CN105111160A - 一种利奈唑胺的制备方法 - Google Patents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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Abstract
本发明公开了一种利奈唑胺的制备方法。以二氯甲烷为溶剂，加入溴化钾溶液，冷却，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮，搅拌下加入催化剂四甲基哌啶氮氧化物，滴加次氯酸钠溶液，滴加完毕后，0～10℃反应1～3小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮。以甲醇为溶剂，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮升温到20～50℃，缓慢加入乙酰胺，液相色谱跟踪反应，反应结束后直接加入还原剂，析出沉淀，过滤，得到利奈唑胺。该方法反应条件温和，环境友好，可以用于工业化大生产。
Description
技术领域
本发明涉及化合物的合成工艺，尤其涉及一种利奈唑胺的制备方法。
背景技术
利奈唑胺为人工合成的唑烷酮类抗生素，2000年获得美国FDA批准，用于治疗革兰阳性(G+)球菌引起的感染，包括由MRSA引起的疑似或确诊院内获得性肺炎(HAP)、社区获得性肺炎(CAP)、复杂性皮肤或皮肤软组织感染(SSTI)以及耐万古霉素肠球菌(VRE)感染。利奈唑胺为细菌蛋白质合成抑制剂，作用于细菌50S核糖体亚单位，并且最接近作用部位。与其它药物不同，利奈唑胺不影响肽基转移酶活性，只是作用于翻译系统的起始阶段，抑制mRNA与核糖体连接，阻止70S起始复合物的形成，从而抑制了细菌蛋白质的合成。利奈唑胺的作用部位和方式独特，因此在具有本质性或获得性耐药特征的阳性细菌中，都不易与其它抑制蛋白合成的抗菌药发生交叉耐药，在体外也不易诱导细菌耐药性的产生。文献(陈炜,胡建良,张兴贤.利奈唑胺合成路线图解[J].中国医药工业杂志,2010,41(1):62-63；何飚,张乐.噁唑烷酮类抗菌药物的合成[J].国外医药:抗生素分册,2009,30(2):82-88.)综述了利奈唑胺的合成方法，其中较好的工艺有以下几种。：①(S)-环氧氯丙烷和苯甲醛在氨水中反应，生成的亚胺经盐酸水解得(2S)-1-氨基-3-氯-2-丙醇，双乙酰化反应后在无水叔丁醇锂作用下与N-苄氧羰基-3-氟-4-吗啉基苯胺缩合得利奈唑胺，总收率约50％(PerraultWR,PearlmanBA,GodrejDB,etal.ThesynthesisofN-aryl-5-(S)-aminomethyl-2-oxazolidinoneantibacterialsandderivativesinonestepfromarylcarbamates[J].OrgProcessResDev,2003,7(4):533-546)，该法原料易得，操作步骤较少，但需使用价昂且极易吸潮的无水叔丁醇锂。②(S)-丁酸缩水甘油酯在-78℃与正丁基锂作用，得(S)-3-(3-氟-4-吗啉苯基)-5-羟甲基-1,3-噁唑烷-2-酮，经甲磺酰化和叠氮化反应后，再经还原及乙酰化得利奈唑胺(BricknerSJ,HutchinsonDK,BarbachynMR,etal.SynthesisandantibacterialactivityofU-100592andU-100766,twooxazolidinoneantibacterialagentsforthepotentialtreatmentofmultidrug-resistantgram-positivebacterialinfections[J].JMedChem,1996,39(3):673-679.)该法步骤较多、反应条件苛刻，且需使用易爆的叠氮钠。③用3-氟-4-吗啉苯基异氰酸酯在溴化锂和三正丁基氧膦作用下与(S)-丁酸缩水甘油酯缩合构建(S)-噁唑烷酮母核，经进一步转化得利奈唑胺，(黄强,李华,牛柏林,等.(R-N-(3-氟-4-吗啉苯基)-噁唑酮-5-甲基醇制备工艺:中国,1772750[P].2006-05-17)该法步骤较多、原料价昂，总收率较低。④3-氟-4-吗啉基溴苯与5-[(S)-(1-苯乙基)氨甲基]-(S)-1,3-噁唑烷-2-酮在碘化亚铜作用下经Ullmann偶联、催化氢解和乙酰化得利奈唑胺(RamallalRM,LizR,GotorV.Regioselectiveandstereospecificsynthesisofenantiopure1,3-oxazolidin-2-onesbyintramolecularringopeningof2-(Bocaminomethyl)aziridines.preparationoftheantibioticlinezolid[J].OrgLett,2008,10(10):1935-1938)该法原料不易得、反应条件苛刻。
发明内容
本发明的目的是克服现有技术的不足，提供一种利奈唑胺的制备方法。
本发明的技术方案如下：
一种利奈唑胺的制备方法包括如下步骤：
以二氯甲烷为溶剂，加入质量百分比浓度为20％的溴化钾溶液，冷却到-5～5℃，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮，溴化钾与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为1～10：100；搅拌下加入催化剂四甲基哌啶氮氧化物，四甲基哌啶氮氧化物与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为0.01～0.1:100；滴加质量百分比浓度为6.5％的次氯酸钠溶液，6.5％的次氯酸钠与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为10～20:1；滴加完毕后，0～10℃反应1～3小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮，
以甲醇为溶剂，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮，升温到20～50℃，缓慢加入乙酰胺，乙酰胺与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮的摩尔比为1～1.5:1，液相色谱跟踪反应，反应结束后直接加入还原剂，还原剂与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮的摩尔比为1～1.5:1，析出沉淀，过滤，得到利奈唑胺。
所述的还原剂为硼氢化钠或硼氢化钾。
该方法反应条件温和，环境友好，可以用于工业化大生产。
具体实施方式
本发明反应方程式如下：
以二氯甲烷为溶剂，加入质量百分比浓度为20％的溴化钾溶液，冷却到-5～5℃，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮，溴化钾与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为1～10：100；搅拌下加入催化剂四甲基哌啶氮氧化物，四甲基哌啶氮氧化物与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为0.01～0.1:100；滴加质量百分比浓度为6.5％的次氯酸钠溶液，6.5％的次氯酸钠与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为10～20:1；滴加完毕后，0～10℃反应1～3小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮。以甲醇为溶剂，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮。升温到20～50℃，缓慢加入乙酰胺，乙酰胺与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮的摩尔比为1～1.5:1，液相色谱跟踪反应，反应结束后直接加入还原剂，还原剂与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮的摩尔比为1～1.5:1，析出沉淀，过滤，得到利奈唑胺。所述的还原剂为硼氢化钠或硼氢化钾。
实施例1
在1000ml的反应瓶中加入200ml的二氯甲烷、(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮40克，20％的溴化钾水溶液2克，冷却到-5℃，搅拌下加入催化剂四甲基哌啶氮氧化物0.4g，滴加质量百分比浓度为6.5％的次氯酸钠溶液400克，滴加完毕后，0℃反应1小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮粗品36.5克，收率91.8％。将(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮粗品36.5克溶于500ml甲醇，升温到20℃，缓慢加入乙酰胺7.3克，液相色谱跟踪反应，反应结束后直接加入硼氢化钠4.7克，析出沉淀，过滤，得到利奈唑胺33.9克，收率81.0％。mp:(l8l.5～182.5℃)。IR(film)cm-1:3338,2968,2862,1743,1664,1518,1425,1228,1117,937。1H-NMR(CDCl3,500MHz)δ：7.474(dd,1H,Ar-H),7.061(dd,1H,Ar-H),6.999(t,1H,Ar-H),6.133(bs,t,1H,-NH-),4.769(m,1H,H-5),4.018(t,1H,H-4),3.881(t,4H,-CH2-O-CH2-),3.747(dd,1H,H-4),3.650(m,2H,-CH2-OH),3.092(t,4H,-CH2-N-CH2-),2.019(s,3H,-COCH3)。13C-NMR(CDCl3,75.500MHz)δ：171.102,157.257,154.396(d),136.768,133.156,119.080,114.124,107.917(d),72.130,67.228,51.331(d),47.968,42.316,23.500。
实施例2
在1000ml的反应瓶中加入200ml的二氯甲烷、(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮20克，20％的溴化钾水溶液10克，冷却到5℃，搅拌下加入催化剂四甲基哌啶氮氧化物2g，滴加质量百分比浓度为6.5％的次氯酸钠溶液400克，滴加完毕后，10℃反应3小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮粗品15.6克，收率78.5％。将(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮粗品15.6克溶于500ml甲醇，升温到50℃，缓慢加入乙酰胺4.7克，液相色谱跟踪反应，反应结束后直接加入硼氢化钾4.3克，析出沉淀，过滤，得到利奈唑胺16.4克，收率91.6％。
实施例3
在1000ml的反应瓶中加入200ml的二氯甲烷、(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮30克，20％的溴化钾水溶液10克，冷却到2℃，搅拌下加入催化剂四甲基哌啶氮氧化物2g，滴加质量百分比浓度为6.5％的次氯酸钠溶液400克，滴加完毕后，5℃反应2小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮粗品25.7克，收率86.2％。将(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮粗品25.7克溶于500ml甲醇，升温到30℃，缓慢加入乙酰胺7.0克，液相色谱跟踪反应，反应结束后直接加入硼氢化钾6.5克，析出沉淀，过滤，得到利奈唑胺27.0克，收率92.0％。
Claims (2)
1.一种利奈唑胺的制备方法，其特征在于包括如下步骤：
以二氯甲烷为溶剂，加入质量百分比浓度为20％的溴化钾溶液，冷却到-5～5℃，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮，溴化钾与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为1～10：100；搅拌下加入催化剂四甲基哌啶氮氧化物，四甲基哌啶氮氧化物与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为0.01～0.1:100；滴加质量百分比浓度为6.5％的次氯酸钠溶液，6.5％的次氯酸钠与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-羟甲基-2-恶唑烷酮的质量比为10～20:1；滴加完毕后，0～10℃反应1～3小时，加入二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩完溶剂后得到(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮，
以甲醇为溶剂，加入(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮，升温到20～50℃，缓慢加入乙酰胺，乙酰胺与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮的摩尔比为1～1.5:1，液相色谱跟踪反应，反应结束后直接加入还原剂，还原剂与(5R)-3-[3-氟-4-(4-啉基)苯基]-5-甲醛-2-恶唑烷酮的摩尔比为1～1.5:1，析出沉淀，过滤，得到利奈唑胺。
2.根据权利要求1所述的一种一种利奈唑胺的制备方法，其特征在于所述的还原剂为硼氢化钠或硼氢化钾。
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| CN113979961A (zh) * | 2021-11-08 | 2022-01-28 | 湖南增达生物科技有限公司 | 一种利奈唑胺杂质及其制备方法 |
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