CN106831811A - A kind of method for preparing high content nimoctin - Google Patents

A kind of method for preparing high content nimoctin Download PDF

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Publication number
CN106831811A
CN106831811A CN201710239714.1A CN201710239714A CN106831811A CN 106831811 A CN106831811 A CN 106831811A CN 201710239714 A CN201710239714 A CN 201710239714A CN 106831811 A CN106831811 A CN 106831811A
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nimoctin
oxygen
protection group
reaction
preparing
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CN106831811B (en
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戴耀
李贺先
刘玲玲
赵宇航
王荣良
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Inner Mongolia Ruimi Fine Chemical Co
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Inner Mongolia Ruimi Fine Chemical Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a kind of method for preparing high content nimoctin, belong to technical field of organic chemistry.The method is with 5 oxygen after crystallization and purification（Protection group）23 oxo nimoctins are raw material, by reduction, deprotection and silica gel post separation, obtain high content nimoctin, gained nimoctin HPLC purity >=95.0A%, content >=93.0wt.%.The method should have post processing simple, and post separation number of times is few and the advantages of nimoctin content high.

Description

A kind of method for preparing high content nimoctin
Technical field
The present invention relates to the preparing technical field of nimoctin in organic chemistry, and in particular to one kind prepares high content Buddhist nun not The method in gram spit of fland.
Background technology
Nimoctin（Nemadectin）It is a kind of ten hexa-atomic macrolides antibiosis produced by cyaneogriseus streptomyces fermentation Element（J.Chem.Soc.,Chem.Commun.,1987,(6), 402-404）, it is a kind of anti-parasite medicine.Nimoctin is again Through further chemical modification, first oximido group is introduced at its 23（=N-OCH3）Activity insecticide Moses gram higher can be obtained Spit of fland（Moxidectin）, the product should be extensively at present a kind of wide spectrum, efficient, Novel macrocyclic lactone expelling parasite in veterinary clinic Antibiotic.
Cyaneogriseus streptomyces during the fermentation except generate nimoctin in addition to, while also produce various structures analog, this A little impurity compositions are difficult to remove.The nimoctin of high content is prepared at present, and main method is inhaled by different types of macropore Attached resin carries out multiple post separation and is isolated and purified, yet with fermentation process produce analogue in resin column Property is also similar to very much, can not effectively be removed even across separating for several times enrichment, the usual ＜ of gained nimoctin content 90wt.%（CN101372492,2008；CN103588784,2013）.
But need often to use in the technical process of nimoctin fermenting step and production moxidectin>90Wt.% High content nimoctin（As standard items）Carry out technology assessment.Current content>The nimoctin standard items price of 90wt.% Hundreds thousand of units/gram, price is very expensive, and be difficult purchase.Therefore, exploitation one kind prepares content>The Buddhist nun of 90wt.% is not Gram spit of fland method has practical significance very much.
The content of the invention
In order to overcome the low problem of nimoctin product content present in prior art, the present invention to provide one kind and prepare height The method of content nimoctin, the method has post processing simple, and post separation number of times is few and the advantages of nimoctin content high.
To achieve the above object, the technical solution adopted by the present invention is as follows：
A kind of method for preparing high content nimoctin, the method is with the 5- oxygen after crystallization and purification（Protection group）- 23- oxo Buddhist nuns Mack spit of fland or 5- oxygen（Protection group）- 23- first oxime nimoctins high content nimoctin for raw material is prepared.Wherein：When With the 5- oxygen after crystallization and purification（Protection group）- 23- oxos nimoctin for raw material prepare when, first pass around reduction reaction and obtain 5- Oxygen（Protection group）- nimoctin, then nimoctin crude product is obtained by protective reaction, it is finally to obtain using silica gel post separation The high content nimoctin；5- oxygen after with crystallization and purification（Protection group）- 23- first oxime nimoctins for raw material prepare when, 5- oxygen is obtained by de-oxime reaction first（Protection group）- 23- oxo nimoctins, then obtain 5- oxygen by reduction reaction（Protect Shield base）- nimoctin, then nimoctin crude product is obtained by protective reaction, it is finally to obtain described using silica gel post separation High content nimoctin.
The 5- oxygen（Protection group）- 23- oxos nimoctin and 5- oxygen（Protection group）Guarantor in -23- first oxime nimoctins Shield base is 4- nitro benzoyls or 4- chlorophenoxy acetyl group.
5- oxygen after the crystallization and purification（Protection group）- 23- oxos nimoctin or 5- oxygen（Protection group）- 23- first oxime Buddhist nuns Mack spit of fland refers to raw materials used 5- oxygen（Protection group）- 23- oxos nimoctin or 5- oxygen（Protection group）- 23- first oxime nimoctins Purity >=95%, acquisition can be prepared by the method in patent CN1051043 or CN104017001.
The present invention is prepared during high content nimoctin, and the go back original reagent used in the reduction reaction is hydroboration Sodium, reaction dissolvent is methyl alcohol or ethanol；
The reduction reaction detailed process is：
In 5- oxygen（Protection group）Reaction dissolvent is added in -23- oxo nimoctins（Methyl alcohol or ethanol）, breast is obtained after stirring White suspension, adds sodium borohydride under the conditions of 0 ~ 5 DEG C, after insulated and stirred 0.5-3.0h, reaction solution is poured into water, and uses dichloro Ethane is obtained by extraction 5- oxygen（Protection group）- nimoctin；Wherein：5- oxygen（Protection group）- 23- oxos nimoctin and sodium borohydride Part by weight be 4：（0.4-1.5）.
The deprotection reagent that the protective reaction is used is 3-5wt.% sodium hydrate aqueous solutions, and reaction dissolvent is alcohols （Methyl alcohol or ethanol）The mixed solvent constituted with dichloromethane or dichloroethanes；
The protective reaction detailed process is：
By the 5- oxygen（Protection group）- nimoctin reaction dissolvent it is molten it is clear after be cooled to -10 ~ -7 DEG C, add NaOH molten Be poured into water for gained reaction solution by liquid, insulated and stirred 5-8h, is extracted with dichloroethanes and obtains nimoctin crude product；Wherein：5- oxygen （Protection group）- nimoctin is 4 with the part by weight of sodium hydroxide solution：（0.4-1.0）.
The de- oxime reagent that the de-oxime reaction is used is hydrochloric acid（Hydrogen chloride）, reaction dissolvent is dioxane, dichloroethanes Or the mixed solvent system that methyl alcohol is constituted with water；
The de-oxime reaction detailed process is：
In the 5- oxygen（Protection group）Add reaction dissolvent molten clear in -23- first oxime nimoctins, be subsequently added concentration 36wt.%'s Hydrochloric acid, is heated to 50-60 DEG C of insulated and stirred 8-10h；Gained reaction solution is poured into water, is extracted with dichloroethanes and is obtained 5- oxygen （Protection group）- 23- oxo nimoctins；Wherein：5- oxygen（Protection group）The weight of -23- first oxime nimoctins and 36wt.% hydrochloric acid Ratio is 4：（8-12）.
The use of silica gel mesh number is 100 ~ 300 mesh in the silica gel column separation process, eluant, eluent be petroleum ether or normal heptane with The mixed solvent of ethyl acetate composition.
The high content nimoctin obtained using above-mentioned technique of the invention, its purity >=95.0A %, nimoctin content >= 93.0wt.%。
The principle of the invention is as follows：
5- oxygen（Protection group）- 23- oxos nimoctin and 5- oxygen（Protection group）- 23- first oximes nimoctin can using crystallize into Row is isolated and purified, and is effectively removed due to the analogue that fermentation is produced（CN1051043,1990；CN104017001,2014）. The present invention is with the 5- oxygen after crystallization and purification（Protection group）- 23- oxo nimoctins（Purity >=95%）For raw material is first passed around also Original reaction obtains 5- oxygen（Protection group）- nimoctin, then be that can obtain nimoctin by protective reaction, finally using silica gel Post simple separation can obtain high content nimoctin.Because raw material is by crystallization and purification, the analogue for producing that ferments is big Part has removed, and chemical reaction process can't increase analogue impurity as fermentation process, therefore, gained Buddhist nun is not Gram spit of fland crude product can obtain high content nimoctin by simple silica gel post separation.If same with the 5- oxygen after crystallization and purification （Protection group）- 23- first oxime nimoctins（Purity >=95%）5- oxygen is obtained for raw material only needs to one step de-oxime reaction of increase（Protection Base）- 23- oxo nimoctins, later step with 5- oxygen（Protection group）- 23- oxos nimoctin is stock preparation process phase Together.Its reaction process such as following formula（1）：
（1）
Formula（1）In, P is protection group, specially 4- nitro benzoyls or 4- chlorophenoxy acetyl group, and its molecular formula is as follows respectively Formula（2）With（3）.
（2）（3）
The beneficial effects of the invention are as follows：
The method that the present invention prepares high content nimoctin, is with by the 5- oxygen after crystallization and purification（Protection group）- 23- oxo Buddhist nuns Mack spit of fland or 5- oxygen（Protection group）- 23- first oximes nimoctin is raw material, the analogue produced by fermentation in crystallization process Major part has been removed, and chemical reaction process can't increase analogue impurity as fermentation process, therefore, gained Buddhist nun Mack spit of fland crude product can obtain high content nimoctin by silica gel post separation（Purity >=96.0%, content >=93.0wt.%）, tool There is post processing simple, post separation number of times is few and the advantages of nimoctin content high.
Brief description of the drawings
Fig. 1 is high content nimoctin HPLC spectrograms.
Specific embodiment
Below in conjunction with drawings and Examples in detail the present invention is described in detail.
Embodiment 1
The technological process that the present embodiment prepares high content nimoctin is as follows：
（1）Reduction reaction：
5- oxygen is added in 100mL there-necked flasks（4- nitro benzoyls）- 23- oxo nimoctins 4.0g（5.0mmol, 1.0eq, HPLC purity 95.0A%, white powder）, add methyl alcohol 40.0g to obtain milky suspension after stirring, it is put into ice-water bath cold But to 0 ~ 5 DEG C, it is dividedly in some parts sodium borohydride 567mg（15.0mmol, 3.0eq）, rear insulated and stirred 1.0h is added, reaction solution is fallen Enter in 40.0g water, extracted at twice with dichloroethanes 40.0g, gained oil reservoir negative pressure revolving takes off dry solvent and obtains faint yellow 5- oxygen （4- nitro benzoyls）- nimoctin 4.0g（4.9mmol, HPLC purity 94.0A%）.
（2）Protective reaction：
By step（1）Gained 5- oxygen（4- nitro benzoyls）- nimoctin 4.0g（4.9mmol, 1.0eq）Use dichloroethanes （20.0g）And methyl alcohol（20.0g）Mixed solvent it is molten it is clear after be transferred to 100mL there-necked flasks, be put into low temperature bath and be cooled to -10 ~ -7 DEG C, add 4% sodium hydroxide solution 0.5g（0.5mmol, 0.1eq）, gained reaction solution pours into 40.0g water by insulated and stirred 6.0h In, being extracted at twice with dichloroethanes 20.0g, gained oil reservoir negative pressure revolving takes off dry solvent and obtains faint yellow nimoctin crude product 4.1g（Deduct HPLC purity 95.2A% after by-product 4- nitrobenzene methyls）.
（3）Silica gel post separation：
Nimoctin crude product loading is to equipped with silica gel 20.0g（200 ~ 300 mesh）Chromatographic column in, use petroleum ether and ethyl acetate Mixed solvent system carry out affording high content nimoctin 3.0g（HPLC purity 96.1A%, content 93.4wt.%, white Solid）, spectrogram such as Fig. 1.
Embodiment 2
The technological process that the present embodiment prepares high content nimoctin is as follows：
（1）Reduction reaction：
5- oxygen is added in 250mL there-necked flasks（4- chlorophenoxy acetyl group）- 23- oxo nimoctins 8.1g（10.0mmol, 1.0eq, HPLC purity 96.2A%, white powder）, add methyl alcohol 81.0g to obtain milky suspension after stirring, it is put into ice Water-bath is cooled to 0 ~ 5 DEG C, is dividedly in some parts sodium borohydride 1135mg（30.0mmol, 3.0eq）, rear insulated and stirred 1.0h is added, will Reaction solution is poured into 80.0g water, is extracted at twice with dichloroethanes 80.0g, and gained oil reservoir negative pressure revolving takes off dry solvent and obtains light Yellow 5- oxygen（4- chlorophenoxy acetyl group）- nimoctin 8.0g（9.8mmol, HPLC purity 96.0A%）.
（2）Protective reaction：
Above-mentioned 5- oxygen（4- chlorophenoxy acetyl group）- nimoctin 8.0g（9.8mmol, 1.0eq）Use dichloroethanes 40.0g, first Alcohol 40.0g it is molten it is clear after be transferred to 250mL there-necked flasks, be put into low temperature bath and be cooled to -10 ~ -7 DEG C, add 4% sodium hydroxide solution 0.5g（1.0mmol, 0.1eq）, insulated and stirred 6.0h pours into 80.0g water reaction solution, with dichloroethanes 40.0g at twice Extraction, gained oil reservoir negative pressure revolving takes off dry solvent and obtains faint yellow nimoctin crude product 8.2g（Deduct by-product 4- chlorophenoxy second HPLC purity 95.9A% after sour methyl esters）.
（3）Silica gel post separation：
Above-mentioned crude product loading is to equipped with silica gel 40.0g（200 ~ 300 mesh）Chromatographic column in, use petroleum ether, ethyl acetate mix Dicyandiamide solution carries out affording nimoctin 6.1g（HPLC purity 96.3A%, content 94.0wt.%, white solid）.
Embodiment 3
The technological process that the present embodiment prepares high content nimoctin is as follows：
（1）De-oxime reaction：
5- oxygen is added in 100mL there-necked flasks（4- nitro benzoyls）- 23- first oxime nimoctins 4.0g（4.9mmol, 1.0eq, HPLC purity 97.02A%, white powder）, add dioxane 40.0g molten clear, it is subsequently added 3.6g hydrochloric acid（9.9g, 97.6mmol, 20.0eq, content 36wt.%）, it is subsequently heated to 50 DEG C of insulated and stirred 10.0h.Reaction solution is poured into water 40.0g In, being extracted at twice with dichloroethanes 40.0g, gained oil reservoir negative pressure revolving takes off dry solvent and obtains faint yellow 5- oxygen（Protection group）- 23- oxo nimoctins 3.8g（4.8mmol, HPLC purity 96.5A%, yield 98.0%）.
（2）Reduction reaction, protective reaction and silicagel column point process are same as Example 1, finally obtain nimoctin 2.8g（HPLC purity 96.5A%, content 93.7wt.%, white solid）.
Embodiment 4
The technological process that the present embodiment prepares high content nimoctin is as follows：
（1）De-oxime reaction：
5- oxygen is added in 100mL there-necked flasks（4- chlorophenoxy acetyl group）- 23- first oxime nimoctins 4.2g（5.0mmol, 1.0eq, HPLC purity 96.9A%, white powder）, add dioxane 40.0g molten clear, it is subsequently added 3.6g hydrochloric acid（10.1g, 100.0mmol, 20.0eq, content 36wt.%）, it is subsequently heated to 50 DEG C of insulated and stirred 12.0h.Reaction solution is poured into water 40.0g In, being extracted at twice with dichloroethanes 40.0g, gained oil reservoir negative pressure revolving takes off dry solvent and obtains faint yellow 5- oxygen（Protection group）- 23- oxo nimoctins 4.0g（4.9mmol, HPLC purity 96.0A%, yield 98.0%）.
（2）Reduction reaction, protective reaction and silicagel column point process are same as Example 2, finally obtain nimoctin 2.8g（HPLC purity 96.1A%, content 94.0wt.%, white solid）.

Claims (8)

1. a kind of method for preparing nimoctin, it is characterised in that：With the 5- oxygen after crystallization and purification（Protection group）- 23- oxo Buddhist nuns Mack spit of fland is raw material, by sodium borohydride reduction reaction, NaOH protective reaction and silica gel post separation, prepares Buddhist nun's Mack Spit of fland.
2. the method for preparing nimoctin according to claim 1, it is characterised in that：The 5- oxygen（Protection group）- 23- oxo nimoctins refer to 5- oxygen（4- nitro benzoyls）- 23- oxos nimoctin or 5- oxygen（4- chlorophenoxy acetyl Base）- 23- oxo nimoctins.
3. the method for preparing nimoctin according to claim 1, it is characterised in that：5- oxygen after the crystallization and purification（Protect Shield base）- 23- oxo nimoctins refer to raw materials used 5- oxygen（Protection group）- the HPLC purity of 23- oxo nimoctins >= 95.0A%。
4. the method for preparing nimoctin according to claim 1, it is characterised in that：Reaction dissolvent in the reduction reaction It is methyl alcohol or ethanol.
5. the method for preparing nimoctin according to claim 1 or 4, it is characterised in that：The specific mistake of reduction reaction Cheng Wei：In 5- oxygen（Protection group）Reaction dissolvent is added in -23- oxo nimoctins, milky suspension is obtained after stirring, Sodium borohydride is added under the conditions of 0 ~ 5 DEG C, after insulated and stirred 0.5-3.0h, reaction solution is poured into water, extracted with dichloroethanes To 5- oxygen（Protection group）- nimoctin；Wherein：5- oxygen（Protection group）The part by weight of -23- oxos nimoctin and sodium borohydride It is 4：0.4-1.5.
6. the method for preparing nimoctin according to claim 1, it is characterised in that：Used in the protective reaction Deprotection reagent is 3-5wt.% sodium hydrate aqueous solutions, and reaction dissolvent is alcohols mixed with what dichloromethane or dichloroethanes were constituted Bonding solvent.
7. the method for preparing nimoctin according to claim 1 or 6, it is characterised in that：The protective reaction is specific Process is：By the 5- oxygen（Protection group）- nimoctin reaction dissolvent it is molten it is clear after be cooled to -10 ~ -7 DEG C, add NaOH Be poured into water for gained reaction solution by solution, insulated and stirred 5-8h, is extracted with dichloroethanes and obtains nimoctin crude product；Wherein：5- Oxygen（Protection group）- nimoctin is 4 with the part by weight of sodium hydroxide solution：0.4-1.0.
8. the method for preparing nimoctin according to claim 1, it is characterised in that：In the silica gel column separation process, The use of silica gel mesh number is 100 ~ 300 mesh, eluant, eluent is the mixed solvent of petroleum ether or normal heptane and ethyl acetate composition.
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CN106896163A (en) * 2015-12-18 2017-06-27 河北圣雪大成制药有限责任公司 The method that nimoctin content is detected based on liquid chromatograph external standard method

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