CN104860961A - Method for preparing high-purity 5-oxy(p-nitrobenzoyl)-nemadectin - Google Patents
Method for preparing high-purity 5-oxy(p-nitrobenzoyl)-nemadectin Download PDFInfo
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- CN104860961A CN104860961A CN201510168065.1A CN201510168065A CN104860961A CN 104860961 A CN104860961 A CN 104860961A CN 201510168065 A CN201510168065 A CN 201510168065A CN 104860961 A CN104860961 A CN 104860961A
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- nimoctin
- oxygen
- oil
- mirbane formyl
- high purity
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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
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing high-purity 5-oxy(p-nitrobenzoyl)-nemadectin. According to the invention, nemadectin is adopted as a reaction initial raw material, and p-nitrobenzoyl chloride is adopted as an -OH protecting reagent, such that a 5-oxy(p-nitrobenzoyl)-nemadectin crude product is prepared; the 5-oxy(p-nitrobenzoyl)-nemadectin crude product is adopted as a raw material and is mixed with a solvent, such that a solution is prepared; an eluting agent is added, and cooling crystallization is carried out, such that 5-oxy(p-nitrobenzoyl)-nemadectin with higher purity is obtained. The method provided by the invention has the advantages of short crystallization time, low cost, high product purity and high yield. With the method, a basis is provided for the preparation of high-purity moxidectin.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis field, specifically, be to provide the method that one prepares high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin.
Background technology
Mosictin is the semisynthetic macrolide antibiotics produced by cyaneogriseus streptomyces fermentation, is the derivative of nimoctin.Mosictin has wider anthelmintic activity, the characteristic such as long-lasting and safe relative to ivermectin and Avrmectin due to the unicity of its composition.
The synthetic route of mosictin take nimoctin as starting material, and through 5-OH protection, 23-OH is oxidized, and removing of blocking group prepares mosictin with oximation reaction or oximation reaction and removing of blocking group.The synthetic route of mosictin is not very complicated, but the major cause that this product is difficult to large-scale industrial production is that the purification of product also exists certain difficulty.
Chinese patent CN101372492A discloses a kind of method of purification of nimoctin, and after this method uses absorption with macroporous adsorbent resin, chromatography obtains the nimoctin preliminary purification liquid of purity 40 ~ 50%.The nimoctin of this kind of purity obtains purity through the resin separation purification of upper protective reaction, upper protection and is greater than protection on 85%; obtain mosictin reaction solution through oxidation, deprotection and oximation reaction again, mosictin reaction solution obtains highly purified mosictin solution through the separation and purification rear of resin column again.This method purification procedures is more, and relate to and use expensive resin column and consume a large amount of solvents, cost is higher.
Patent CN103588784A discloses a kind of method preparing high-purity nemadectin, and this method employs the nimoctin that a kind of anionite-exchange resin and the combined method of two kinds of macroporous adsorbent resins prepare purity more than 90%.Only the resin that the purification of nimoctin has just used three kinds of specifications, the difficulty of visible separation and purification.
Therefore the purification about mosictin and intermediate has great importance, and we find with paranitrobenzoyl chloride to be that upper protection 5-oxygen (p-oil of mirbane formyl)-nimoctin prepared by protection reagent can be purified by the method for crystallization.This method cost is low, and working method is simple, is suitable for suitability for industrialized production.
Summary of the invention
The invention provides the method that one prepares high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin, product purity prepared by present method significantly improves, and simple to operate, cost is low, with short production cycle, prepared by high-purity moxidectin to the later stage significant.
For achieving the above object, the present invention takes following technical scheme:
One prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin; it is characterized in that; take nimoctin as reaction starting raw material; paranitrobenzoyl chloride is that-OH protects reagent to prepare 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product, is that raw material is purified by following steps with 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product:
(1) organic solvent mixes with 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product, stirs and obtain transparent 5-oxygen (p-oil of mirbane formyl)-nimoctin solution under 60 ~ 80 DEG C of conditions;
(2) under the condition stirred, in above-mentioned solution, dissolved agent is added;
(3) above-mentioned solution is under the condition stirred, and is cooled to 5 ~ 15 DEG C, filters and obtains 5-oxygen (p-oil of mirbane formyl)-nimoctin crystal;
(4) above-mentioned crystal under vacuum drying obtain high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin.
On the basis of technique scheme, the present invention also has following technical characteristic:
Described organic solvent is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol;
The weight ratio of described organic solvent and 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product is (0.6 ~ 1): 1;
Described dissolved agent is ionized water;
The weight ratio of described dissolved agent and 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product is (5 ~ 10): 1;
When adding dissolved agent, stir speed (S.S.) is 20 ~ 40 r/min;
During cooling, stir speed (S.S.) is 40 ~ 60 r/min;
Rate of temperature fall is 4 ~ 10 DEG C/h.
It is low that the method that the present invention prepares high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin has cost, and solvent is recyclable, the advantage that with short production cycle and purity significantly improves, and prepares high-purity moxidectin significant to the later stage.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, is not limitation of the invention.
Embodiment 1:
In 250 mL round-bottomed flasks, drop into 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product (20 g, purity 88.7%), methyl alcohol 20 mL, be warming up to 60 DEG C, be stirred to clearly molten.Drip 120 mL deionized water, then programmed coolings, cooling per hour 6 DEG C, is cooled to 15 DEG C, filters, filter cake 15 DEG C of deionized water drip washing.Filter cake is at 80 DEG C of vacuum-drying 20 h, and obtain high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin 15g, purity is 94.5%.
Embodiment 2:
Drop into 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product (20 g, purity 88.7%), n-propyl alcohol 20 mL in 250mL round-bottomed flask, be warming up to 80 DEG C, be stirred to clearly molten.Drip 100 mL deionized water, then programmed coolings, cooling per hour 4 DEG C, is cooled to 10 DEG C, filters, filter cake 10 DEG C of deionized water drip washing.Filter cake is at 80 DEG C of vacuum-drying 20 h, and obtain high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin 14.4g, purity is 95.4%.
Embodiment 3:
Drop into 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product (20g, purity 88.7%), Virahol 14mL in 250 mL round-bottomed flasks, be warming up to 80 DEG C, be stirred to clearly molten.Drip 140 mL deionized water, then programmed coolings, cooling per hour 6 DEG C, is cooled to 10 DEG C, filters, filter cake 10 DEG C of deionized water drip washing.Filter cake was 80 DEG C of vacuum-dryings 20 hours, and obtain high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin 16.7g, purity is 92.6%.
Embodiment 4:
Drop into 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product (20g, purity 88.7%), ethanol 12mL in 250mL round-bottomed flask, be warming up to 75 DEG C, be stirred to clearly molten.Drip 200mL deionized water, then programmed cooling, cooling per hour 10 DEG C, is cooled to 5 DEG C, filters, filter cake 5 DEG C of deionized water drip washing.Filter cake is at 80 DEG C of vacuum-drying 20 h, and obtain high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin 17.5g, purity is 89.7%.
The present embodiment not does any pro forma restriction to the present invention; Any those of ordinary skill in the art, do not departing under technical solution of the present invention ambit, the Method and Technology content of above-mentioned announcement all can be utilized to make many possible variations and modification to technical solution of the present invention, or be revised as the Equivalent embodiments of equivalent variations.Therefore, every content not departing from technical solution of the present invention, according to technical spirit of the present invention to any simple modification made for any of the above embodiments, equivalent replacement, equivalence change and modification, all still belongs in the scope of technical solution of the present invention protection.
Claims (8)
1. prepare the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin for one kind; take nimoctin as reaction starting raw material; paranitrobenzoyl chloride is that-OH protects reagent to prepare 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product; it is characterized in that, be that raw material is purified by following steps with 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product:
(1) organic solvent mixes with 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product, stirs and obtain transparent 5-oxygen (p-oil of mirbane formyl)-nimoctin solution under 60 ~ 80 DEG C of conditions;
(2) under the condition stirred, in above-mentioned solution, dissolved agent is added;
(3) above-mentioned solution is under the condition stirred, and is cooled to 5 ~ 15 DEG C, filters and obtains 5-oxygen (p-oil of mirbane formyl)-nimoctin crystal;
(4) above-mentioned crystal under vacuum drying obtain high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin.
2. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, and it is characterized in that, described organic solvent is the one in methyl alcohol, ethanol, n-propyl alcohol, Virahol.
3. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, it is characterized in that, the weight ratio of described organic solvent and 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product is (0.6 ~ 1): 1.
4. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, and it is characterized in that, described dissolved agent is ionized water.
5. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, it is characterized in that, the weight ratio of described dissolved agent and 5-oxygen (p-oil of mirbane formyl)-nimoctin crude product is (5 ~ 10): 1.
6. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, it is characterized in that, when adding dissolved agent, stir speed (S.S.) is 20 ~ 40 r/min.
7. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, and it is characterized in that, during cooling, stir speed (S.S.) is 40 ~ 60 r/min.
8. one prepares the method for high purity 5-oxygen (p-oil of mirbane formyl)-nimoctin according to claim 1, and it is characterized in that, rate of temperature fall is 4 ~ 10 DEG C/h.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510168065.1A CN104860961B (en) | 2015-04-10 | 2015-04-10 | One kind prepares 5 oxygen（P-nitrophenyl formyl）The method of nimoctin |
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| CN201510168065.1A CN104860961B (en) | 2015-04-10 | 2015-04-10 | One kind prepares 5 oxygen（P-nitrophenyl formyl）The method of nimoctin |
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| CN104860961A true CN104860961A (en) | 2015-08-26 |
| CN104860961B CN104860961B (en) | 2017-08-04 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0259686A1 (en) * | 1986-09-12 | 1988-03-16 | American Cyanamid Company | Novel mono and diacyl derivatives of LL-F28249 compounds |
| CN1051043A (en) * | 1989-09-11 | 1991-05-01 | 美国氰胺公司 | 23-(C 1-C 6The alkyl oxime)-preparation method of LL-F28249 compound |
| CN1064866A (en) * | 1986-12-11 | 1992-09-30 | 三共株式会社 | The preparation of Macrocyclic lactone compounds and their purposes |
| AU2006100658B4 (en) * | 2006-05-08 | 2006-10-05 | Wyeth | Process |
| US20080021093A1 (en) * | 2006-06-22 | 2008-01-24 | Wyeth | Oxidation process with enhanced safety useful in the manufacture of Moxidectin |
| CN101372492A (en) * | 2007-06-29 | 2009-02-25 | 浙江海正药业股份有限公司 | Method for preparing high-purity moxidectin |
-
2015
- 2015-04-10 CN CN201510168065.1A patent/CN104860961B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0259686A1 (en) * | 1986-09-12 | 1988-03-16 | American Cyanamid Company | Novel mono and diacyl derivatives of LL-F28249 compounds |
| CN1064866A (en) * | 1986-12-11 | 1992-09-30 | 三共株式会社 | The preparation of Macrocyclic lactone compounds and their purposes |
| CN1051043A (en) * | 1989-09-11 | 1991-05-01 | 美国氰胺公司 | 23-(C 1-C 6The alkyl oxime)-preparation method of LL-F28249 compound |
| AU2006100658B4 (en) * | 2006-05-08 | 2006-10-05 | Wyeth | Process |
| AU2006100658C4 (en) * | 2006-05-08 | 2009-07-23 | Wyeth | Process |
| US20080021093A1 (en) * | 2006-06-22 | 2008-01-24 | Wyeth | Oxidation process with enhanced safety useful in the manufacture of Moxidectin |
| CN101372492A (en) * | 2007-06-29 | 2009-02-25 | 浙江海正药业股份有限公司 | Method for preparing high-purity moxidectin |
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Address after: 234000 No. 158, No. five, Jintai Road, Suzhou Economic Development Zone, Anhui Applicant after: XINYU PHARMACEUTICAL CO.,LTD. Address before: 234000 No. 24, Huaihailu Road, Anhui, Suzhou Applicant before: ANHUI WANBEI PHARMACEUTICAL Co.,Ltd. |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Method for Preparing 5-Oxy (p-Nitrobenzoyl) Nimoxetine Effective date of registration: 20230626 Granted publication date: 20170804 Pledgee: Suzhou Financing Guarantee Group Co.,Ltd. Pledgor: XINYU PHARMACEUTICAL CO.,LTD. Registration number: Y2023980045703 |
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