CN114920789B - Preparation method of tylosin key intermediate - Google Patents
Preparation method of tylosin key intermediate Download PDFInfo
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- CN114920789B CN114920789B CN202210791306.8A CN202210791306A CN114920789B CN 114920789 B CN114920789 B CN 114920789B CN 202210791306 A CN202210791306 A CN 202210791306A CN 114920789 B CN114920789 B CN 114920789B
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- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 title claims abstract description 48
- 239000004182 Tylosin Substances 0.000 title claims abstract description 46
- 229960004059 tylosin Drugs 0.000 title claims abstract description 46
- 229930194936 Tylosin Natural products 0.000 title claims abstract description 45
- 235000019375 tylosin Nutrition 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 38
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 32
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 26
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000019253 formic acid Nutrition 0.000 claims abstract description 19
- 238000005580 one pot reaction Methods 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 35
- ICVKYYINQHWDLM-KBEWXLTPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 ICVKYYINQHWDLM-KBEWXLTPSA-N 0.000 claims description 9
- 229960001717 tylosin tartrate Drugs 0.000 claims description 9
- NBOODGNJLRRJNA-IAGPQMRQSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl Chemical compound OP(O)(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 NBOODGNJLRRJNA-IAGPQMRQSA-N 0.000 claims description 8
- 229940031989 tylosin phosphate Drugs 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 23
- 238000007086 side reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 18
- 238000006460 hydrolysis reaction Methods 0.000 description 16
- 238000006268 reductive amination reaction Methods 0.000 description 15
- 230000007062 hydrolysis Effects 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 125000003172 aldehyde group Chemical group 0.000 description 7
- 238000005576 amination reaction Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- HNDXPZPJZGTJLJ-UEJFNEDBSA-N (4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-5,9,13-trimethyl-7-(2-piperidin-1-ylethyl)-15-(piperidin-1-ylmethyl)-1-oxacyclohexadeca-11,13-diene-2,10-dione Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1CCCCC1)CN1CCCCC1)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O HNDXPZPJZGTJLJ-UEJFNEDBSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000006192 iodination reaction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000413 hydrolysate Substances 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229960002659 tildipirosin Drugs 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000606748 Actinobacillus pleuropneumoniae Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000588779 Bordetella bronchiseptica Species 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606807 Glaesserella parasuis Species 0.000 description 1
- 241000606788 Haemophilus haemolyticus Species 0.000 description 1
- 241000606831 Histophilus somni Species 0.000 description 1
- 241000606856 Pasteurella multocida Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003525 allosyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940051027 pasteurella multocida Drugs 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- 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
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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a key intermediate of tylosin, which comprises the steps of adding 4-dimethylaminopyridine as a catalyst and piperidine in the presence of formic acid aqueous solution, adopting a one-pot process to directly react and generate the key intermediate of tylosin. The method has the advantages of high total yield, less side reaction, low cost, simple and feasible operation and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of chemical industry, and particularly relates to a preparation method of a key intermediate of tylosin.
Background
Tylosin (Tildipirosin) is a macrolide semisynthetic antibiotic, a derivative of tylosin. The Tildipirosin has CAS number 328898-40-4, molecular formula of C41H71N3O8, molecular weight of 734.02, melting point of 192 deg.C, and is slightly soluble in polar organic solvent (such as methanol, acetone, etc.). The tylosin is a broad-spectrum antibacterial agent, has antibacterial activity on some gram-positive bacteria and gram-negative bacteria, is particularly sensitive to pathogenic bacteria causing respiratory diseases of pigs and cattle, such as actinobacillus pleuropneumoniae, pasteurella multocida, bordetella bronchiseptica, haemophilus parasuis, haemophilus haemolyticus, and histophilus somni, and is used for preventing and treating respiratory infectious diseases of pigs and cattle.
Patent document US6514946B1 discloses a method for preparing tylosin, the starting material is 20, 23-diiodo-5-0-carbomycaminose-tylosin, the compound is expensive and not easy to obtain, and the final product needs column chromatography purification and is not suitable for industrial production.
Patent document WO2008012343 discloses another method for preparing tylosin, the starting material is tylosin, hydroxyl is exposed at the 23 rd position after 20 th position is subjected to reductive amination and hydrolysis, the 23 rd position hydroxyl is activated, and finally the tylosin is prepared by amination. The final product of the method needs multiple recrystallisation and has low yield.
Patent document CN102863487a discloses another method for preparing tylosin, which uses tylosin tartrate as a starting material, and forms a final product through hydrolysis, reductive amination and iodo-reammoniation, and the synthetic route needs to use a large amount of expensive iodine, which results in higher cost.
Patent document CN104892704a reports a preparation method of tylosin, which hydrolyzes tylosin tartrate, oxidizes the exposed hydroxyl into aldehyde group by using TEMPO oxidation system and then performs reductive amination to prepare the tylosin.
Patent document CN105384788a reports another preparation method of tylosin, which is to hydrolyze tylosin, oxidize the exposed hydroxyl group into aldehyde group by using NaNO 2/acetic anhydride oxidation system, and then carry out reductive amination to prepare the tylosin. Both methods oxidize hydroxyl into aldehyde group by adopting selective oxidation reaction, the oxidation method is not easy to strictly control the reaction process in the stage of generating aldehyde group, side reactions are more, and aldehyde group compounds are unstable.
Patent document CN104558076a reports another preparation method of tylosin, which comprises the steps of reducing aldehyde groups in tylosin into hydroxyl groups, then hydrolyzing, iodizing and aminating to obtain the tylosin, wherein the two hydroxyl groups are required to be iodized, and the dosage of iodine is increased, so that the cost is increased.
Patent document CN104497082a reports another preparation method of tylosin, which is to prepare the tylosin by 5 steps of reactions of hydrolysis, reductive amination, sulfonic acid esterification, iodination and amination of tylosin, and the method has more reaction steps and is not beneficial to industrialized scale-up production.
Patent document CN105254693a reports another preparation method of tylosin, which is to carry out silylation protection on hydroxyl groups on allose groups and two hydroxyl groups in carbanilate groups after carrying out reductive amination and hydrolysis of tylosin to remove one sugar, then carry out iodination reaction with trimethyliodosilane, finally carry out amination reaction to obtain the tylosin, and the method has more reaction steps, and the silylation protection is not thorough and is easy to generate side reaction.
Another preparation method of tylosin is reported in patent document CN106749457a, which is to hydrolyze tylosin in an acidic solution, then add a sulfonic acid esterification reagent into the hydrolyzed product to carry out sulfonic acid esterification reaction, add piperidine and formic acid into the obtained sulfonic acid esterification product to carry out reductive amination reaction, add piperidine and alkali into the obtained reductive amination product to carry out amination reaction, and adjust alkali after the reaction is completed, thus obtaining the final product tylosin. The aldehyde groups of the reaction sites are easily destroyed in the hydrolysis process of the method, thereby influencing the subsequent reaction.
Patent document CN113121625 reports a method for preparing tylosin comprising: carrying out primary hydrolysis reaction on tylosin or salt thereof in an acid solution with the pH value of 1-3 to generate a compound 1; subjecting compound 1 to reductive amination with piperidine in the presence of a reducing agent to yield compound 2; subjecting compound 2 to secondary hydrolysis reaction in an acidic solution to produce compound 3; the compound 3 and a sulfoacid reagent are subjected to a sulfoacid esterification reaction, and then subjected to an amination reaction with piperidine to generate the tylosin. The method has the advantages of mild reaction condition, less side reaction, high yield, low cost and simple operation, and is suitable for industrialized mass production.
The above documents present various processes for the preparation of tylosin, mainly comprising a primary hydrolysis, a secondary hydrolysis, a reductive amination, an iodination, an amination, or a sulphonation reaction and an amination, or an oxidation reaction and a reductive amination. In either scheme, the synthetic route is long, the process is complicated, and key intermediates must be prepared as follows:
The key intermediates are all obtained by primary hydrolysis, reductive amination and secondary hydrolysis. The process route is long, the yield is low, and the cost is high.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: the preparation method of the key intermediate of the tylosin has the advantages of short process route, high yield and low cost.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
The invention discloses a preparation method of a key intermediate of tylosin, which comprises the steps of adding 4-dimethylaminopyridine as a catalyst and piperidine into tylosin or a salt thereof in the presence of formic acid aqueous solution, and directly reacting to generate a compound shown in the following formula by adopting a one-pot process:
As a further improvement, the tylosin or a salt thereof according to the present invention is specifically tylosin tartrate or tylosin phosphate.
As a further improvement, the mass concentration of the formic acid aqueous solution is 1-10%.
As a further improvement, the mass ratio of the formic acid aqueous solution to tylosin tartrate or tylosin phosphate raw material: 5: 1-50: 1.
As a further improvement, the tylosin tartrate or tylosin phosphate according to the present invention: piperidine: the molar ratio of 4-dimethylaminopyridine is 1:1.1-1.5:1.1-2.0.
As a further improvement, the reaction temperature is reflux temperature and the reaction time is 2-4 hours.
As a further improvement, the molar yield of the key intermediate of the one-pot process tylosin exceeds 98 percent and the content exceeds 99 percent.
The beneficial technical effects of the invention
Compared with the prior art, the preparation method provided by the invention has one or more of the following advantages:
(1) The one-pot process is used, three reaction steps of primary hydrolysis, reductive amination and secondary hydrolysis in the prior art are simplified into one-step reaction, the key intermediate of the tylosin is directly obtained, the process route is greatly shortened, and the operation is not complicated.
(2) In the reaction research, three reaction conditions which are completely different are needed for the original three-step reaction, and the post-treatment is troublesome. The inventors have unexpectedly found that by introducing 4-dimethylaminopyridine as a catalyst, the three reactions can be effectively and fully activated, so that the three-step reaction can be efficiently completed by a one-pot method.
(3) In the method, no extra solvent is used as a reaction medium, and excessive formic acid can be recycled, so that the process is environment-friendly.
(4) The method has milder reaction conditions and simpler post-treatment, the molar yield of the key intermediate of the tylosin by the one-pot process exceeds 98 percent, and the content exceeds 99 percent. The method has the advantages of high total yield, less side reaction, low cost, simple and feasible operation and suitability for industrial production.
Detailed Description
Example 1
In the presence of formic acid aqueous solution, 4-dimethylaminopyridine is added as a catalyst, piperidine is added, and a one-pot process is adopted to directly react to generate the compound A shown in the following formula.
To a 1000ml reaction vessel, 400g of aqueous formic acid solution having a mass concentration of 10% was added, and 80g (0.079 mol) of tylosin phosphate was added. Then, piperidine 0.1185mol was added thereto with stirring, and 4-dimethylaminopyridine 0.158mol was added thereto. The temperature was raised to reflux and the reaction time was 2 hours.
And after the reaction is finished, cooling. Recovering the aqueous formic acid solution. Adding cold dilute alkali solution, controlling ph to 7-9, fully stirring, and filtering to obtain an off-white product A. The molar yield of the reaction is 98.0 percent, and the product content is 99.3 percent.
Example 2
In the presence of formic acid aqueous solution, 4-dimethylaminopyridine is added as a catalyst, piperidine is added, and a one-pot process is adopted to directly react to generate the compound A.
To a 5000ml reaction vessel, 4000g of an aqueous formic acid solution having a mass concentration of 1% was added, and 80g (0.087 mol) of tylosin was added. Then, 0.096mol of piperidine was added thereto with stirring, and 0.096mol of 4-dimethylaminopyridine was added thereto. The temperature was raised to reflux and the reaction time was 4 hours.
And after the reaction is finished, cooling. Recovering the aqueous formic acid solution. Adding cold dilute alkali solution, controlling ph to 7-9, fully stirring, and filtering to obtain an off-white product A. The molar yield of the reaction is 98.5 percent and the product content is 99.4 percent.
Example 3
In the presence of formic acid aqueous solution, 4-dimethylaminopyridine is added as a catalyst, piperidine is added, and a one-pot process is adopted to directly react to generate the compound A.
1600G of formic acid aqueous solution with mass concentration of 5% and 80g (0.076 mol) of tylosin tartrate are added into a 2000ml reaction kettle. Then, 0.099mol of piperidine was added thereto while stirring, and 0.115mol of 4-dimethylaminopyridine was added thereto. The temperature was raised to reflux and the reaction time was 3 hours.
And after the reaction is finished, cooling. Recovering the aqueous formic acid solution. Adding cold dilute alkali solution, controlling ph to 7-9, fully stirring, and filtering to obtain an off-white product A. The molar yield of the reaction is 99.1 percent, and the product content is 99.6 percent.
Comparative example 1
(1) One-time hydrolysis
80G (0.079 mol) of tylosin phosphate was dissolved in 3000mL of water, and 40mL of sulfuric acid with a mass fraction of 20% was added to obtain a reaction solution with a pH of 2. Heating the reaction solution to 35 ℃ and preserving heat for 1h, cooling to room temperature after the reaction is monitored by liquid chromatography, adding 300mL of butyl acetate into the reaction solution, adding 24mL of 30% NaOH solution with stirring to adjust the pH value to be about 10, separating the solution after stirring, and taking an upper organic phase to obtain a primary hydrolysate. The organic phase was directly taken to the next reaction.
(2) Reductive amination
7.5G (0.088 mol) of piperidine and 5g (0.108 mol) of formic acid are added into the organic phase obtained in the step (1), the mixture is reacted at 70 ℃ for 3 hours in a heat preservation way, 150mL of hydrochloric acid solution with the mass fraction of 5% is added after the temperature is reduced to room temperature, the pH value is adjusted to be about 3, then the mixture is separated, and the aqueous phase is taken to obtain a reductive amination product. The aqueous phase is directly passed to the next reaction.
(3) Secondary hydrolysis
Adding the water phase obtained in the previous reaction into a flask, then adding 250mL of 40% hydrobromic acid (1.7 mol) solution heated to 70 ℃ to obtain hydrolysis reaction solution, heating to 70 ℃, reacting for 1h at 70 ℃, then reducing to below 30 ℃, transferring the liquid into a separating funnel, washing with 500mL of dichloromethane, transferring the water phase into the flask, slowly adding 30% sodium hydroxide solution with mass fraction to adjust the pH value to 9-11 after dilution, separating out solids, filtering, drying to obtain 48g of secondary hydrolysate of off-white solid, wherein the molar yield is 61.2%, and the purity is 93.5% through HPLC detection.
As can be seen, compared with comparative example 1 and the examples, the one-pot process of catalyzing 4-dimethylaminopyridine is not used, so that the reaction route is long, the operation is complicated, the yield is low, the product quality is poor, and the industrial value is limited.
Finally, it should also be noted that the above list is merely a specific example of the invention. Obviously, the invention is not limited to the above embodiment examples, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.
Claims (3)
1. A preparation method of a key intermediate of tylosin is characterized in that tylosin salt is added with 4-dimethylaminopyridine as a catalyst and piperidine in the presence of formic acid aqueous solution, and a one-pot process is adopted to directly react to generate a compound shown as the following formula:
The tylosin salt is specifically tylosin tartrate or tylosin phosphate, and the mass ratio of the formic acid aqueous solution to the tylosin tartrate or tylosin phosphate raw material is 5: 1-50: 1, the tylosin tartrate or tylosin phosphate: piperidine: the molar ratio of 4-dimethylaminopyridine is 1:1.1-1.5:1.1-2.0, wherein the reaction temperature is reflux temperature, and the reaction time is 2-4 hours.
2. The preparation method of the tylosin key intermediate according to claim 1, wherein the mass concentration of the formic acid aqueous solution is 1% -10%.
3. The preparation method of the key intermediate of tylosin according to claim 1 or 2, wherein the molar yield of the key intermediate of tylosin in the one-pot process is more than 98%, and the content is more than 99%.
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| CN102863487A (en) * | 2012-10-08 | 2013-01-09 | 齐鲁动物保健品有限公司 | Process for preparing 20,23-bi-piperidyl-5-O-carbon mould amine glycosyl-tylosin lactone |
| CN103880903A (en) * | 2014-03-21 | 2014-06-25 | 烟台万润药业有限公司 | Method for preparing tylosin macrolide and derivatives thereof |
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| CN104774223A (en) * | 2015-03-26 | 2015-07-15 | 宁夏泰瑞制药股份有限公司 | Method for producing tildipirosin by using tylosin alkali |
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| CN103880903A (en) * | 2014-03-21 | 2014-06-25 | 烟台万润药业有限公司 | Method for preparing tylosin macrolide and derivatives thereof |
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