CN109206487B - Improved process for the preparation of telavancin or a salt thereof - Google Patents
Improved process for the preparation of telavancin or a salt thereof Download PDFInfo
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- CN109206487B CN109206487B CN201710531493.5A CN201710531493A CN109206487B CN 109206487 B CN109206487 B CN 109206487B CN 201710531493 A CN201710531493 A CN 201710531493A CN 109206487 B CN109206487 B CN 109206487B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
- C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
Abstract
The invention belongs to the field of medicine synthesis, and particularly relates to an improved preparation method of telavancin or a salt thereof. The preparation method adjusts the feeding sequence of the Mannich reaction, controls the reaction temperature, greatly shortens the reaction time and obviously reduces the content of the bis-Mannich by-product. In addition, the intermediate compound III obtained by post-treatment through a low-boiling point solvent is easy to industrially operate, and the purity of the intermediate compound III is over 95 percent.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to an improved preparation method of telavancin or hydrochloride thereof.
Background
Telavancin hydrochloride (Telavancin) is a semisynthetic lipopeptide antibiotic jointly developed by Theravance and Clinigen company, with the trade name of Vibativ, and is approved by the united states Food and Drug Administration (FDA) to be marketed at the earliest 9 th and 11 th in 2009, and then approved by the european drug administration (EMA) to be marketed at 2 nd 9 th and 2011 in 2011. Telavancin hydrochloride is suitable for complex skin and skin structural infections (cSSSI) caused by sensitive gram-positive bacteria and nosocomial and ventilator-associated bacterial pneumonia (HABP/VABP) caused by sensitive staphylococcus aureus by interfering with peptidoglycan polymerization and cross-linking, inhibiting bacterial cell wall synthesis, and having a barrier function of binding to bacterial cell membranes and disrupting the membranes. Telavancin: chemical name: n3 "- [2- (decylamino) ethyl ] -29- [ [ (phosphonomethyl) amino ] methyl ] -vancomycin, chemical structure:
compared with general chemical synthesis products, the compound has the characteristics of low purity, complex components, more active groups (such as hydroxyl, amino, aldehyde and the like) in a molecular structure, most of the active groups have configuration problems and the like, so that various byproducts are generated, and therefore, compared with the pure chemical synthesis products, the impurity spectrum analysis of the antibiotic product is more complex and the impurities are more difficult to predict and control.
CN1432023 discloses a reductive alkylation process for vancomycin and analogues thereof; CN1671732 a method for isolating and purifying glycopeptide phosphonate derivatives using a resin containing polystyrene is disclosed; CN1610692 discloses a method for preparing glycopeptide phosphonate derivatives having amino-containing side chains and CN1547481 discloses a method for preparing telavancin hydrochloride. Wherein in the post-treatment of the first two steps of reaction, the reaction solution is poured into a saturated solution of sodium chloride for crystallization, and the product is difficult to filter and is in a colloid state. CN1871253 discloses that the two-step reaction obtains an intermediate N with the purity of 85% after post-treatmentvan-2- (n-decylamino) ethyl vancomycin hydrochloride.
In addition, NvanThe (E) -2- (n-decylamino) ethyl vancomycin hydrochloride, aminomethylphosphonic acid and formaldehyde are subjected to Mannich condensation reaction to obtain telavancin, and the Mannich condensation reaction can generate impurities, particularly, a multi-aminomethylated product, namely a bis-Mannich byproduct is produced. The bis-mannich by-product in patent CN1547481 was 3.6%. The properties of the bis-Mannich by-product are close to those of main component telavancin, the retention time in a high performance liquid chromatogram is short, and the bis-Mannich by-product is difficult to remove in a purification process. Therefore, there is a need to find an effective way to reduce the content of by-products and to increase the purity of the prepared telavancin hydrochloride.
Disclosure of Invention
In one aspect of the present application, there is provided a process for the preparation of telavancin (a compound of formula IV), or a salt thereof, comprising:
(1) mixing a tertiary amine, water and aminomethylphosphonic acid to obtain a reaction mixture of aminomethylphosphonic acid;
(2) mixing a tertiary amine, an inert diluent and a compound of formula iii to provide a reaction mixture of the compound of formula iii;
(3) mixing the reaction mixture obtained in the step (1) and the reaction mixture obtained in the step (2), and maintaining the temperature of the obtained mixture at-20-0 ℃;
(4) mixing the formaldehyde aqueous solution and the mixture obtained in the step (3), and maintaining the temperature of the obtained mixture at-20-0 ℃ to obtain telavancin;
(5) if desired, to an acid addition salt of telavancin (compound of formula IV).
Wherein, in the step (1), the tertiary amine includes but is not limited to triethylamine, N-diisopropylethylamine, N-methylmorpholine and the like; more preferred bases are N, N-diisopropylethylamine; in some embodiments, the molar ratio of the tertiary amine to the aminomethylphosphonic acid in step (1) is 0.5:1 to 2:1, preferably 1: 1. The temperature of the mixture is maintained at-5 to 10 ℃, preferably 0 to 5 ℃.
The tertiary amine in the step (2) includes but is not limited to triethylamine, N-diisopropylethylamine, N-methylmorpholine and the like; more preferred bases are N, N-diisopropylethylamine; in some embodiments, the molar ratio of the tertiary amine of step (2) to the compound of formula iii is 8:1 to 15:1, preferably 10: 1. In some embodiments, the inert diluent of step (2) is selected from acetonitrile, water, or mixtures thereof. In a preferred embodiment, the inert solvent is an acetonitrile/water mixture. The temperature of the mixture is maintained at-20 to 0 ℃, preferably-15 to-5 ℃.
The temperature of the mixture in the step (3) is controlled to be-15 to-5 ℃. In some embodiments, the reaction mixture of step (1) and step (2) in step (3) is the reaction mixture of aminomethylphosphonic acid and the reaction mixture of the compound of formula III, respectively, in a molar ratio of 4:1 to 6:1, preferably 5: 1.
The temperature of the mixture in the step (4) is controlled to be-15 to-5 ℃. In some embodiments, the molar ratio of the aqueous formaldehyde solution of step (4) to the compound of formula iii is 1:1 to 3:1, preferably 2: 1. In some embodiments, the mixing reaction time of step (4) is 4 to 6 hours.
Step (5) the resulting compound of formula IV is isolated by conventional procedures including precipitation, filtration, and the like, and suitable acids (HA) include, but are not limited to, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid) and organic acids (e.g., maleic acid, fumaric acid, oxalic acid, citric acid, salicylic acid, acetylsalicylic acid), and in a preferred embodiment, the acid is hydrochloric acid, and the pH of the reaction mixture is adjusted to 2.0 to 3.0. The temperature of the mixture is maintained at-20 to 0 ℃ during acidification, preferably-15 to-5 ℃.
Wherein, the acid addition salt of the telavancin (compound shown in formula IV) obtained by the method is a mixture of dihydrochloride and trihydrochloride, and the content of chloride ions is in the range of 4.2-5.7%. In a preferred embodiment, the chloride ion content of the acid addition salt of telavancin is in the range of 4.5% to 4.7%.
In some embodiments, step (1): mixing N, N-diisopropylethylamine, water and aminomethyl phosphonic acid, wherein the molar ratio of the N, N-diisopropylethylamine to the aminomethyl phosphonic acid is 1:1, obtaining a reaction mixture of the aminomethyl phosphonic acid, and maintaining the temperature of the obtained mixture at 0-5 ℃;
step (2): mixing a mixture of a compound of formula III, N, N-diisopropylethylamine and acetonitrile/water, wherein the molar ratio of the N, N-diisopropylethylamine to the compound of formula III is 10:1, preparing a reaction mixture of the compound of formula III, and maintaining the temperature of the obtained mixture at-15 to-5 ℃;
and (3): mixing the reaction mixtures obtained in the step (1) and the step (2), wherein the molar ratio of the mixture obtained in the step (1) to the mixture obtained in the step (2) is 5:1, and maintaining the temperature of the obtained mixture at-15 to-5 ℃;
and (4): dropwise adding an aqueous formaldehyde solution into the mixture obtained in the step (3), wherein the molar ratio of the aqueous formaldehyde solution to the compound shown in the formula III is 2:1, and maintaining the temperature of the obtained mixture at-15 to-5 ℃ to obtain telavancin;
and (5): and (3) adjusting the pH of the mixture obtained in the step (4) to 2.0-3.0 by using 3mol/L hydrochloric acid solution, and converting the telavancin (the compound shown in the formula IV) into hydrochloride of the telavancin.
In another aspect of the present application, there is provided a process for the preparation of a compound of formula III, or a salt thereof, comprising the steps of:
a) reacting vancomycin, a compound of formula II and with a reducing agent to give a compound of formula I or a salt thereof; in the presence of a low-boiling point solvent, controlling the temperature to be 10-30 ℃, stirring for crystallization, filtering, and drying under reduced pressure to obtain a purified product of the intermediate compound shown in the formula I or a salt thereof;
b) reacting a compound of formula I with an amine to provide a compound of formula III or a salt thereof; in the presence of a low-boiling point solvent, controlling the temperature to be 10-30 ℃, stirring for crystallization, filtering, and drying under reduced pressure to obtain a purified product of the intermediate compound shown in the formula III or a salt thereof;
wherein the compound of formula II R1Is an amino protecting group which is removed upon nucleophilic amine treatment. Preferably, R1Is 9-fluorenylmethoxycarbonyl.
In step a), vancomycin and the compound of formula II are reacted in the presence of an excess of a suitable base, which serves to neutralize the vancomycin salt and promote the formation of imines and/or hemiaminals, including organic bases, such as amines, alkali metal carboxylates (e.g., sodium acetate, etc.), and inorganic bases, such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, etc.); preferably, the base is a tertiary amine including, but not limited to, triethylamine, N-diisopropylethylamine, N-methylmorpholine, and the like; more preferred bases are N, N-diisopropylethylamine; an excess of base relative to vancomycin is typically employed. Preferably, the base is used in an amount of about 3 to about 4 equivalents to vancomycin. The inert agent is an inert diluent including, but not limited to, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and the like or mixtures thereof, preferably N, N-dimethylformamide.
In step a), when the formation of the imine and/or hemiaminal mixture is substantially complete, the reaction mixture is acidified with an excess of acid. Suitable acids include, but are not limited to, carboxylic acids (e.g., acetic acid, trichloroacetic acid, citric acid, formic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, and the like), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and the like. Preferably, the acid is trifluoroacetic acid. A molar excess of acid relative to vancomycin (and base) is typically added. Preferably, the acid is used in an amount of about 3 to about 6 equivalents of vancomycin. The anhydrous solvent includes but is not limited to one or more mixtures of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, tetrahydrofuran, 1, 2-dimethoxyethane, etc., preferably anhydrous methanol.
In step a), after acidification, the reaction intermediate is contacted with a reducing agent to reduce the imine and/or hemiaminal. Suitable reducing agents include, but are not limited to, sodium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, pyridine/borane, tert-butylamine/borane, N-methylmorpholine/borane, ammonia/borane, dimethylamine/borane, triethylamine/borane, trimethylamine/borane, and the like. Preferred reducing agents are amine/borane complexes, such as tert-butylamine/borane complex.
In the step a), the low boiling point solvent is used for carrying out post-treatment on the reaction filtrate in several times to separate out a solid product. The low-boiling point solvent comprises but is not limited to an ether solvent and a nitrile solvent, wherein the ether solvent comprises but is not limited to one or a mixture of dimethyl ether, diethyl ether, isopropyl ether, tetrahydrofuran and methyl tert-butyl ether; the nitrile solvent includes but is not limited to acetonitrile, propionitrile or a mixture of more than one of acetonitrile and propionitrile. The preferred ether solvent is isopropyl ether. The crystallization temperature is within the range of 10-30 ℃, and preferably 10-20 ℃.
In step b), the amino protecting group is removed with an amine. Controlling the temperature of the reaction solution within the range of 10-20 ℃, adding amine, raising the temperature to 20-35 ℃, and stirring for reaction, wherein the stirring reaction temperature is preferably 23-33 ℃. Suitable amines include, but are not limited to, methylamine, ethylamine, diethylamine, tert-butylamine, triethylamine, piperidine, morpholine, ammonium hydroxide. The preferred amine is diethylamine. The reaction solvent is an inert diluent including, but not limited to, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and the like or mixtures thereof, preferably N, N-dimethylformamide.
In the step b), the low boiling point solvent is used for carrying out post-treatment on the reaction filtrate in several times to separate out a solid product. The low-boiling point solvent comprises but is not limited to an ether solvent and a nitrile solvent, wherein the ether solvent comprises but is not limited to one or a mixture of dimethyl ether, diethyl ether, isopropyl ether, tetrahydrofuran and methyl tert-butyl ether; the nitrile solvent includes but is not limited to acetonitrile, propionitrile or a mixture of more than one of acetonitrile and propionitrile. The preferred ether solvent is isopropyl ether. The crystallization temperature is within the range of 10-30 ℃, and preferably 10-20 ℃.
The application also provides an impurity B, a preparation method and application thereof in product detection, wherein the impurity B is a bis-Mannich by-product generated by a Mannich reaction in the preparation method of telavancin (a compound shown in a formula IV).
In the presence of alkali, mixing aminomethylphosphonic acid, formaldehyde and a compound shown in formula III in an inert diluent for reaction, controlling the temperature to be 10-15 ℃, and acidifying with a proper acid HA to obtain an impurity B compound.
Wherein this step of the process is typically carried out in the presence of a base, the aminomethylphosphonic acid is commercially available or can be prepared by conventional procedures using commercially available starting materials and reagents; before reaction, the aminomethyl phosphonic acid is contacted with a proper alkali solution and stirred until the solution is clear; before reaction, the purified product of the intermediate compound shown in the formula III or the salt thereof is contacted with a proper alkali solution and stirred until the solution is clear; in the reaction, the aminomethylphosphonic acid mixture is added dropwise to the intermediate III solution, and the formaldehyde is then added, usually as an aqueous solution.
In some embodiments of the present application, the reaction temperature of the process is 10 to 15 ℃. Suitable bases include organic bases such as amines, alkali metal carboxylates (e.g., sodium acetate, etc.), and inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, etc.); preferably, the base is a tertiary amine including, but not limited to, triethylamine, N-diisopropylethylamine, N-methylmorpholine, and the like; more preferred bases are N, N-diisopropylethylamine; inert diluents include, but are not limited to, water, acetonitrile, or mixtures thereof, and the like. In a preferred embodiment, this step of the process is carried out in an acetonitrile/water mixture.
In some embodiments herein, the resulting impurity B compound is isolated by conventional techniques, including precipitation, filtration, and the like, and suitable acids (HA) include, but are not limited to, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid) and organic acids (e.g., maleic acid, fumaric acid, oxalic acid, citric acid, salicylic acid, acetylsalicylic acid), and in a preferred embodiment, the acid is hydrochloric acid, adjusting the pH of the reaction mixture to 2.0 to 3.0. In addition, acetonitrile is added to facilitate precipitation of the reaction product (i.e., impurity B compound), and the resulting precipitate is collected by filtration, optionally washed with additional acetonitrile.
The term "vancomycin" is used herein in a art-recognized manner to refer to a glycopeptide antibiotic referred to as vancomycin. See, for example, r. nagarajan, "glycooptide antibiotics," Marcel Dekker, inc. (1994), and references cited therein. The label "N3" - "indicates a substitution at the vancomycin (vancosamine) nitrogen atom. This position is also known as N of vancomycinvan-a bit. In addition, using the conventional vancomycin numbering system, the label "29-" indicates the carbon atom position between the two hydroxyl groups on the phenyl ring of amino acid 7 (AA-7). This position is also sometimes referred to as the "7 d" or "resorcinol position" of vancomycin.
The method is used for preparing the Mannich condensation reaction of telavancin, the feeding sequence is adjusted, the aminomethyl phosphonic acid mixture and the compound mixture shown in the formula III are sequentially prepared, the aminomethyl phosphonic acid mixture and the compound mixture are mixed and added into a formaldehyde solution dropwise, the reaction temperature is-15 to-5 ℃, the reaction time is greatly shortened to 4 to 6 hours, and the content of a bis-Mannich byproduct is obviously reduced to 1.2 to 1.3 percent. In addition, the products of the steps a) and b) are post-treated by a low boiling point solvent, so that the reaction mixture is easy to separate from the inert solvent N, N-dimethylformamide, the industrial operation is easy, and the intermediate compound III of white powdery solid is obtained, and the purity is over 95 percent. The application also provides an impurity B and a preparation method thereof, and the impurity B is used as a reference substance to detect the quality of the telavancin hydrochloride product.
Detailed Description
The present application is further described with reference to the following examples, which should be construed as limiting the scope of the present application.
EXAMPLE 1 preparation of Compound I
Adding 40L of N, N-dimethylformamide and 4kg of vancomycin hydrochloride into a 100L reaction tank, stirring for 10 minutes, controlling the temperature of the material liquid to be 0-10 ℃, dropwise adding 1.6L of N, N-diisopropylethylamine, stirring for 10 minutes after dropwise adding, controlling the temperature of the material liquid to be 0-10 ℃, slowly adding 1.6kg of decyl (2-oxoethyl) carbamic acid 9H-fluorene-9-methyl ester (compound shown in formula II), stirring for 24 hours after adding, controlling the temperature of the material liquid to be 5 +/-5 ℃, and sampling, tracking and detecting by HPLC to reach the end point of the reaction.
Adding 16L of anhydrous methanol, controlling the temperature to be 0-10 ℃, slowly dropwise adding 1.1L of trifluoroacetic acid into the feed liquid, keeping the temperature of the feed liquid at 5 +/-5 ℃ for stirring reaction for 1 hour after dropwise adding, adding 0.4kg of borane-tert-butylamine complex, keeping the temperature of the feed liquid at 0-10 ℃ for stirring reaction for 4 hours, carrying out HPLC tracking reaction until the end point is reached, filtering, and collecting filtrate.
Adding 300L of isopropyl ether into a 500L reaction kettle, controlling the temperature to be 10-20 ℃, dropwise adding the collected filtrate, keeping the temperature of the feed liquid to be 10-20 ℃, stirring and crystallizing for more than 2 hours, after crystallization, performing spin filtration, and averagely pulping a filter cake twice by using 66L of isopropyl ether. Drying under reduced pressure at 25 + -5 deg.C for more than 20 hr to obtain 6.16kg of intermediate compound of formula I of telavancin hydrochloride (loss on drying: 11.54%, yield: 102.8%, purity 95.04%).
EXAMPLE 2 preparation of Compound III
Adding 22L of N, N-dimethylformamide and 6.16kg of a compound shown in the formula I into a 50L reaction tank, stirring for 10 minutes, cooling to 10-20 ℃, slowly dropwise adding 1.13L of diethylamine into the material liquid, heating, controlling the temperature of the material liquid to 23-33 ℃, stirring for reacting for 2 hours, sampling, and carrying out HPLC tracking detection until the reaction end point is reached. Filtering and collecting filtrate.
Adding 327L isopropyl ether into a 500L reaction kettle, controlling the temperature to be 10-20 ℃, slowly dripping the collected filtrate into the isopropyl ether while stirring, keeping the temperature of the feed liquid to be 10-20 ℃, stirring and crystallizing for more than 2 hours, throwing and filtering after crystallization is finished, evenly pulping a filter cake twice by using 65L isopropyl ether, and drying under reduced pressure at 25 +/-5 ℃ for more than 12 hours to obtain 5.02kg of the intermediate compound III of telavancin (the drying weight loss: 13.52%, the purity: 95.50%, and the yield: 91.9%).
EXAMPLE 3 preparation of Compound IV
Preparing an aminomethyl phosphonic acid solution: adding 13L of purified water into a 20L glass reaction tank at room temperature, adding 1.5kg of aminomethylphosphonic acid while stirring, stirring for 10 minutes, slowly dropwise adding 2.17L of N, N-diisopropylethylamine, stirring until the feed liquid is clear, and cooling to 0-5 ℃ for later use.
Adding 35.2L of acetonitrile, 30.4L of purified water and 5.02kg of compound shown in the formula III into a 200L reaction tank, stirring for 10 minutes, cooling, controlling the temperature of the feed liquid to be-15 to-5 ℃, slowly dropwise adding 4.48L of N, N-diisopropylethylamine into the feed liquid, and stirring until the feed liquid is clear after dropwise adding. Controlling the temperature of the feed liquid to be-15 to-5 ℃, dropwise adding the aminomethyl phosphonic acid solution into the solution of the compound in the formula III, and stirring for 10 minutes at the temperature of the feed liquid to be-15 to-5 ℃. Controlling the temperature of the feed liquid to be-15 to-5 ℃, dropwise adding 0.43kg of formaldehyde aqueous solution, keeping the temperature of the feed liquid to be-15 to-5 ℃, stirring and reacting for 4 hours, sampling, and carrying out HPLC tracking detection until the reaction end point. And after the reaction is finished, controlling the temperature of the feed liquid to be-15 to-5 ℃, adjusting the pH of the feed liquid to be 2.0 to 3.0 by using 3mol/L hydrochloric acid solution of 3.8L, stirring for 30 minutes after the adjustment is finished, filtering, and collecting filtrate.
Adding 440L of acetonitrile into a 1000L reaction tank, controlling the temperature to be 10-20 ℃, dropwise adding the collected filtrate into the acetonitrile under stirring, keeping the temperature of the feed liquid to be 10-20 ℃, stirring and crystallizing for more than 2 hours, filtering by throwing, and evenly pulping a filter cake twice by using 44L of acetonitrile to obtain 9.42kg of crude telavancin hydrochloride (the weight loss on drying: 45.36%, the purity: 82.16%, and the yield: 82.7%). Example 4 preparation of Compound impurity B
Adding a compound of formula III into a reaction bottle, adding acetonitrile, stirring for 10 minutes, adding purified water, stirring until the solution is clear, cooling to-5-10 ℃, dropwise adding N, N-diisopropylethylamine, stirring for 10 minutes, dropwise adding an aminomethylphosphonic acid mixture solution, stirring for 10 minutes after the addition is finished, dropwise adding a formaldehyde solution, controlling the temperature to be 10-15 ℃, stirring for reacting for 5 hours, dropwise adding 3mol/L hydrochloric acid to adjust the pH to 2.5, cooling to-5-10 ℃, stirring for 30 minutes, filtering, dropwise adding a filtrate into acetonitrile, and crystallizing for more than 2 hours at the temperature of 10-15 ℃. Filtering, washing the filter cake with acetonitrile twice, and performing suction filtration to obtain the telavancin hydrochloride impurity B compound.
Claims (3)
1. A process for preparing a hydrochloride salt of a compound of formula IV comprising the steps of:
a) reacting vancomycin with a compound of formula II in the presence of N, N-diisopropylethylamine, after formation of the imine and/or hemiaminal mixture, acidifying the mixture with trifluoroacetic acid, contacting after acidification with a tert-butylamine/borane complex as reducing agent to give a compound of formula I or a salt thereof; in the presence of isopropyl ether, controlling the temperature to be 10-30 ℃, stirring for crystallization, filtering, and drying under reduced pressure to obtain a purified product of the intermediate compound shown in the formula I or a salt thereof;
b) reacting a compound of formula I with diethylamine to give a compound of formula III or a salt thereof; in the presence of isopropyl ether, controlling the temperature to be 10-30 ℃, stirring for crystallization, filtering, and drying under reduced pressure to obtain a purified product of the intermediate compound shown in the formula III or a salt thereof; wherein the compound of formula II R1Is a 9-fluorenylmethoxycarbonyl group,
(1) mixing N, N-diisopropylethylamine, water and aminomethyl phosphonic acid, wherein the molar ratio of the N, N-diisopropylethylamine to the aminomethyl phosphonic acid is 1:1, so as to obtain a reaction mixture of the aminomethyl phosphonic acid;
(2) mixing N, N-diisopropylethylamine, a mixture of acetonitrile/water and a compound of a formula III, wherein the molar ratio of the N, N-diisopropylethylamine to the compound of the formula III is 10:1, so as to obtain a reaction mixture of the compound of the formula III;
(3) mixing the reaction mixture obtained in the step (1) and the reaction mixture obtained in the step (2), and maintaining the temperature of the obtained mixture at-20-0 ℃;
(4) mixing a formaldehyde aqueous solution and the mixture obtained in the step (3), maintaining the temperature of the obtained mixture at-20-0 ℃, and reacting for 4-6 hours to obtain a compound shown in a formula IV;
(5) the conversion of the compound of formula IV of step (4) to the hydrochloride salt of the compound of formula IV is a mixture of the dihydrochloride salt and the trihydrochloride salt.
2. The method of claim 1, wherein the temperature of the mixture of step (4) is maintained at-15 to-5 ℃.
3. The process of claim 1 wherein the chloride ion content of the hydrochloride salt of the compound of formula IV is in the range of 4.5% to 4.7%.
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Non-Patent Citations (2)
| Title |
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| 特拉万星合成工艺研究;熊伦，等;《中国药科大学学报》;20170430;第48卷(第2期);全文，尤其是Scheme 1、第1.2.4-1.2.6、2.5节和摘要 * |
| 特拉万星的制备工艺研究及其类似物的合成与抗菌活性筛选;熊伦;《华东理工大学专业学位硕士论文》;中国优秀硕士学位论文全文数据库;20160831;全文，尤其是Scheme2.4、第2.3.3、2.4节和摘要 * |
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