CN111040007B - Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a - Google Patents
Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a Download PDFInfo
- Publication number
- CN111040007B CN111040007B CN201911331173.0A CN201911331173A CN111040007B CN 111040007 B CN111040007 B CN 111040007B CN 201911331173 A CN201911331173 A CN 201911331173A CN 111040007 B CN111040007 B CN 111040007B
- Authority
- CN
- China
- Prior art keywords
- gentamicin
- stirring
- triacetyl
- reaction
- concentrating
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention relates to a preparation method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, which is characterized by comprising the following steps: 1) dissolving gentamicin C1a in a solvent, adding a Boc-reagent, and stirring for reaction; 2) cooling the reaction liquid, adding acetic anhydride and alkali, stirring for reaction, adding water, removing the solvent, and concentrating; 3) adding hydrochloric acid into the concentrated solution, stirring for reaction, adding ammonia water for neutralization, and concentrating; 4) separating and purifying the concentrated solution by silica gel column chromatography to obtain the 1, 3, 2' -N, N, N-triacetyl gentamicin C1 a.
Description
The technical field is as follows:
the invention relates to the field of pharmaceutical chemistry, in particular to a method for preparing an aminoglycoside compound intermediate, and specifically relates to a method for synthesizing 1, 3, 2' -N, N, N-triacetyl gentamicin C1 a.
Background art:
etimicin sulfate, the structural formula is as follows:
chemical name: o-2-amino-2, 3,4, 6-tetradeoxy-6-amino-alpha-D-erythro-hexopyranosyl- (1 → 4) -O- [ 3-deoxy-4-C-methyl-3 (methylamino) -beta-L-arabinopyranosyl- (1 → 6) ] -2-deoxy-N-ethyl-L-streptomycin amine sulfate
Molecular formula (C) 21 H 43 N 5 O 7 ) 2 ·5H 2 SO 4
Molecular weight: 1445.58
Etimicin sulfate is a derivative of gentamicin C1a, and currently, injection products are on the market.
Etimicin sulfate (Etimicin sulfate) is developed by scientific researchers in China, has independent intellectual property rights, is a new generation of high-efficiency, low-toxicity and drug-resistant bacteria-resistant semisynthetic aminoglycoside antibiotic, and is the only anti-infective drug for obtaining a new drug certificate in China. The etimicin sulfate injection is suitable for various infections caused by sensitive escherichia coli, klebsiella pneumoniae, serratia, citrobacter, enterobacter, acinetobacter, proteus, hemophilus influenza bacillus, pseudomonas aeruginosa, staphylococcus and the like.
6' -N-ethyl gentamicin C1a, the chemical structure is as follows:
the etimicin sulfate is one of main impurities remained in etimicin sulfate bulk drugs and preparations, and 6' -N-ethyl gentamicin C1a standard products are not sold at home and abroad.
In the research process of improving the quality standard of etimicin sulfate bulk drugs and preparations thereof, an impurity reference substance is inevitably required to be used. Therefore, the prepared high-purity 6' -N-ethyl gentamicin C1a reference substance has great significance for improving the quality of etimicin sulfate medicines and improving the safety of clinical medication. The preparation of the intermediate 1, 3, 2'-N, N, N-triacetyl gentamicin C1a is important for obtaining high-purity 6' -N-ethyl gentamicin C1 a.
Chinese patent application No.: 201910746675.3 discloses a preparation method of 6 '-N-ethyl gentamicin C1a, which comprises the synthesis of related substance 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, and the chemical structure is as follows:
the invention particularly aims at the preparation method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, and refers to Chinese patent application numbers: 201910746675.3, in which triethylamine is used as a base in the Boc protection, too strong a base causes insignificant steric hindrance, poor reaction selectivity and increased side reactions. In the reaction, after the Boc protection, the subsequent treatments such as liquid separation and concentration were performed using ethyl acetate, and the operation was complicated. In the reaction, strong alkali sodium hydroxide is used for adjusting the pH value of the solution, and then the solution is concentrated, so that the pH value of the solution is increased easily, and hydrolysis side reaction is caused.
The invention provides different technical schemes, the gentamicin C1a directly adds Boc chemical reagent in solvent, no extra alkali is needed to be added, 6 '-N is protected by utilizing self alkalinity and steric hindrance effect, no aftertreatment is needed, acetylation reagent and alkali are directly added in the reaction to protect N at 1, 3 and 2' positions, and the method has the advantages of simple operation, less side reaction, high yield and high synthesis efficiency. After the Boc protection is removed by hydrochloric acid, ammonia water is used for neutralizing and adjusting pH, the condition is mild, and the danger is small.
The invention provides a synthesis method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a,
the invention content is as follows:
the invention aims to provide a method for synthesizing an etimicin sulfate impurity 6 '-N-ethyl gentamicin C1a intermediate 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, which is simple and convenient to operate and high in synthesis efficiency.
The preparation method comprises the following steps:
1) dissolving gentamicin C1a in a solvent, adding a Boc chemical reagent, and stirring for reaction;
2) cooling the reaction liquid, adding acetic anhydride and alkali, stirring for reaction, adding water, removing the solvent, and concentrating;
3) adding hydrochloric acid into the concentrated solution, stirring for reaction, adding ammonia water for neutralization, and concentrating;
4) separating and purifying the concentrated solution with silica gel column chromatography to obtain 1, 3, 2' -N, N, N-triacetyl gentamicin
C1a。
Wherein the solvent in step 1 is selected from: one or more of methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide and dimethyl sulfoxide; boc reagent is selected from: boc anhydride (di-tert-butyl dicarbonate) or Boc-ON (2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile); mass ratio of Boc-forming reagent to gentamicin C1a was 0.8: 1-1.5: 1; the stirring time is 12-48 hours; gentamicin C1a is known in the art and is either commercially available or synthesized by itself. Preferably, the solvent in step 1 is methanol or ethanol; boc reagent is Boc-ON (2-tert-butyloxycarbonyloxyimino-2-benzyl cyanide); mass ratio of Boc reagent to gentamicin C1a was 0.9: 1-1.1: 1; the stirring time is 18-36 hours.
Wherein the base in step 2 is selected from: one or more of triethylamine, N-diisopropylethylamine and N-methylmorpholine. The mass ratio of acetic anhydride to gentamicin C1a was 3: 1-10: 1; the mass ratio of the alkali to gentamicin C1a was 3: 1-10: 1; the stirring time is 1-3 hours. Preferably, the mass ratio of acetic anhydride to gentamicin C1a in step 2 is 3.5: 1-6: 1; the mass ratio of the base to gentamicin C1a was 4: 1-7: 1; the stirring time is 1.5-2.5 hours.
Wherein the concentration of the hydrochloric acid in the step 3 is 2-6 mol/L, and the stirring time is 1-6 hours; and the pH value after neutralization is 7-10. Preferably, the concentration of the hydrochloric acid in the step 3 is 3-5 mol/L, and the stirring time is 2-4 hours; and the pH value after neutralization is 8-9.
Wherein, the silica gel column chromatography separation and purification in the step 4 is preferably carried out by the following method:
passing the concentrated solution through silica gel column (silica gel model: ZCX II, reagent grade, 200 meshes, 300 meshes, column size: 5cm × 40cm), eluting with mixed solvent (chloroform, methanol and ammonia water mixed, separating, taking the lower layer, mixing in proportion of 5: 1: 1-2: 1: 1), collecting the part with purity of more than 95%, and concentrating. Most preferably, the preparation method comprises the following steps:
dissolving gentamicin C1a 5g in methanol 50mL, adding Boc-ON 0.9eq, stirring for 24h, cooling the reaction liquid to 0-5 ℃, adding acetic anhydride 4.2eq and triethylamine 4.8eq, stirring for 2h, adding water 50mL, concentrating to remove methanol, adding hydrochloric acid 50mL at a concentration of 4mol/L, stirring for 2h, adding ammonia water to neutralize to pH 8, concentrating, and separating and purifying the concentrated solution by silica gel column chromatography to obtain 1, 3, 2' -N, N, N-triacetyl gentamicin C1 a.
The preparation method of the 1, 3, 2' -N, N, N-triacetyl gentamicin C1a has the following reaction route:
compared with the prior art, the preparation method of the invention has the following beneficial effects:
the method is characterized in that a Boc chemical reagent is directly added into a solvent of gentamicin C1a, no extra alkali is needed to be added, 6 '-N is protected by utilizing self alkalinity and steric hindrance effect, no aftertreatment is needed, and acetylation reagent and alkali are directly added into the reaction to protect N at positions 1, 3 and 2'. Compared with the general method of adding alkali for Boc protection and then carrying out post-treatment, the method has the advantages of simple operation, less side reaction, high yield and high synthesis efficiency. After the Boc protection is removed by hydrochloric acid, ammonia water is used for neutralizing and adjusting pH, the condition is mild, and the danger is small.
The beneficial effects of the present invention are further illustrated by the comparative data below:
the specific implementation mode is as follows:
the invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1
Dissolving 1a 10g of gentamicin C1 in 100mL of methanol, adding 5.34g of Boc anhydride (di-tert-butyl dicarbonate), stirring at room temperature for 24h, cooling the reaction solution to 0-5 ℃, adding 9mL of acetic anhydride and 15mL of triethylamine, stirring for 2h, adding 100mL of water, and concentrating to remove methanol. Adding 100mL of 4mol/L hydrochloric acid into the concentrated solution under stirring, stirring at room temperature for 2h, adding ammonia water to neutralize the solution to about pH 8 after the reaction is completed, concentrating the solution to remove the solvent, separating the concentrated solution by silica gel column chromatography, and eluting the solution by chloroform, methanol and ammonia water according to a certain proportion to obtain 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, wherein the yield is 62 percent, and the purity is 97.2 percent.
Example 2
Dissolving gentamicin C1a 3g in methanol 30mL, adding Boc-ON (2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile) 1.6g, stirring at room temperature for 30h, cooling the reaction solution to 0-5 ℃, adding acetic anhydride 2.7mL and triethylamine 4.5mL, stirring for 2h, adding water 30mL, and concentrating to remove methanol. Adding 30mL of 4mol/L hydrochloric acid into the concentrated solution under stirring, stirring at room temperature for 2h, after the reaction is completed, adding ammonia water to neutralize the solution to about pH 8, concentrating the solution to remove the solvent, separating the concentrated solution by silica gel column chromatography, and eluting the solution by chloroform, methanol and ammonia water according to a certain proportion to obtain 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, wherein the yield is 75 percent, and the purity is 98.5 percent.
Example 3
Dissolving gentamicin C1a 5g in methanol 50mL, adding Boc-ON (2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile) 2.5g, stirring at room temperature for 24h, cooling the reaction solution to 0-5 ℃, adding acetic anhydride 4.5mL and triethylamine 7.5mL, stirring for 2h, adding water 30mL, and concentrating to remove methanol. Adding 30mL of 4mol/L hydrochloric acid into the concentrated solution under stirring, stirring at room temperature for 2h, adding ammonia water to neutralize the solution to about pH 8 after the reaction is completed, concentrating the solution to remove the solvent, separating the concentrated solution by silica gel column chromatography, and eluting the solution by chloroform, methanol and ammonia water according to a certain proportion to obtain 1, 3, 2' -N, N, N-triacetyl gentamicin C1a, wherein the yield is 82 percent, and the purity is 98.8 percent.
Claims (1)
1. A preparation method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a is characterized by comprising the following steps:
dissolving gentamicin C1a 5g in 50mL of methanol, adding Boc-ON 0.9eq, stirring for 24h, cooling the reaction solution to 0-5 ℃, adding acetic anhydride 4.2eq and triethylamine 4.8eq, stirring for 2h, adding 50mL of water, concentrating to remove methanol, adding 4mol/L hydrochloric acid 50mL into the concentrated solution, stirring for 2h, adding ammonia water to neutralize to pH 8, concentrating, and separating and purifying the concentrated solution by silica gel column chromatography to obtain 1, 3, 2' -N, N, N-triacetyl gentamicin C1 a.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911331173.0A CN111040007B (en) | 2019-12-21 | 2019-12-21 | Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911331173.0A CN111040007B (en) | 2019-12-21 | 2019-12-21 | Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111040007A CN111040007A (en) | 2020-04-21 |
| CN111040007B true CN111040007B (en) | 2022-09-06 |
Family
ID=70238290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911331173.0A Active CN111040007B (en) | 2019-12-21 | 2019-12-21 | Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111040007B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113960183A (en) * | 2020-12-28 | 2022-01-21 | 常州方圆制药有限公司 | Method for detecting acetylation impurities in etimicin intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498823A (en) * | 2019-08-14 | 2019-11-26 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 6 "-N- ethyl Gentamicin C1as |
-
2019
- 2019-12-21 CN CN201911331173.0A patent/CN111040007B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498823A (en) * | 2019-08-14 | 2019-11-26 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 6 "-N- ethyl Gentamicin C1as |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111040007A (en) | 2020-04-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20180016359A1 (en) | Sugammadex preparation and purification method | |
| EP2504298B1 (en) | Preparation and purification of iodixanol | |
| EP3828170A1 (en) | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene | |
| CN115505051A (en) | Method for refining sugammadex sodium | |
| CN1453284A (en) | Synthesis of trichlorosucrose | |
| CN111040007B (en) | Synthetic method of 1, 3, 2' -N, N, N-triacetyl gentamicin C1a | |
| CN104356012B (en) | The preparation method of sarpogrelate hydrochloride light degradation impurity | |
| CN1844110A (en) | Method for synthesizing Valsartan with high optical purity | |
| CN1896050A (en) | Production of gabapendin | |
| EP4083039A1 (en) | Method for preparing isavuconazonium sulfate | |
| CN109836424B (en) | Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt | |
| CN110498823B (en) | Synthetic method of 6' -N-ethyl gentamicin C1a | |
| CN110372760A (en) | A kind of synthetic method of 3-N- ethyl Gentamicin C1a | |
| CN112694445A (en) | Purification method of oxalaggrin sodium intermediate | |
| CN103450331B (en) | A kind of process for purification of bortezomib | |
| CN110128449A (en) | 7- phenylacetyl amido -3- desacetoxycephalosporanic acid salt and its preparation method and application | |
| WO2013159285A1 (en) | Method for preparing (s)-oxiracetam | |
| CN108822014A (en) | A kind of synthetic method of AVM hereinafter Batan intermediate | |
| CN110256464B (en) | Method for preparing cefditoren pivoxil ring-opening dimer | |
| WO2013159283A1 (en) | Method for preparing (s)-oxiracetam | |
| CN114249723A (en) | Preparation method of zolpidem and key intermediate thereof | |
| CN108484689B (en) | Synthesis method of valrubicin | |
| CN111004255A (en) | Preparation method of cefcapene lactone compound or hydrochloride thereof | |
| US20210252037A1 (en) | Process for the preparation of hydroxocobalamin hydrochloride | |
| CN106317064B (en) | The preparation method of methylnaltrexone bromide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 214028 Changjiang South Road, new Wu District, Wuxi, Jiangsu Province, No. 12 Applicant after: Wuxi Jiyu Shanhe Pharmaceutical Co.,Ltd. Address before: 214028 No. 12 Changjiang South Road, New District, Jiangsu, Wuxi Applicant before: WUXI JIMIN KEXIN SHANHE PHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |