CN114920789A - Preparation method of tildipirosin key intermediate - Google Patents
Preparation method of tildipirosin key intermediate Download PDFInfo
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- CN114920789A CN114920789A CN202210791306.8A CN202210791306A CN114920789A CN 114920789 A CN114920789 A CN 114920789A CN 202210791306 A CN202210791306 A CN 202210791306A CN 114920789 A CN114920789 A CN 114920789A
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- tylosin
- key intermediate
- tildipirosin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 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 title claims description 26
- 229960002659 tildipirosin Drugs 0.000 title claims description 25
- 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
- 238000000034 method Methods 0.000 claims abstract description 29
- 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 claims abstract description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000004182 Tylosin Substances 0.000 claims abstract description 26
- 229930194936 Tylosin Natural products 0.000 claims abstract description 26
- 229960004059 tylosin Drugs 0.000 claims abstract description 26
- 235000019375 tylosin Nutrition 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 14
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 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
- XMEGXHDYCSUOJC-KXOLBLKYSA-N 2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-16-ethyl-4,6-dihydroxy-15-(hydroxymethyl)-5,9,13-trimethyl-2,10-dioxo-1-oxacyclohexadeca-11,13-dien-7-yl]acetaldehyde Chemical compound CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O)[C@@H](CC=O)C[C@@H](C)C(=O)\C=C\C(\C)=C\[C@@H]1CO XMEGXHDYCSUOJC-KXOLBLKYSA-N 0.000 claims description 6
- XMEGXHDYCSUOJC-UHFFFAOYSA-N Tylonolide Natural products CCC1OC(=O)CC(O)C(C)C(O)C(CC=O)CC(C)C(=O)C=CC(=CC1CO)C XMEGXHDYCSUOJC-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 abstract description 10
- 238000007086 side reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 18
- 230000007062 hydrolysis Effects 0.000 description 15
- 238000006268 reductive amination reaction Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 11
- 238000005576 amination reaction Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000003172 aldehyde group Chemical group 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 238000006192 iodination reaction Methods 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012467 final product Substances 0.000 description 4
- 230000026045 iodination Effects 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 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
- 238000001914 filtration Methods 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 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
- 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
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 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
- 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
- 241000606807 Glaesserella parasuis Species 0.000 description 1
- 241000606831 Histophilus somni Species 0.000 description 1
- 241001293418 Mannheimia haemolytica 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
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process 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
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 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
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 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
- IJUPCLYLISRDRA-ULAWRXDQSA-N mycaminose Chemical group C[C@@H](O)[C@@H](O)[C@H](N(C)C)[C@@H](O)C=O IJUPCLYLISRDRA-ULAWRXDQSA-N 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
- 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
- 238000000926 separation method Methods 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a tylosin key intermediate, which comprises the steps of adding 4-dimethylaminopyridine as a catalyst into tylosin or a salt thereof in the presence of a formic acid aqueous solution, adding piperidine, and adopting a one-pot process to directly react to generate the tylosin key intermediate. The method has the advantages of high total yield, less side reaction, low cost, simple and easy operation, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical industry, and particularly relates to a preparation method of a tildipirosin key intermediate.
Background
Tyldinoside (Tildipirosin) is a semi-synthetic macrolide antibiotic that is a derivative of tylosin. Tildipirosin has CAS number of 328898-40-4, molecular formula of C41H71N3O8, molecular weight of 734.02, melting point of 192 deg.C, solubility in polar organic solvent (such as methanol and acetone), and slight solubility in water. Tildipirosin is a broad-spectrum antibacterial drug, has antibacterial activity on some gram-positive 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, mannheimia haemolytica, histophilus somni and the like, and is used for preventing and treating respiratory infectious diseases of pigs and cattle.
Patent document US6514946B1 discloses a method for preparing tylonolide, starting from 20, 23-diiodo-5-0-mycaminosyl-tylonolide, which is expensive and not easily available, and the final product requires column chromatography purification and is not suitable for industrial production.
Patent document WO2008012343 discloses another method for preparing tylosin, wherein the starting material is tylosin, the 23-position hydroxyl group is exposed after reductive amination and hydrolysis at the 20-position, the 23-position hydroxyl group is activated, and finally amination is performed to prepare the tylosin. The final product of the method needs to be recrystallized for many times, and the yield is low.
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, iodination and re-amination, and the synthetic route needs to use a large amount of expensive iodine, resulting in high cost.
Patent document CN104892704A reports a method for preparing tylosin, which comprises hydrolyzing tylosin tartrate, oxidizing the exposed hydroxyl group to aldehyde group with TEMPO oxidation system, and performing reductive amination to obtain tylosin.
Patent document CN105384788A reports another preparation method of tylonolide, which comprises hydrolyzing tylosin, oxidizing the exposed hydroxyl group into aldehyde group with a NaNO 2/acetic anhydride oxidation system, and then carrying out reductive amination to obtain the tylonolide. In both methods, a selective oxidation reaction is adopted to oxidize hydroxyl into aldehyde group, the oxidation method is not easy to strictly control the reaction process at the stage of generating aldehyde group, side reactions are more, and aldehyde group compounds are unstable.
Patent document CN104558076A reports another method for preparing tildipirosin, in which aldehyde group in tylosin is reduced to hydroxyl group, and then hydrolysis, iodination, and amination are performed to obtain tildipirosin.
Patent document CN104497082A reports another preparation method of tildipirosin, which is to prepare tildipirosin by subjecting tylosin to hydrolysis, reductive amination, sulfoacid esterification, iodination and amination for 5 steps, which has many reaction steps and is not suitable for industrial scale-up production.
Patent document CN105254693A reports another method for preparing tildipirosin, which comprises subjecting tylosin to reductive amination and hydrolysis to remove one sugar, performing silanization protection on the hydroxyl group on the allose group and two hydroxyl groups in the mycaminose group, performing iodination reaction with trimethylsilyl iodide, and finally performing amination reaction to obtain tildipirosin.
Patent document CN106749457A reports another method for preparing tildipirosin, which comprises hydrolyzing tylosin in an acidic solution, adding a sulfoesterification reagent to the hydrolysis product to perform a sulfoesterification reaction, adding piperidine and formic acid to the prepared sulfoesterification product to perform a reductive amination reaction, adding piperidine and alkali to the obtained reductive amination product to perform an amination reaction, and adjusting alkali after the reaction is completed to obtain the final product tildipirosin. The aldehyde group of the reaction site is easily damaged in the hydrolysis process of the method, thereby influencing the subsequent reaction.
Patent document CN113121625 reports a process for preparing tylonolide, comprising: carrying out primary hydrolysis reaction on tylosin or a salt thereof in an acidic 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 produce compound 2; carrying out secondary hydrolysis reaction on the compound 2 in an acid solution to generate a compound 3; leading the compound 3 and a sulfoesterification reagent to have sulfoesterification reaction, and further leading the compound and piperidine to have amination reaction to generate the tildipirosin. The method has the advantages of mild reaction conditions, few side reactions, high yield, low cost and simple operation, and is suitable for industrial large-scale production.
The above documents show various processes for preparing tylonolide, mainly comprising primary hydrolysis, secondary hydrolysis, reductive amination, iodination, amination, or sulfonatolation and amination, or oxidation and reductive amination. In any scheme, the synthesis route is long, the process is complicated, and key intermediates are prepared as follows:
the key intermediate is obtained by primary hydrolysis, reductive amination and secondary hydrolysis. Long process route, low yield and high cost.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the preparation method of the tildipirosin key intermediate 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 tylosin key intermediate, which comprises the steps of adding 4-dimethylaminopyridine as a catalyst into tylosin or a salt thereof in the presence of a formic acid aqueous solution, adding piperidine, and directly reacting to generate a compound shown in the following formula by adopting a one-pot process:
as a further improvement, the salt in the tylosin or the salt thereof 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 the tylosin tartrate or tylosin phosphate raw material is as follows: 5: 1-50: 1.
as a further improvement, the tylosin tartrate or tylosin phosphate according to the present invention: piperidine: the molar ratio of the 4-dimethylamino pyridine is 1: 1.1-1.5:1.1-2.0.
As a further improvement, the reaction temperature of the invention is reflux temperature, and the reaction time is 2-4 hours.
As a further improvement, the molar yield of the key intermediate of the tildipirosin prepared by the one-pot process exceeds 98%, and the content exceeds 99%.
The invention has the beneficial technical effects
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 tildipirosin is directly obtained, the process route is greatly shortened, and the operation is not complicated.
(2) In the reaction research, the original three-step reaction needs three completely different reaction conditions, and the post-treatment is troublesome. The inventor surprisingly finds that by introducing 4-dimethylaminopyridine as a catalyst, three reactions can be sufficiently activated effectively, so that the three reactions can be efficiently completed by a one-pot method.
(3) In the method, no extra solvent is used as a reaction medium, the excessive formic acid can be recycled, and the process is green and environment-friendly.
(4) The method has the advantages of mild reaction conditions, simple post-treatment, more than 98 percent of molar yield of the tildipirosin key intermediate and more than 99 percent of content in the one-pot process. The method has the advantages of high total yield, less side reaction, low cost, simple and easy operation, and is suitable for industrial production.
Detailed Description
Example 1
Under the existence of aqueous solution of formic acid, tylosin is added with 4-dimethylamino pyridine as a catalyst, piperidine is added, and a one-pot process is adopted to directly react to generate a compound A shown in the following formula.
400g of a 10% formic acid aqueous solution and 80g (0.079mol) of tylosin phosphate were put into a 1000ml reaction vessel. While stirring, 0.1185mol of piperidine was added thereto, and 0.158mol of 4-dimethylaminopyridine 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 the white-like product A. The reaction molar yield is 98.0%, and the product content is 99.3%.
Example 2
Under the existence of aqueous solution of formic acid, tylosin is added with 4-dimethylamino pyridine as a catalyst, piperidine is added, and a one-pot process is adopted to directly react to generate a compound A.
4000g of a 1% formic acid aqueous solution and 80g (0.087mol) of tylosin were put into a 5000ml reaction vessel. While stirring, 0.096mol of piperidine and 0.096mol of 4-dimethylaminopyridine were added. 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 be 7-9, fully stirring, and filtering to obtain a white-like product A. The reaction molar yield is 98.5%, and the product content is 99.4%.
Example 3
Under the existence of formic acid aqueous solution, adding 4-dimethylamino pyridine as a catalyst and piperidine, and directly reacting to generate a compound A by adopting a one-pot process.
1600g of a 5% formic acid aqueous solution and 80g (0.076mol) of tylosin tartrate were put into a 2000ml reaction vessel. While stirring, 0.099mol of piperidine was added thereto, 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 the white-like product A. The reaction molar yield is 99.1%, and the product content is 99.6%.
Comparative example 1
(1) Primary hydrolysis
80g (0.079mol) of tylosin phosphate was dissolved in 3000mL of water, and 40mL of 20% by mass sulfuric acid was added to obtain a reaction solution having a pH of 2. Heating the reaction solution to 35 ℃ and keeping the temperature for 1h, cooling to room temperature after the reaction is completely monitored by liquid chromatography, adding 300mL of butyl acetate into the reaction solution, adding 24mL of NaOH solution with the mass fraction of 30% while stirring to adjust the pH value to be about 10, separating liquid after stirring, and taking an upper organic phase to obtain a primary hydrolysate. The organic phase was directly sent to the next reaction.
(2) Reductive amination
Adding 7.5g (0.088mol) of piperidine and 5g (0.108mol) of formic acid into the organic phase obtained in the step (1), carrying out heat preservation reaction at 70 ℃ for 3h, cooling to room temperature, adding 150mL of hydrochloric acid solution with the mass fraction of 5%, adjusting the pH value to be about 3, then carrying out liquid separation, and taking a water phase to obtain a reductive amination product. The aqueous phase was directly sent to the next reaction.
(3) Secondary hydrolysis
Adding the water phase obtained by the reaction in the previous step into a flask, adding 250mL of 40% hydrobromic acid (1.7mol) solution heated to 70 ℃ to obtain a hydrolysis reaction solution, heating to 70 ℃, reacting at 70 ℃ for 1h, then cooling to below 30 ℃, transferring the liquid into a separating funnel, washing with 500mL of dichloromethane, transferring the water phase into the flask, diluting, slowly adding 30% sodium hydroxide solution in mass fraction to adjust the pH value to 9-11, separating out solids, performing suction filtration and drying to obtain 48g of secondary hydrolysate of white-like solids, wherein the molar yield is 61.2%, and the purity is 93.5% by HPLC detection.
It can be seen that, compared with the comparative example 1, the reaction route is long, the operation is complicated, the yield is low, the product quality is poor and the industrial value is limited because the one-pot process catalyzed by 4-dimethylaminopyridine is not used.
Finally, it should also be noted that the above list is only a specific implementation example of the present invention. It is obvious that the invention is not limited to the above embodiment examples, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Claims (8)
1. A preparation method of a tylosin key intermediate is characterized in that tylosin or a salt thereof is added with 4-dimethylamino pyridine as a catalyst and piperidine in the presence of aqueous formic acid, and a one-pot process is adopted to directly react to generate a compound shown in the following formula:
2. the process for preparing tylosin key intermediate according to claim 1, wherein the salt of tylosin or a salt thereof is specifically tylosin tartrate or tylosin phosphate.
3. The method for preparing the tildipirosin key intermediate according to claim 2, wherein the mass concentration of the aqueous formic acid solution is 1% -10%.
4. The method for preparing the tylonolide key intermediate according to claim 2 or 3, wherein the mass ratio of the aqueous formic acid solution to the tylosin tartrate or tylosin phosphate raw material is as follows: 5: 1-50: 1.
5. the method for preparing a tylosin key intermediate according to claim 4, wherein the ratio of tylosin tartrate or tylosin phosphate: piperidine: the molar ratio of the 4-dimethylamino pyridine is 1: 1.1-1.5:1.1-2.0.
6. The process for preparing a tildipirosin key intermediate according to claim 1, 2, 3 or 5, wherein the reaction temperature is reflux temperature and the reaction time is 2-4 hours.
7. The method for preparing the key intermediate of tildipirosin according to claim 1, 2, 3 or 5, wherein the molar yield of the key intermediate of tildipirosin in the one-pot process is more than 98% and the content is more than 99%.
8. The method for preparing the tildipirosin key intermediate according to claim 6, wherein the molar yield of the tildipirosin key intermediate is over 98% and the content is over 99% in the one-pot process.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104497082A (en) * | 2015-01-13 | 2015-04-08 | 中国兽医药品监察所 | Synthetic method for Tildipirosin |
| 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 |
| US20180148434A1 (en) * | 2015-04-16 | 2018-05-31 | Haiqing Yuan | Novel 16-member triamilide derivatives and uses thereof |
| CN113121625A (en) * | 2019-12-31 | 2021-07-16 | 湖北龙翔药业科技股份有限公司 | Preparation method of tildipirosin |
-
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104497082A (en) * | 2015-01-13 | 2015-04-08 | 中国兽医药品监察所 | Synthetic method for Tildipirosin |
| 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 |
| US20180148434A1 (en) * | 2015-04-16 | 2018-05-31 | Haiqing Yuan | Novel 16-member triamilide derivatives and uses thereof |
| CN113121625A (en) * | 2019-12-31 | 2021-07-16 | 湖北龙翔药业科技股份有限公司 | Preparation method of tildipirosin |
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