control and application of human parasite.In the latest 20 years, using natural avermectin component as parent
It closes object progress structural modification transformation and achieves good progress, ivermectin (Ivermectin), doractin
(Doramectin), moxidectin (Moxidectin), eprinomectin (Eprinomectin) and selamectin
(Selamectin) be successful example, their anthelmintic activity and pharmacokinetic properties compared with parent compound have into
The raising and improvement of one step.
Selamectin (also referred to as hila rhzomorph) by genetic recombination Avid kyowamycin (Streptanyces avem
Itilis) new strains ferment, and are developed by Pfizer pharmacy, and to doractin progress chemical synthesis structural modification
It obtains, in July, 1999 lists in Britain for the first time, trade name Revolution.Its safety improves a lot, and takes orally, injection
There is good result, is a kind of inside and outside insecticide mainly for the adult flea of pet cat and dog, filaria and scabies.Its chemical name
(1- first propyl) -5- deoxidation -22,23- dihydro -5- (oximido)-AVERMECTIN B1 monosaccharide, molecular weight are removed for 25- cyclohexyl -25-
It is 769.96, for white or light yellow crystalline powder.
Chinese patent 94101917.9 is the compound patent of the selamectin of Pfizer Inc's application, the patent
Disclose the structural formula and preparation method of selamectin.It should be the preparation method comprises the following steps: being starting material, first step hydrogenation by doractin
Reaction uses Wilkinson catalyst, and toluene makees solvent preparation formula (II) compound, and second step desugar reaction is using sulfuric acid different
It is carried out in propyl alcohol.Third step oxidation reaction is carried out in anhydrous ether in the presence of activated manganese dioxide.4th step oximation reaction
It is completed in anhydrous pyridine using hydroxylamine hydrochloride.Most get Sai La bacterium is purified through silica gel chromatography and high pressure liquid chromatography afterwards
Element.On the whole, whole route prepares selamectin through over hydrogenation, desugar, oxidation, oximate and silica gel column purification.This technique is
The basic patent process route of selamectin, it is domestic more multi-vendor using the route, but the process overall yields are not high, and each
Intermediate requires silica gel chromatograph separation, and the selamectin crude product finally obtained is also needed by silica gel chromatography and high pressure
Liquid chromatography purification, entire technique are highly detrimental to industrialized production.
Chinese patent 98808106.7 is that follow-on selamectin preparation method of Pfizer Inc's application is special
Benefit, whole route have passed through hydrogenation, oxidation, desugar, oximate, and wherein desugar and oximate are that a step is completed, although the route phase
To shorter, but the toluene or methanol that the purifying of gained final product selamectin uses, both solvents do not have certain several impurity
Removal effect, resulting purification selamectin purity are still not high enough.And whole route yield is relatively low, only about 30%
~35%.
Chinese patent 201210102405.7 discloses the new technique for synthesizing of selamectin, as follows:
But it is lower by the selamectin crude product purity that the technique obtains, from 65.2%-81.2% etc., final step
The reverse phase C18 silica gel preparation higher selamectin of purity is still needed to, it is unfavorable to use industrialized production.
Veterinary drug registration technology requires report in international coordination meeting (VICH) GL 10, identifies and define limit and be respectively
0.10%, the 0.20% and 0.50% multiple unknown impurities of selamectin according to obtained by existing patent level at present are more than identification limit
(0.20%), and we when comparing the former triturate of Pfizer, find these it is more difficult purify in the impurity that goes there are two types of or
Two or more is not known impurities, therefore in imitative medicine process exploitation, and the selamectin that high-purity high-yield how is made will
Seem particularly critical.
Summary of the invention
The present invention provides a kind of improved selamectin preparation process, the route of the technique is as follows:
The present invention the specific process is as follows:
(1) doractin DL is in the presence of Wilson catalyst, hydrogen reducing, obtains intermediate SL1；
(2) the intermediate SL1 that step (1) obtains carries out recrystallization purifying using methanol；
(3) the intermediate SL1 that step (2) obtains obtains intermediate SL2 through persulfuric acid desugar；
(4) the intermediate SL2 that step (3) obtains passes through manganese dioxide, obtains intermediate SL3；
(5) the intermediate SL3 that step (4) obtains passes through the oximate of hydroxylamine hydrochloride, obtains selamectin SL；
(6) the crude product SL that step (5) obtains is recrystallized three times by toluene, acetone, methanol, obtains SL after purification.
Wherein, in step (2), the weight ratio of SL1 and methanol is 1:1~1:3, preferably 1:2；In step (6), SL and toluene
Weight ratio be 1:2~1:3, preferably 1:2.5；In step (6), the weight ratio of SL and acetone by toluene crystallization be 1:1~
1:3, preferably 1:2；In step (6), the weight ratio of SL and methanol by acetone crystallization are 1:1~1:3, preferably 1:2.
Preferably, technique of the invention is as follows:
(1) doractin DL is in the presence of Wilson catalyst, hydrogen reducing, obtains intermediate SL1；
(2) the intermediate SL1 that step (1) obtains carries out recrystallization purifying using methanol, and the weight ratio of SL1 and methanol is 1:
2；
(3) the intermediate SL1 that step (2) obtains obtains intermediate SL2 through persulfuric acid desugar；
(4) the intermediate SL2 that step (3) obtains passes through manganese dioxide, obtains intermediate SL3；
(5) the intermediate SL3 that step (4) obtains passes through the oximate of hydroxylamine hydrochloride, obtains selamectin SL；
(6) the crude product SL that step (5) obtains uses toluene crystallization, and the weight ratio of SL and toluene is 1:2.5；By toluene knot
Brilliant SL reuses acetone and crystallizes, and the weight ratio of SL and acetone is 1:2；Methanol crystallization is finally used by the SL that acetone crystallizes,
The weight ratio of SL and methanol is 1:2.
More specifically, the crystallization purifications of step (2) are as follows: methanol is added in SL1 crude product, after dissolution, stirring is precipitated solid
Body, natural cooling is cooled to room temperature, then is cooled to 15-17 DEG C, stirs, and is centrifuged, dry, obtains SL1 after purification.
More specifically, the crystallization purifications of step (6) are as follows: toluene is added in the crude product SL that step (5) obtains, is warming up to
45-50 DEG C, dissolution, natural cooling is cooled to room temperature, then is cooled to 0-5 DEG C, stirs, and filters, drying.
Acetone is added, is warming up to 40-45 DEG C, the product of previous step is added, all after dissolution, solid, heat preservation is precipitated in solid
40-45 DEG C of stirring, natural cooling are cooled to 10-15 DEG C of stirring, filter, and acetone elution filters, drying.
Methanol is added, is warming up to 40-45 DEG C, is added the product of previous step, after product dissolved clarification, solid is precipitated, keeps the temperature 40-45
DEG C stirring, natural cooling are cooled to 10-15 DEG C, filter, and methanol elution filters, drying.
Grope to test by early period, invention technician's discovery:
(1) route of the present invention is used, during the preparation process, intermediate SL1 does not use refining methanol, and crude product is directly launched and connect
The reaction got off obtains crude product SL, and SL is after toluene, methanol crystallize twice, purity 92%, even if using methanol-toluene
System crystallizes again, and purity promotion is smaller, and only 93.4%, repeat to crystallize using this method does not have purification effect substantially, always receives
Rate but declines to a great extent to 38%.
(2) route of the present invention is used, during the preparation process, intermediate SL1 uses refining methanol, and fine work is directly launched and connect down
The reaction come, obtains crude product SL, SL is after toluene, methanol crystallize twice, purity 96%, even if using methanol-toluene body
System crystallizes again, and purity promotion is smaller, and still only 97.2%, total recovery but declines to a great extent to 32.9%.
(3) using 98808106.7 route and method prepare selamectin, total recovery 31.5%, purity 92.5%,
Yield and purity is not high, even if invention technician is crystallized again using methanol-toluene system, purity 93.5%, and yield
Drop to 21.6%.
During the preparation process, intermediate SL1 can also not use refining methanol to present invention process, and crude product is directly launched and connect down
The reaction come obtains crude product SL, and for SL after toluene, acetone, methanol, acetone four times crystallizations, purity is single miscellaneous up to 99.4%
Content is respectively less than 0.2%.
Compared with prior art, the present invention main technical contribution be SL crystallized three times by toluene, acetone, methanol or
By toluene, acetone, methanol, acetone four times crystallizations, brought beneficial effect is: obtained selamectin finished product
Purity is very high, is greater than 99.4%, and the miscellaneous content of all lists is respectively less than 0.2%.More preferably technical solution is that SL1 uses methanol knot
Brilliant fine work SL1 launches next reaction after purification, obtains crude product SL, and SL is crystallized three times by toluene, acetone, methanol, passed through
Such technical solution not only makes the purity of selamectin be greater than 99.5%, moreover it is possible to guarantee higher total recovery, about
44.6%.
Detailed description of the invention
Fig. 1: the final sterling HPLC figure of the selamectin that embodiment 6 obtains.
Fig. 2: the final sterling HPLC figure of the selamectin that embodiment 7 obtains.
Fig. 3: the final sterling HPLC figure of the selamectin that embodiment 8 obtains.
Fig. 4: the final sterling HPLC figure of the selamectin that embodiment 9 obtains.
Fig. 5: the final sterling HPLC figure of the selamectin that embodiment 10 obtains.
Specific embodiment
Summary of the invention is made further explanation and description below with reference to specific embodiment, still, they are not constituted
Limitation of the scope of the invention or restriction.
The preparation of 1 SL1 crude product of embodiment
40kg DL is added in 300L hydriding reactor, and 184kg acetone vacuumizes N2Displacement 3 times, stops stirring, and Wilkinson is added and urges
Agent, N2Displacement 3 times, H2Displacement 3 times.Stirring is opened, 35-40 DEG C, Hydrogen Vapor Pressure 0.3-0.4Mpa, is reacted 3-4 hours, HPLC prison
Control, DL raw material peak area < 1.0% stop reaction, N2Displacement.40-50 DEG C of water pump reduced pressure of outer bath is evaporated to obtain crude product
40.5kg, purity 88.8%.
The purification of 2 SL1 of embodiment
Methanol 81kg is added into 40.5kg crude product, dissolves quickly, about stirs precipitation solid natural cooling cooling in 5 minutes
To room temperature, then it is cooled to 15-17 DEG C of stirring 10-12 hours, is centrifuged wet product 39kg, 40 DEG C of baking 4h of vacuum drying oven water-bath obtain SL1
Crystalline solid 36kg, purity 96.6%.
The preparation of 3 SL2 of embodiment
36kg SL1 and the 250kg isopropanol that embodiment 2 obtains is added in 1000L stainless steel cauldron, stirs lower muddy shape
State, temperature are that the 13.1kg concentrated sulfuric acid is slowly added dropwise in 20.2 DEG C of, and being about added dropwise 20 minutes terminates, after nitrogen vacuum breaker under nitrogen protection
22-24 DEG C of stir about 0.5h is kept the temperature, system dissolved clarification stirs HPLC monitoring in 2 hours, and SL1 < 6% stops reaction, reaction solution is poured into
In 1000kg ice water, the extraction of 500kg methylene chloride is added, water layer uses 250kg methylene chloride to extract again, merges organic layer, with 5%
Sodium bicarbonate washed once, then every time with 5% brine It three times.The dry 1h of organic addition 35kg anhydrous sodium sulfate, filters
Solid 60kg eluent methylene chloride, concentration dryed product are 36kg, purity 83.5%.
The preparation of 4 SL3 of embodiment
N2Protection, the 36kgSL2 crude product that 570kg methylene chloride is added in 1000L stainless steel cauldron, embodiment 3 obtains stir
Lower addition 72kg electrolytic manganese dioxide is mixed, plus, (20-25 DEG C) of nitrogen protection room temperature is stirred after manganese dioxide is soaked with methylene chloride
1.5-2.5 hours, HPLC monitoring, SL2 < 1.0% stopped reaction, pads diatomite, filters, eluent methylene chloride filter cake, merged filter
Liquid, 45-50 DEG C of water pump concentration of outer bath is dry to obtain crude product 36kg, purity 84.5%.
The preparation of 5 SL crude product of embodiment
N2SL3 the and 330kg isopropanol that embodiment 4 obtains, stirring and dissolving is added in protection, 1000L stainless steel kettle.Heat preservation
10-15 DEG C, vacuum is pumped into the solution that 21.5kg hydroxylamine hydrochloride is dissolved in 60kg distilled water, and used time 1-2 hour, it is broken true to finish nitrogen
Nitrogen protection after sky, 25-30 DEG C of heat preservation are stirred to react 3-5 hours, and HPLC monitoring, SL3 < 1.0% stops reaction, by reaction solution
It being pumped into 1000kg ice water, the extraction of 500kg methylene chloride is added, water layer uses 250kg methylene chloride to extract again, merge organic layer,
It washed once with 5% sodium bicarbonate of 200kg, then primary with 200kg5% brine It.Outer 45-50 DEG C of bath is concentrated with water pump
Dry crude product 36kg, purity 81.7%.
The purification of 6 SL of embodiment
90kg toluene is added into the 36kg crude product that embodiment 5 obtains, is warming up to 45-50 DEG C, dissolution, natural cooling cools down
To room temperature (25-30 DEG C), then it is cooled to 0-5 DEG C of stirring 12-15 hours, filters wet product 45.8kg, 40-43 DEG C of vacuum drying oven water-bath
Dry 12h discharging 26.7kg, purity 92%.
53.4kg acetone is added in 200L stainless steel kettle, is warming up to 40-45 DEG C, is added at one time the product of previous step
Solid is precipitated in 26.7kg, solid quickly after all dissolving, keep the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15
DEG C stirring 5h is filtered, and is eluted with the cold acetone of 3L, filters wet product 23kg, and workshop vacuum drying oven room temperature draws 12h to discharge 20kg, purity
97.3%.
40kg methanol is added in 200L stainless steel kettle, is warming up to 40-45 DEG C, is added at one time the product 20kg of previous step, produces
Solid is slowly precipitated in dissolved clarification to object quickly after about 30 minutes, keeps the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15
DEG C, it filters, a small amount of cold methanol elution filters wet product 17.6kg, dries 15.3kg, purity 99.5%.
The total recovery of embodiment 1 to embodiment 6 is 44.6%, and finished product purity is greater than 99.5%.
Analyze the final sterling of selamectin that embodiment 6 obtains: selamectin purity is 99.518%, total miscellaneous <
0.5%, all miscellaneous equal < 0.2% of list.
Embodiment 7
SL1 preparation:
40g DL is added in 500mL hydriding reactor, and 184g acetone vacuumizes N2Displacement 3 times, stops stirring, and Wilkinson is added and urges
Agent, N2Displacement 3 times, H2Displacement 3 times.Stirring is opened, 35-40 DEG C, Hydrogen Vapor Pressure 0.3-0.4Mpa, is reacted 3-4 hours, HPLC prison
Control, DL raw material peak area < 1.0% stop reaction, N2Displacement.40-50 DEG C of water pump reduced pressure of outer bath is evaporated to obtain crude product 40g,
Purity 88.5%.
SL2 preparation:
40g crude product SL1 and 320g isopropanol obtained in the previous step is added in 1000mL reaction flask, stirs lower cloudy state, temperature
Degree is that the 13.1g concentrated sulfuric acid is slowly added dropwise in 20.2 DEG C of, and being about added dropwise 20 minutes terminates, and 22-24 DEG C of stir about is kept the temperature under nitrogen protection
0.5h system dissolved clarification stirs HPLC monitoring in 2 hours, and SL1 < 6% stops reaction, reaction solution is poured into 1000g ice water, is added
The extraction of 500g methylene chloride, water layer use 250g methylene chloride to extract again, merge organic layer, washed once with 5% sodium bicarbonate, then
With 5% brine It.The dry 1h of organic addition 35g anhydrous sodium sulfate, filters mother liquor concentrations and does 41g, purity 78.2%.
SL3 preparation:
N2570g methylene chloride, 41g SL2 crude product obtained in the previous step stirring is added in protection, 1000mL stainless steel cauldron
Lower addition 72g electrolytic manganese dioxide, plus, (20-25 DEG C) of nitrogen protection room temperature is stirred after manganese dioxide is soaked with methylene chloride
1.5-2.5 hours, HPLC monitoring, SL2 < 1.0% stopped reaction, pads diatomite, filters, eluent methylene chloride filter cake, merged filter
Liquid, 45-50 DEG C of water pump concentration of outer bath is dry to obtain product 42g, purity 79%.
The preparation of SL crude product:
N2The dry 42gSL3 and 330g isopropanol of step concentration, stirring and dissolving is added in protection, 1000mL stainless steel kettle.Heat preservation
10-15 DEG C, vacuum is pumped into the solution that 21.5g hydroxylamine hydrochloride is dissolved in 60g distilled water, used time 1-2 hour, nitrogen protection, heat preservation
25-30 DEG C is stirred to react 3-5 hours, and HPLC monitoring, SL3 < 1.0% stops reaction, and reaction solution is pumped into 1000g ice water, is added
Enter the extraction of 500g methylene chloride, water layer uses 250g methylene chloride to extract again, merges organic layer, is washed with 200g5% sodium bicarbonate
Once, then it is primary with 200g5% brine It.45-50 DEG C of outer bath is concentrated dry crude product 42.5g with water pump.Purity 77.2%.
The crystallization of SL crude product methylbenzene methanol:
60g toluene is added in the 21.5g crude product done to above-mentioned concentration, is warming up to 45-50 DEG C, dissolution, natural cooling cools down
To room temperature (25-30 DEG C), then it is cooled to 0-5 DEG C of stirring 12-15 hours, filters wet product 26g, 40-43 DEG C of vacuum drying oven water-bath baking
12h discharging 12g.Purity 88%.
20g methanol is added in 100mL vial, is warming up to 40-45 DEG C, is added at one time the product 12g of previous step, solid is complete
30 minutes precipitation solids are stirred after portion's dissolution, keep the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15 DEG C of stirring 5h
It filters, is eluted with 20ml cold methanol, filter wet product 11g, vacuum drying oven room temperature draws 12h discharging 8.4g, purity 92%, total recovery
49.1%.
15g methanol is added in 50mL vial, is warming up to 40-45 DEG C, is added at one time the product 8.4g of previous step, keeps the temperature
40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15 DEG C of stirring 5h and filters, and is eluted with 20ml cold methanol, filters wet
Product 11g, vacuum drying oven room temperature draw 12h discharging 7.2g, purity 93%.
The product 7.2g that 20g toluene is added at one time previous step is added in 50mL vial, is warming up to 45-50 DEG C, stirs 6h
Natural cooling is cooled to room temperature (25-30 DEG C), then is cooled to 0-5 DEG C of stirring 12-15 hours, filters wet product 26g, vacuum drying oven water
40-43 DEG C of baking 12h discharging 6.5g of bath, total recovery 38%, purity 93.4%.
Analyze the final sterling of selamectin that embodiment 7 obtains: selamectin purity is 93.465%, total miscellaneous >
6.5%, the miscellaneous > 0.2% of 8 lists.
Embodiment 8
60g toluene is added in the 20gSL crude product that embodiment 7 is obtained, is warming up to 45-50 DEG C, dissolution, natural cooling cools down
To room temperature (25-30 DEG C), then it is cooled to 0-5 DEG C of stirring 12-15 hours, filters wet product 25g, 40-43 DEG C of vacuum drying oven water-bath baking
12h discharging 11.8g, purity 87.7%.
20g acetone is added in 100mL vial, is warming up to 40-45 DEG C, is added at one time product 11.8g obtained in the previous step,
Solid is precipitated in solid quickly after all dissolving, keep the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15 DEG C of stirring 5h
It filters, is eluted with 20ml cold methanol, filter wet product 12g, vacuum drying oven room temperature draws 12h discharging 8g.Purity 92.4%
16g methanol is added in 50mL vial, is warming up to 40-45 DEG C, is added at one time product 8g obtained in the previous step, solid
30 minutes precipitation solids all are stirred after dissolution, keep the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15 DEG C of stirring 5h
It filters, is eluted with 15ml cold methanol, filter wet product 10g, vacuum drying oven room temperature draws 12h discharging 6.5g.Purity 96.8%
10g acetone is added in 50mL vial, is warming up to 40-45 DEG C, is added at one time product 6.5g obtained in the previous step, Gu
Solid is precipitated in body quickly after all dissolving, keep the temperature 40-45 DEG C stirring 5-6 hours, and natural cooling is cooled to 10-15 DEG C of stirring 5h and takes out
Filter is eluted with 20ml cold methanol, filters wet product 8g, and vacuum drying oven room temperature draws 12h discharging 5.5g, purity 99.4%, yield
32%.
Analyze the final sterling of selamectin that embodiment 8 obtains: selamectin purity is 99.424%, single miscellaneous equal
< 0.2%.
Embodiment 9
100g toluene is added in the dry SL crude product 36g of the concentration of above-described embodiment 5, is warming up to 45-50 DEG C, dissolution is naturally cold
But it is cooled to room temperature (25-30 DEG C), then is cooled to 0-5 DEG C of stirring 12-15 hours, filters wet product 44g, vacuum drying oven water-bath 40-
43 DEG C of baking 12h discharging 26g, purity 92.4%.
40g methanol is added in 200mL vial, is warming up to 40-45 DEG C, is added at one time product 26g obtained in the previous step, Gu
Body stirs 30 minutes precipitation solids after all dissolving, keep the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to 10-15 DEG C and stirs
5h suction filtration is mixed, is eluted with 10ml cold methanol, wet product 20g is filtered, vacuum drying oven room temperature draws 12h discharging 17g, purity 96%.
32g methanol is added in 100mL vial, is warming up to 40-45 DEG C, is added at one time product 18g obtained in the previous step, protects
Warm 40-45 DEG C of stirring 5-6 hours, natural cooling was cooled to 10-15 DEG C of stirring 5h and filters, and was eluted with 10ml cold methanol, filtered
Wet product 20g, vacuum drying oven room temperature draw 12h discharging 14g, purity 96.8%
Product 14g obtained in the previous step is added in 100mL vial, and 40g toluene is added, is warming up to 45-50 DEG C of stirring 6h, from
It so cools to room temperature (25-30 DEG C), then is cooled to 0-5 DEG C of stirring 12-15 hours, filter wet product 21g, vacuum drying oven water-bath
40-43 DEG C of baking 12h discharging 11.3g total recovery 32.9%, purity 97.2%.
Analyze the final sterling of selamectin that embodiment 9 obtains: selamectin purity is 97.206%, 3 lists
Miscellaneous > 0.2%.
Embodiment 10
According to the route and method of Chinese invention patent 98808106.7, selamectin is prepared.
SL1 preparation
300g DL is added in 3000mL hydriding reactor, stops stirring after 1500ml acetone stirring dissolved clarification, Wilkinson catalyst is added
5.7g, N2Displacement 3 times.Open stirring at room temperature, Hydrogen Vapor Pressure 0.3-0.4Mpa reacts 7-9 hours, HPLC monitoring, DL raw material peak
Area < 1.0% stops reaction, N2Displacement.40-50 DEG C of water pump reduced pressure is bathed outside filtering insoluble substance mother liquor is evaporated addition acetonitrile
Dry the product 240g of 50 degrees Celsius of vacuum of washing, purity 88.3%.
SL preparation
Above-mentioned SL1 150g is added in 2000ml reaction flask, and the manganese dioxide of activation is added after acetone 1200ml stirring dissolved clarification
362.2g stirs 1-2h at room temperature, and HPLC monitoring pads suction filtered through kieselguhr after reaction, collects mother liquor after solid acetonide elution, will
Isopropanol is added when mother liquor is distilled to small system continues distillation to temperature and rise to 80 DEG C, is made by continuing to distill or isopropanol is added
Volume reaches 500ml and 5ml water is added, be naturally cooling to room temperature be precipitated solid and be stirred overnight suction filtration obtain 50 DEG C of product drying
106g purity 87%.
Above-mentioned SL2 90g is added in 2000ml reaction flask room temperature, and isopropanol 720ml, water 90ml are added with stirring hydroxylamine hydrochloride
28.02g, system are warming up to 40-45 DEG C of gradually dissolved clarification, and insulated and stirred 17h HPLC monitoring reaction terminates, and system is poured into cold
The extraction of 600ml methylene chloride is added in 750ml water, the back extraction of water layer 300ml methylene chloride is primary, organic phase sodium bicarbonate washing one
Secondary, sodium chloride washing is primary, and toluene is added when distilling to small size for organic phase until temperature rises to 110 DEG C, then passes through distillation
Or the mode of addition toluene makes volume 720ml, is down to the suction filtration that is stirred overnight at room temperature and obtains 50 DEG C of drying 52.3g purity of product
91%.
100g methanol is added in 500mL vial, is warming up to 40-45 DEG C, is added at one time SL crude product (toluene crystallization)
52.3g, solid stir 30 minutes precipitation solids after all dissolving, keep the temperature 40-45 DEG C stirring 5-6 hours, natural cooling is cooled to
10-15 DEG C of stirring 5h is filtered, and is eluted with 10ml cold methanol, and wet product 50g is filtered, and vacuum drying oven room temperature draws 12h discharging 43g.Always
Yield 31.5%, purity 92.5%, above data are coincide with 98808106.7.
Reuse the crystallization of methanol-toluene system
90g methanol is added in 500mL vial, 40-45 DEG C is warming up to, after being added at one time methanol crystallization obtained in the previous step
Product 43g, 40-45 DEG C of heat preservation stirring 5-6 hours, natural cooling was cooled to 10-15 DEG C of stirring 5h suction filtration, with the first that 10ml is cold
Alcohol elution, filters wet product 44g, and vacuum drying oven room temperature draws 12h discharging 36g, purity 93.2%
Product 37g obtained in the previous step is added in 200mL vial, and 80g toluene is added, is warming up to 45-50 DEG C of stirring 6h, from
It so cools to room temperature (25-30 DEG C), then is cooled to 0-5 DEG C of stirring 12-15 hours, filter wet product 21g, vacuum drying oven water-bath
40-43 DEG C of baking 12h discharging 29.5g total recovery 21.6%, purity 93.5%.
Analyze the final sterling of selamectin that embodiment 10 obtains: selamectin purity is 93.534%, total miscellaneous
> 6.4%, the miscellaneous > 0.2% of 9 lists.
Claims (6)
1. a kind of preparation process of selamectin:
(1) doractin DL is in the presence of Wilson catalyst, hydrogen reducing, obtains intermediate SL1；
(2) the intermediate SL1 that step (1) obtains carries out recrystallization purifying using methanol；
(3) the intermediate SL1 that step (2) obtains obtains intermediate SL2 through persulfuric acid desugar；
(4) the intermediate SL2 that step (3) obtains passes through manganese dioxide, obtains intermediate SL3；
(5) the intermediate SL3 that step (4) obtains passes through the oximate of hydroxylamine hydrochloride, obtains selamectin SL；
(6) the crude product SL that step (5) obtains is recrystallized three times by toluene, acetone, methanol, obtains SL after purification；
Wherein, the crystallization purifications of step (6) are as follows: toluene is added in the crude product SL that step (5) obtains, is warming up to 45-50 DEG C,
Dissolution, natural cooling is cooled to room temperature, then is cooled to 0-5 DEG C, stirs, and filters, drying；
Acetone is added, is warming up to 40-45 DEG C, the product of previous step is added, solid all after dissolution, is precipitated solid, keeps the temperature 40-45
DEG C stirring, natural cooling is cooled to 10-15 DEG C of stirring, filters, and acetone elution is filtered, dried；
Methanol is added, is warming up to 40-45 DEG C, is added the product of previous step, after product dissolved clarification, solid is precipitated, 40-45 DEG C of heat preservation is stirred
It mixes, natural cooling is cooled to 10-15 DEG C, filters, and methanol elution filters, drying；
In step (6), the weight ratio of SL and toluene is 1:2~1:3, and the weight ratio of SL and acetone by toluene crystallization are 1:1
The weight ratio of~1:3, SL and methanol by acetone crystallization are 1:1~1:3.
2. preparation process as described in claim 1, the weight ratio of SL1 and methanol is 1:1~1:3 in step (2).
3. the weight ratio of preparation process as claimed in claim 2, SL1 and methanol is 1:2.
4. preparation process a method according to any one of claims 1-3, the crystallization purifications of step (2) are as follows: first is added in SL1 crude product
Alcohol, after dissolution, solid is precipitated in stirring, and natural cooling is cooled to room temperature, then is cooled to 15-17 DEG C, is stirred, and is centrifuged, dry, is obtained
SL1 after purification.
5. preparation process as described in claim 1, in step (6), the weight ratio of SL and toluene is 1:2.5, by toluene knot
The weight ratio of brilliant SL and acetone are 1:2, and the weight ratio of SL and methanol by acetone crystallization are 1:2.
6. preparation process a method as claimed in any one of claims 1 to 5, are as follows:
(1) doractin DL is in the presence of Wilson catalyst, hydrogen reducing, obtains intermediate SL1；
(2) the intermediate SL1 that step (1) obtains carries out recrystallization purifying using methanol: methanol is added in SL1 crude product, after dissolution,
Solid is precipitated in stirring, and natural cooling is cooled to room temperature, then is cooled to 15-17 DEG C, stirs, and is centrifuged, dry, obtains after purification
The weight ratio of SL1, SL1 and methanol is 1:2；
(3) the intermediate SL1 that step (2) obtains obtains intermediate SL2 through persulfuric acid desugar；
(4) the intermediate SL2 that step (3) obtains passes through manganese dioxide, obtains intermediate SL3；
(5) the intermediate SL3 that step (4) obtains passes through the oximate of hydroxylamine hydrochloride, obtains selamectin SL；
(6) the crude product SL that step (5) obtains is recrystallized three times by toluene, acetone, methanol: toluene being added in crude product SL, heats up
To 45-50 DEG C, dissolution, natural cooling is cooled to room temperature, then is cooled to 0-5 DEG C, stirs, and filters, drying；
Acetone is added, is warming up to 40-45 DEG C, the product of previous step is added, solid all after dissolution, is precipitated solid, keeps the temperature 40-45
DEG C stirring, natural cooling is cooled to 10-15 DEG C of stirring, filters, and acetone elution is filtered, dried；
Methanol is added, is warming up to 40-45 DEG C, is added the product of previous step, after product dissolved clarification, solid is precipitated, 40-45 DEG C of heat preservation is stirred
It mixes, natural cooling is cooled to 10-15 DEG C, filters, and methanol elution filters, and drying obtains SL after purification, wherein SL and toluene
Weight ratio be 1:2.5, the weight ratio of SL and acetone by toluene crystallization is 1:2, the SL's and methanol by acetone crystallization
Weight ratio is 1:2.
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| KR102020062B1 (en) * | 2017-11-17 | 2019-09-10 | 주식회사 종근당바이오 | New Selamectin Intermediates, Preparation Method Thereof And Preparation Method For Selamectin Using The Same |
| CN109734760A (en) * | 2018-11-01 | 2019-05-10 | 丽珠集团新北江制药股份有限公司 | A kind of preparation method of doractin impurity |
| CN111116692A (en) * | 2020-01-14 | 2020-05-08 | 北大方正集团有限公司 | Synthesis method of high-purity selamectin |
| CN114106071A (en) * | 2021-11-11 | 2022-03-01 | 浙江荣耀生物科技股份有限公司 | Synthesis method of selamectin |
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| WO1994029328A1 (en) * | 1993-06-12 | 1994-12-22 | Pfizer Limited | Antiparasitic agents |
| CN1141044A (en) * | 1994-02-16 | 1997-01-22 | 美国辉瑞有限公司 | Antiparasitic agents |
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