CN106478781B - Preparation method of caspofungin - Google Patents
Preparation method of caspofungin Download PDFInfo
- Publication number
- CN106478781B CN106478781B CN201510556712.6A CN201510556712A CN106478781B CN 106478781 B CN106478781 B CN 106478781B CN 201510556712 A CN201510556712 A CN 201510556712A CN 106478781 B CN106478781 B CN 106478781B
- Authority
- CN
- China
- Prior art keywords
- caspofungin
- formula
- reaction
- compound
- compound shown
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Peptides Or Proteins (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a preparation method of caspofungin, which comprises the step of substituting p-toluenesulfophenol for pneumocandin B0Then reducing the amido group with a reducing agent, and finally substituting ethylenediamine for p-toluenesulfonyl to obtain caspofungin. The invention adopts proper solvent for crystallization and separation of the intermediate, avoids the separation and purification operation of multiple preparative chromatographic columns in the prior art, reduces the reaction time, avoids the degradation of the intermediate, simplifies the operation, obtains the caspofungin with high purity and high yield, and is particularly suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of caspofungin.
Background
Caspofungin (Caspofungin) is pulmonary leukocidin B0The structure of the semisynthetic derivative is shown in the following, and the acetate of the semisynthetic derivative is firstly marketed in the United states in 2001. Caspofungin is a broad spectrum antibiotic suitable for empirical treatment of neutropenia, suspected fungal infections in febrile patients, candidemia and infections with candida including abdominal abscesses, peritonitis, pleural space, esophageal candidiasis, invasive aspergillosis that is ineffective or intolerant to other treatments, etc.
Caspofungin is usually composed of pneumocandin B0(Pneumocandin B0Formula (I)) by reducing the amido group thereof with a reducing agent and substituting the hydroxyl group thereof with ethylenediamine.
William R.Leonard, Jr et al (J.org.chem.2007,72,2335-0) Discloses the substitution of thiophenol for pneumocandin B0And then reducing the amido group by using a reducing agent, and finally substituting the thiophenyl group by using ethylenediamine to obtain the caspofungin.
However, thiophenols used in the above-mentioned methods are highly toxic chemicals, and have offensive odors and irritations, and are not suitable for industrial production.
The Chinese patent application CN102219833A adopts 2-mercaptobenzothiazole or 1-phenyl-5-mercapto-tetrazole to substitute pneumocandin B0And then reducing the amido group by using a reducing agent, and finally substituting the 1-phenyl-tetrazole-5-sulfydryl group by using ethylenediamine to obtain the caspofungin. The 2-mercaptobenzothiazole or 1-phenyl-5-mercapto-tetrazole adopted by the method is expensive and difficult to remove after the reaction is finished.
Meanwhile, the reaction product (formula (IV)) in the second step of the above synthesis method is purified by preparative chromatography, which is not suitable for industrial production because the chromatographic purification is expensive, complicated to operate and requires a long time, while the compound of formula (IV) is unstable, is easily degraded during the purification process, and the degradation product is difficult to separate and purify.
Due to the complex chemical structure of caspofungin and the proximity of a plurality of impurities to the caspofungin structure, the caspofungin has similar physical and chemical properties and is difficult to separate and purify, and the caspofungin with medicinal purity can be obtained by purifying through a plurality of preparative chromatographic columns in the prior art. CN102153616A discloses a method for separating and purifying caspofungin by using macroporous adsorption resin, which obtains caspofungin with purity of > 99%, however, the applicant repeats the method disclosed in the application, and does not obtain the technical effect disclosed in the specification.
Disclosure of Invention
The invention aims to provide a preparation method of caspofungin, which comprises the following steps:
step 1, reacting a compound of formula (I) with p-toluenesulfonol to generate a compound of formula (II), reacting the compound of formula (II) with a reducing agent to generate a compound of formula (III), adding an organic solvent into a reaction system to precipitate a compound of formula (III)
Step 2, reacting the compound of formula (III) with ethylenediamine to produce caspofungin
In step 1, the organic solvent is one or more selected from acetone, acetonitrile, and ethyl acetate, preferably acetonitrile.
In step 1, the reducing agent is borane tetrahydrofuran.
Optionally, in step 2, the caspofungin produced by the reaction is purified by a preparative chromatographic column.
Optionally, in step 2, the caspofungin generated by the reaction is purified by macroporous adsorbent resin, and then purified by a preparative column.
In step 1, tetrahydrofuran is used as a reaction solvent for preparing the compound of formula (III).
In one embodiment of the present invention, in step 1, acetonitrile is used as a reaction solvent in the preparation of the compound of formula (II), and an aqueous solution of sodium acetate is added to precipitate the compound of formula (II).
The invention avoids the operation of separating and purifying the preparative chromatographic column for many times in the prior art, reduces the reaction time, avoids the degradation of the intermediate, simplifies the operation, obtains the caspofungin with high purity and high yield, and is particularly suitable for industrial production.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit it in any way.
EXAMPLE 1 preparation of caspofungin
Adding 47.5kg of acetonitrile into a 100L reaction tank under stirring, introducing nitrogen for protection, adding 2.0kg of the compound shown in the formula (I) and 458g of phenylboronic acid, stirring for 10 minutes, adding 700g of p-toluene thiophenol, cooling, controlling the temperature of feed liquid at-20 to-15 ℃ for reaction for 2 hours, and slowly dropwise adding 845g of trifluoromethanesulfonic acid. The temperature of the feed liquid is controlled between-20 ℃ and-15 ℃ in the dropping process, after the dropping is finished, the temperature of the feed liquid is controlled between-20 ℃ and-15 ℃, the stirring reaction is carried out for 4 hours, and the HPLC tracking monitoring is carried out until the basic reaction of the raw materials is complete. After the reaction is finished, adding a sodium acetate solution (prepared by adding 462g of anhydrous sodium acetate into 6.8kg of water), heating, and stirring for 2 hours at the temperature of 20-30 ℃. And (4) cooling, and stirring for 20 minutes at the temperature of-5-0 ℃ of the feed liquid. And (3) filtering by throwing till no liquid flows out, stirring and washing a filter cake by using an acetonitrile/water solution (3.6kg of acetonitrile: 0.5kg of water) precooled to 0-5 ℃ for 10 minutes, and filtering by throwing till no liquid flows out.
And (3) drying the obtained wet product by air blowing at 25-35 ℃ for 12 hours, crushing the obtained solid, and drying the crushed solid in vacuum at 25-35 ℃ for 12 hours, wherein the yield is 87% (calculated on the compound of the formula (I)).
Adding 19.0kg of tetrahydrofuran into a 30L reaction tank under stirring, adding 1.0kg of a compound shown in the formula II under the protection of nitrogen, stirring for 10 minutes, adding 145g of phenylboronic acid, heating, controlling the temperature of a feed liquid to be 65-75 ℃ so that a solvent flows through a molecular sieve II drying tower for reflux reaction for 4 hours, cooling to 20-30 ℃, adding 660g N and O-bis (trimethylsilyl) trifluoroacetamide, and after the addition is finished, controlling the temperature of the feed liquid to be 20-30 ℃ and stirring for reaction for 1.5 hours. Cooling to-10-5 ℃, adding 4.3L of borane tetrahydrofuran solution, and continuing to stir for 3 hours at-5-0 ℃. After the reaction is finished, 4L of 2mol/L hydrochloric acid solution is slowly dripped into the reaction solution, and the temperature of the feed solution is controlled to be-5-10 ℃ in the dripping process. After the dropwise addition is finished, the temperature of the feed liquid is controlled to be-5-10 ℃, and the stirring reaction is continued for 2.5 hours. And (3) transferring the reaction liquid to a 100L reaction tank after the reaction is finished, adding acetonitrile precooled to 0-5 ℃, stirring for 10 minutes, and filtering until no liquid flows out. Collecting a filter cake to obtain a compound shown in the formula III, and directly putting the compound into the next step for reaction.
Adding 3.0L of anhydrous ethylenediamine and 0.6L of anhydrous methanol into a 30L reaction tank under stirring, introducing nitrogen for protection, cooling to-5-0 ℃, slowly dropwise adding a methanol solution of the compound of the formula III (1.0kg of the compound of the formula III: 3.0L of anhydrous methanol), and controlling the temperature of the feed liquid below 5 ℃ in the dropwise adding process. After the completion of the dropwise addition, the mixture was stirred at 5 ℃ or lower for 10 minutes. Heating to 20-30 ℃, and continuously stirring for reaction for 24 hours. After the reaction is finished, slowly adding 6.6L of glacial acetic acid into 19L of purified water precooled to 0-5 ℃, controlling the temperature of the feed liquid below 25 ℃ in the adding process, stirring for 20 minutes, then adding 2kg of diatomite, stirring for 10 minutes, carrying out filtration, leaching with 7L of 5 per mill acetic acid aqueous solution, carrying out filtration until no liquid flows out, and combining the filtrates to obtain a crude caspofungin acetate solution.
The caspofungin acetate solution is purified by chromatography, a chromatographic column is C18 reversed-phase filler (DAISO SP-100-10-ODS-P chromatographic filler), and elution is carried out in a gradient manner from low to high according to the acetonitrile content of 10-50 percent (the water phase is 1.0 per thousand of acetic acid aqueous solution). And (4) carrying out nanofiltration and freeze-drying on the eluent to obtain the solid caspofungin acetate. The purity was 99.5% (by HPLC) and the overall yield was 28.2% (based on the compound of formula (I)).
Claims (3)
1. A preparation method of caspofungin comprises the following steps:
step 1, reacting a compound shown in formula (I) with p-toluenesulthiol to generate a compound shown in formula (II), adding acetonitrile as a reaction solvent, adding sodium acetate aqueous solution to precipitate a compound shown in formula (II), reacting the compound shown in formula (II) with a reducing agent to generate a compound shown in formula (III), adding an organic solvent into a reaction system to precipitate a compound shown in formula (III), wherein the organic solvent is one or a mixture of acetone, acetonitrile and ethyl acetate
Step 2, reacting the compound of formula (III) with ethylenediamine to produce caspofungin
Wherein the caspofungin generated by the reaction is purified by a preparative chromatographic column.
2. The process according to claim 1, wherein the organic solvent used in the step 1 is acetonitrile.
3. The process according to claim 1, wherein the compound of formula (III) is prepared in step 1 in tetrahydrofuran as the reaction solvent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510556712.6A CN106478781B (en) | 2015-09-02 | 2015-09-02 | Preparation method of caspofungin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510556712.6A CN106478781B (en) | 2015-09-02 | 2015-09-02 | Preparation method of caspofungin |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106478781A CN106478781A (en) | 2017-03-08 |
CN106478781B true CN106478781B (en) | 2020-04-07 |
Family
ID=58238053
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510556712.6A Active CN106478781B (en) | 2015-09-02 | 2015-09-02 | Preparation method of caspofungin |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106478781B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109721641B (en) * | 2017-10-31 | 2021-08-03 | 鲁南制药集团股份有限公司 | Synthesis method of caspofungin |
CN111808172B (en) * | 2019-04-12 | 2023-05-12 | 上海森辉医药有限公司 | Lung candicillin B 0 Derivatives, preparation method and application thereof |
CN112125957B (en) * | 2019-06-24 | 2023-07-28 | 鲁南制药集团股份有限公司 | Preparation method of caspofungin acetate |
CN113286807B (en) * | 2019-10-20 | 2022-09-30 | 鲁南贝特制药有限公司 | Synthesis method and intermediate of caspofungin |
CN113801203A (en) * | 2020-06-15 | 2021-12-17 | 杭州中美华东制药有限公司 | Preparation method of caspofungin acetate impurity D |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101305018A (en) * | 2005-11-15 | 2008-11-12 | 桑多斯股份公司 | Process and intermediates for the synthesis of caspofungin |
CN102367267A (en) * | 2010-11-10 | 2012-03-07 | 上海天伟生物制药有限公司 | Preparation method of caspofungin |
-
2015
- 2015-09-02 CN CN201510556712.6A patent/CN106478781B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101305018A (en) * | 2005-11-15 | 2008-11-12 | 桑多斯股份公司 | Process and intermediates for the synthesis of caspofungin |
CN102367267A (en) * | 2010-11-10 | 2012-03-07 | 上海天伟生物制药有限公司 | Preparation method of caspofungin |
Non-Patent Citations (1)
Title |
---|
《Synthesis of the Antifungal β-1,3-Glucan Synthase Inhibitor CANCIDAS (Caspofungin Acetate) from Pneumocandin B0》;William R. Leonard等;《Journal of Organic Chemistry》;20070308;第72卷(第7期);第2335-2343页 * |
Also Published As
Publication number | Publication date |
---|---|
CN106478781A (en) | 2017-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106478781B (en) | Preparation method of caspofungin | |
EP3064214B1 (en) | Separation and purification method for vancomycin hydrochloride of high purity | |
JP5911989B2 (en) | Method for producing high purity anhydrous crystalline docetaxel | |
CN109836401B (en) | Method for purifying docetaxel | |
AU2011240493A1 (en) | Purification method of azacyclohexapeptide or its salt | |
CN112979756B (en) | Purification method of daptomycin | |
CN105254721B (en) | Purification and salt conversion method of micafungin | |
KR20170120575A (en) | Compositions Containing Nitrogen Heterocyclic Hexapeptide Precursors and Their Preparation and Use | |
CN108192090B (en) | Purification method of vitamin E polyethylene glycol succinate | |
TW201231475A (en) | Method for separating and purifying cyclohexapeptide compound and salt thereof | |
CN109553645B (en) | Method for extracting low-content erythromycin A in fermentation solution | |
CN106831930B (en) | A kind of extractant and extracting method for ursolic acid extraction | |
US8765196B2 (en) | Method for separating and purifying Ginkgolide C from root bark of ginkgo | |
CN106831809B (en) | A method of it is extracted from fermentation liquid and purifies mibemycin | |
CN109988127B (en) | Method for synthesizing taxol from 7-differential-10-deacetyltaxol | |
CN102557980B (en) | Method for preparing high-purity capsaicine monomer by crystallization | |
CN104231044A (en) | Process for purifying nosiheptide by passing through column | |
CN103694291B (en) | Synthesis method for valrubicin | |
KR101329902B1 (en) | A process for the purification of 10-deacetylbaccatine ⅲ from 10-deacetyl-2-debenzoyl-2-pentenoylbaccatine ⅲ | |
CN104829695B (en) | A method of purifying alarelin | |
WO2010094739A1 (en) | Process for the purification of amorolfine hydrochloride | |
CN107739307B (en) | Method for purifying protocatechuic acid by using dilute alkali solution extraction-solid phase extraction column | |
CN104610411B (en) | Method for purifying compound | |
CN106431877A (en) | Method for preparing licochalcone from licorice residues | |
CN111004292A (en) | Gentamicin derivative and preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20210413 Address after: No. 369, Yuzhou South Road, Lianyungang, Jiangsu Province Patentee after: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Patentee after: LIANYUNGANG RUNZHONG PHARMACEUTICAL Co.,Ltd. Address before: 222006 No. 8 Julong North Road, Sinpo District, Jiangsu, Lianyungang Patentee before: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. |