抗生素药物—吡利霉素的合成研究
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摘要
吡利霉素(pirlimycin, cas:78822-40-9),系法玛西亚-普强公司(Pharmacia& Upjohn Company,现在为辉瑞(Pfizer))创制的林可霉素类抗菌药物。主要用于治疗革兰氏阳性菌所致的牛乳腺炎。
本论文主要研究了一种新的可制得高纯度吡利霉素的合成方法。合成路线包括：(a)将4-乙基吡啶经氧化和氰基化反应得到4-乙基-2-氰基吡啶；(b)通过酯化、氢化以及水解反应,由4-乙基-2-氰基吡啶制备得到4-乙基-哌啶-2-甲酸；(c)4-乙基-哌啶-2-甲酸和氯甲酸酯反应得到N-(取代)苄氧羰基-4-乙基-哌啶-2-甲酸；(d)肼解并氯代林可霉素得到7-C1-MTL;(e)将N-(取代)苄氧羰基-4-乙基-哌啶-2-甲酸和7-C1-MTL两者缩合反应制得吡利霉素中间体N-(取代)苄氧羰酰基吡利霉素；(f)钯炭催化下,氢化还原中间体得到目标产物——吡利霉素。
本论文的工艺中,以cis-4-乙基-哌啶-2-甲酸作为起始原料计算,可以以总收率为37.3%制得成品纯度在98%左右的成品；可以总收率为26.1%制得成品纯度在99%以上的成品。同时原料成本也更低,更适合产业化的生产。
Pirlimycin (CAS No.:78822-40-9) is a lincosamide antibiotic developed by Pharmacia & Upjohn Company (now Pfizer) for the treatment of Gram-positive bacteria-induced bovine mastitis.
In this thesis, a novel efficient synthetic method was reported for the preparation of pirlimycin with high purity. The synthetic procedure included the following steps:(a) the preparation of 4-ethyl-2-cyanopyridine from 4-ethyl pyridine via oxidation and cyanation; (b) the synthesis of 4-ethylpiperidine-2-carboxylic acid from 4-ethyl-2-cyanopyridine through esterification, hydrogenation, and hydrolysis reactions; (c) the protection of 4-ethylpiperidine-2-carboxylic acid with chloroformate to produce the N-substituted piperidine-2-carboxylic acid derivative; (d) the formation of 7-chloro-l-methylthio-lincosamine (7-C1-MTL) via the hydrazinolysis of lincomycin and subsequent chlorination; (e) the condensation of N-substituted piperidine-2-carboxylic acid derivatives with 7-Cl-MTL to furnish the pirlimycin intermediate; (f) the Pd/C-catalyzed hydrogenation of the pirlimycin intermediate to obtain the target product---pirlimycin.
Based on cis-4-ethyl-piperidine-2-formic acid as starting material, a total yield of 37.3% was obtained with about 98% purity pirlimycin. The total yield was 26.1% when the product purity was 99%. The process has a lower cost of raw materials, more suitable for commercial production.
本论文主要研究了一种新的可制得高纯度吡利霉素的合成方法。合成路线包括：(a)将4-乙基吡啶经氧化和氰基化反应得到4-乙基-2-氰基吡啶；(b)通过酯化、氢化以及水解反应,由4-乙基-2-氰基吡啶制备得到4-乙基-哌啶-2-甲酸；(c)4-乙基-哌啶-2-甲酸和氯甲酸酯反应得到N-(取代)苄氧羰基-4-乙基-哌啶-2-甲酸；(d)肼解并氯代林可霉素得到7-C1-MTL;(e)将N-(取代)苄氧羰基-4-乙基-哌啶-2-甲酸和7-C1-MTL两者缩合反应制得吡利霉素中间体N-(取代)苄氧羰酰基吡利霉素；(f)钯炭催化下,氢化还原中间体得到目标产物——吡利霉素。
本论文的工艺中,以cis-4-乙基-哌啶-2-甲酸作为起始原料计算,可以以总收率为37.3%制得成品纯度在98%左右的成品；可以总收率为26.1%制得成品纯度在99%以上的成品。同时原料成本也更低,更适合产业化的生产。
Pirlimycin (CAS No.:78822-40-9) is a lincosamide antibiotic developed by Pharmacia & Upjohn Company (now Pfizer) for the treatment of Gram-positive bacteria-induced bovine mastitis.
In this thesis, a novel efficient synthetic method was reported for the preparation of pirlimycin with high purity. The synthetic procedure included the following steps:(a) the preparation of 4-ethyl-2-cyanopyridine from 4-ethyl pyridine via oxidation and cyanation; (b) the synthesis of 4-ethylpiperidine-2-carboxylic acid from 4-ethyl-2-cyanopyridine through esterification, hydrogenation, and hydrolysis reactions; (c) the protection of 4-ethylpiperidine-2-carboxylic acid with chloroformate to produce the N-substituted piperidine-2-carboxylic acid derivative; (d) the formation of 7-chloro-l-methylthio-lincosamine (7-C1-MTL) via the hydrazinolysis of lincomycin and subsequent chlorination; (e) the condensation of N-substituted piperidine-2-carboxylic acid derivatives with 7-Cl-MTL to furnish the pirlimycin intermediate; (f) the Pd/C-catalyzed hydrogenation of the pirlimycin intermediate to obtain the target product---pirlimycin.
Based on cis-4-ethyl-piperidine-2-formic acid as starting material, a total yield of 37.3% was obtained with about 98% purity pirlimycin. The total yield was 26.1% when the product purity was 99%. The process has a lower cost of raw materials, more suitable for commercial production.
引文
[1]a) Christopher Walsh著王峰,温琦,刘立明译《抗生素Antibiotics》北京：中国轻工业出版社,2009 b)孟繁浩,余瑜《药物化学(案例版)》北京：科学出版社,2009 c)陈新谦,金有豫,汤光《新编药物学》北京：人民卫生出版社,2007
[2]《中国抗生素行业分析研究报告》北京：Hzresearch Inc.,2010
[3]汤光 《现代药物学》 北京：中国医药科技出版社,1997
[4]倪语星,洪秀华 《细菌耐药性监测与抗感染治疗》北京：人民军医出版社,2002
[5]Matthews K. R, Harmon R. J, Langlois B E. Prevalence of Staphylococcus Species during the Periparturient Period in Primiparous and Multiparous Cows Dairy Sci,1992,75, 1835-1839
[6]NADA 141-036 PirsueTM Aqueous Gel-original approval U.S. Food and Drug Administration,1993
[7]Pirsue Aqueous Gel(Upjohn—Canada), The Upjohn Company Rec 6/3/96
[8](a)Robert D. Birkenmeyer, Stephen J. Kroll, Chardles Lewis, Kurt F. Stern, Gary E. Zurenko Synthesis and Antimicrobial Activity of Clindamycin Analogues:Pirlimycin, a Potent Antibacterial Agent J. Med. Chem.1984,27,216-223 (b)Robert D. Birkenmeyer,Comstock Township Lincomycin compounds US 4278789,1981
[9]Robert T. Shuman, Paul L. Ornstein, Jonathan W. Paschal, Paul D. Gesellchen, An improved synthesis of hornoproline and derivatives J. Org. Chem.1990,55,738-741
[10]Robert D. Birkenmeyer, Stephen J. Kroll, Charles Lewis, Kurt F. Stern, Gary E. Zurenko J. Med. Chem.1984,27,216-223
[11]Donald E. Caddy, James H. P. Utley Substituent effects in saturated systems. Preparation, streochemistry, and acidity of pipecolic(Piperidine-2-carboxylic) acid derivatives J. Chem.Soc. Perkin II,1973, issue 9,1258-1262
[12]Francis H. Case, Thomas J. Kasper The preparation of some substituted 2,6-bis-(2-pyridyl)-pyridines J. Am. Chem. Soc.1956,78,5842-5844
[13]Akira Sugimori, Shoji Mori, Kazuo Maeda, Masayuki Nishijima Substitution of alkyl and hydroxyalkyl group for ring hydrogen and of hydroxyalkyl group for cyano group in Gamma-Irradiation of prtidinecarbonitriles in alcohol Chemistry Letters,1984,13,769-772
[14]Alan R.Katritzky, Eric F. V. Scriven, Suman Majumder, Hongbin Tu, Anatoliy V. Vakulenko, Novruz G..Akhmedov, Ramiah Murugan Preparation of Cyanopyridines by Direct Cyanation Synthesis 2005, No.6,0993-0997
[15]a)W. Schroeder, B.Bannister, H. Hoeksema Lincomycin. Ⅲ. The structure and stereochemistry of the carbohydrate moiety J. Am. Chem. Soc.1967,89(10),2448-2453 b) Barney J. Magerlein Process for the production of 6,8-dideosy-6-(1,4-dialkyl-L-2-pyrrolidine-carboxamido)-1-thio-D-errthro-a-D-galacto-octopyranosides US3306892,1967
[16]Robert D.Birkenmeyer, Comstock Township Lincomycin derivatives and process for producing the same US3549615,1970
[17]Terence P. Keenan, David Yaeger, Dennis A. Holt Synthesis of chiral nonracemic 4-trans-substituted pipecolic acid derivatives Tetrahedron:Asymmetry 1999,10,4331-4341
[18]Guido Giffels,Herbert Diehl, Georg Martin, Lutz Frohn, Erich Hammerschmidt Process for preparing piperidines US 6548954,2002
[19]Lohkov R. E. Kinetics of the N-oxidation of some compounds of the pyridime series with perbenzoic acid in chloroform and aqueous dioxane Chemistry of Heterocyclic Compounds 1980,16 (3),264-271
[20]A. R. Katritzkky, J. N. Gardner N-Oxide and related compounds. Part ⅩⅢ. Infrared spectra of 4-substituted pyridine 1-oxides J. Chem. Soc.1958,2192-2195
[21]V. Boekelheide, W. J.Linn Rearrangement of N-oxided. A novel synthesis of pyridyl carbinols and aldehydes J. Am. Chem. Soc.1954,76(5),1286-1291
[22]Robert L. Frank, Pual V. Smith 4-ethylpyridine Organic Syntheses Coll.Vol.3,410
[23]a) Wayne E. Feely, George Evanega, Ellington M. Beavers Organic Syntheses Coll. Vol. 5,269 b)Wayne E. Feely, Ellington M. Beavers Cyanation of amine oxide salts. A new synthesis of cyanopyridines J.Am.Chem.Soc.1959,81,4004-4007
[24]a)Bhaskar D. Hosangadi,Rajesh H.Dave An efficient general method for esterification of aromatic carboxylic acids Tetrahedron Letters,1996,37 (35) 6375-6378 b)J. M. Bobbitt, Daniel A. Scola Synthesis of isoquinoline alkaloids. Ⅱ. The synthesis and reactions of 4-methyl-3-pyridinecarboxaldehyde and other 4-methyl-3-substituted pyridines J. Org. Chem.,1960,25,560-564；c)黄宪,王彦广,陈振初《新编有机合成》北京：化学工业出版社,2005
[25]Greene T. W., Wuts P. G. M著,荣国斌译《Protective Groups In Orgnanic Synthesis有机合成中的保护基》上海：华东理工大学出版社,2004
[26]a) Robert D. Birkenmeyer, Fred Kagan J. Med. Chem.1970,13(4),616-619; b)钱定权,曹如珍,刘纶祖Vilsmeier试剂近年来在有机合成中的应用 有机化学 2000,20(1),30-43 c)同[24](c)
[27]a)Barney J. Magerlein Lincomycin.14. An improved synthesis and resolution of the antimalarial agent, 1'-demethyl-4'-depropyl-4'(R)-and-(S)-pentylclindamycin hydrochloride (U-24,729A) J. Med. Chem 1972,15(12),1255-1259 b)Barney J. Magerlein, Robert D. Birkenmeyer, Ross R. Herr, Fred Kagan Lincomycin. V. Amino acid Fragment J. Am. Chem. Soc.1967,89(10),2459-2464
[2]《中国抗生素行业分析研究报告》北京：Hzresearch Inc.,2010
[3]汤光 《现代药物学》 北京：中国医药科技出版社,1997
[4]倪语星,洪秀华 《细菌耐药性监测与抗感染治疗》北京：人民军医出版社,2002
[5]Matthews K. R, Harmon R. J, Langlois B E. Prevalence of Staphylococcus Species during the Periparturient Period in Primiparous and Multiparous Cows Dairy Sci,1992,75, 1835-1839
[6]NADA 141-036 PirsueTM Aqueous Gel-original approval U.S. Food and Drug Administration,1993
[7]Pirsue Aqueous Gel(Upjohn—Canada), The Upjohn Company Rec 6/3/96
[8](a)Robert D. Birkenmeyer, Stephen J. Kroll, Chardles Lewis, Kurt F. Stern, Gary E. Zurenko Synthesis and Antimicrobial Activity of Clindamycin Analogues:Pirlimycin, a Potent Antibacterial Agent J. Med. Chem.1984,27,216-223 (b)Robert D. Birkenmeyer,Comstock Township Lincomycin compounds US 4278789,1981
[9]Robert T. Shuman, Paul L. Ornstein, Jonathan W. Paschal, Paul D. Gesellchen, An improved synthesis of hornoproline and derivatives J. Org. Chem.1990,55,738-741
[10]Robert D. Birkenmeyer, Stephen J. Kroll, Charles Lewis, Kurt F. Stern, Gary E. Zurenko J. Med. Chem.1984,27,216-223
[11]Donald E. Caddy, James H. P. Utley Substituent effects in saturated systems. Preparation, streochemistry, and acidity of pipecolic(Piperidine-2-carboxylic) acid derivatives J. Chem.Soc. Perkin II,1973, issue 9,1258-1262
[12]Francis H. Case, Thomas J. Kasper The preparation of some substituted 2,6-bis-(2-pyridyl)-pyridines J. Am. Chem. Soc.1956,78,5842-5844
[13]Akira Sugimori, Shoji Mori, Kazuo Maeda, Masayuki Nishijima Substitution of alkyl and hydroxyalkyl group for ring hydrogen and of hydroxyalkyl group for cyano group in Gamma-Irradiation of prtidinecarbonitriles in alcohol Chemistry Letters,1984,13,769-772
[14]Alan R.Katritzky, Eric F. V. Scriven, Suman Majumder, Hongbin Tu, Anatoliy V. Vakulenko, Novruz G..Akhmedov, Ramiah Murugan Preparation of Cyanopyridines by Direct Cyanation Synthesis 2005, No.6,0993-0997
[15]a)W. Schroeder, B.Bannister, H. Hoeksema Lincomycin. Ⅲ. The structure and stereochemistry of the carbohydrate moiety J. Am. Chem. Soc.1967,89(10),2448-2453 b) Barney J. Magerlein Process for the production of 6,8-dideosy-6-(1,4-dialkyl-L-2-pyrrolidine-carboxamido)-1-thio-D-errthro-a-D-galacto-octopyranosides US3306892,1967
[16]Robert D.Birkenmeyer, Comstock Township Lincomycin derivatives and process for producing the same US3549615,1970
[17]Terence P. Keenan, David Yaeger, Dennis A. Holt Synthesis of chiral nonracemic 4-trans-substituted pipecolic acid derivatives Tetrahedron:Asymmetry 1999,10,4331-4341
[18]Guido Giffels,Herbert Diehl, Georg Martin, Lutz Frohn, Erich Hammerschmidt Process for preparing piperidines US 6548954,2002
[19]Lohkov R. E. Kinetics of the N-oxidation of some compounds of the pyridime series with perbenzoic acid in chloroform and aqueous dioxane Chemistry of Heterocyclic Compounds 1980,16 (3),264-271
[20]A. R. Katritzkky, J. N. Gardner N-Oxide and related compounds. Part ⅩⅢ. Infrared spectra of 4-substituted pyridine 1-oxides J. Chem. Soc.1958,2192-2195
[21]V. Boekelheide, W. J.Linn Rearrangement of N-oxided. A novel synthesis of pyridyl carbinols and aldehydes J. Am. Chem. Soc.1954,76(5),1286-1291
[22]Robert L. Frank, Pual V. Smith 4-ethylpyridine Organic Syntheses Coll.Vol.3,410
[23]a) Wayne E. Feely, George Evanega, Ellington M. Beavers Organic Syntheses Coll. Vol. 5,269 b)Wayne E. Feely, Ellington M. Beavers Cyanation of amine oxide salts. A new synthesis of cyanopyridines J.Am.Chem.Soc.1959,81,4004-4007
[24]a)Bhaskar D. Hosangadi,Rajesh H.Dave An efficient general method for esterification of aromatic carboxylic acids Tetrahedron Letters,1996,37 (35) 6375-6378 b)J. M. Bobbitt, Daniel A. Scola Synthesis of isoquinoline alkaloids. Ⅱ. The synthesis and reactions of 4-methyl-3-pyridinecarboxaldehyde and other 4-methyl-3-substituted pyridines J. Org. Chem.,1960,25,560-564；c)黄宪,王彦广,陈振初《新编有机合成》北京：化学工业出版社,2005
[25]Greene T. W., Wuts P. G. M著,荣国斌译《Protective Groups In Orgnanic Synthesis有机合成中的保护基》上海：华东理工大学出版社,2004
[26]a) Robert D. Birkenmeyer, Fred Kagan J. Med. Chem.1970,13(4),616-619; b)钱定权,曹如珍,刘纶祖Vilsmeier试剂近年来在有机合成中的应用 有机化学 2000,20(1),30-43 c)同[24](c)
[27]a)Barney J. Magerlein Lincomycin.14. An improved synthesis and resolution of the antimalarial agent, 1'-demethyl-4'-depropyl-4'(R)-and-(S)-pentylclindamycin hydrochloride (U-24,729A) J. Med. Chem 1972,15(12),1255-1259 b)Barney J. Magerlein, Robert D. Birkenmeyer, Ross R. Herr, Fred Kagan Lincomycin. V. Amino acid Fragment J. Am. Chem. Soc.1967,89(10),2459-2464